Recent Updates on the Synthesis of Bioactive Quinoxaline-Containing Sulfonamides

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Review Recent Updates on the Synthesis of Bioactive Quinoxaline-Containing Sulfonamides

Ali Irfan 1,* , Sajjad Ahmad 2, Saddam Hussain 3, Fozia Batool 4, Haseeba Riaz 4, Rehman Zafar 5 , Katarzyna Kotwica-Mojzych 6 and Mariusz Mojzych 7,*

1 Department of Chemistry, Faculty of Physical Sciences, Government College University Faisalabad, 5-Km, Jhang Road, Faisalabad 38040, Pakistan 2 Department of Chemistry, UET Lahore, Faisalabad Campus, Faisalabad 37630, Pakistan; [email protected] 3 School of Biochemistry, Minhaj University Lahore, Lahore 54000, Pakistan; [email protected] 4 Department of Chemistry, Faculty of Sciences, The University of Lahore, Sargodha Campus, 10 Km, Lahore Road, Sargodha 40100, Pakistan; [email protected] (F.B.); [email protected] (H.R.) 5 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan; [email protected] 6 Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland; [email protected] 7 Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3-go Maja 54, 08-110 Siedlce, Poland * Correspondence: [email protected] (A.I.); [email protected] or [email protected] (M.M.)

Abstract: Quinoxaline is a privileged pharmacophore that has broad-spectrum applications in the fields of medicine, pharmacology and pharmaceutics. Similarly, the sulfonamide moiety is of con- siderable interest in medicinal chemistry, as it exhibits a wide range of pharmacological activities. Therefore, the therapeutic potential and biomedical applications of quinoxalines have been enhanced Citation: Irfan, A.; Ahmad, S.; by incorporation of the sulfonamide group into their chemical framework. The present review Hussain, S.; Batool, F.; Riaz, H.; Zafar, R.; Kotwica-Mojzych, K.; Mojzych, M. surveyed the literature on the preparation, biological activities and structure-activity relationship Recent Updates on the Synthesis of (SAR) of quinoxaline sulfonamide derivatives due to their broad range of biomedical activities, Bioactive Quinoxaline-Containing such as diuretic, antibacterial, antifungal, neuropharmacological, antileishmanial, anti-inflammatory, Sulfonamides. Appl. Sci. 2021, 11, anti-tumor and anticancer action. The current biological diagnostic findings in this literature review 5702. https://doi.org/10.3390/ suggest that quinoxaline-linked sulfonamide hybrids are capable of being established as lead com- app11125702 pounds; modifications on quinoxaline sulfonamide derivatives may give rise to advanced therapeutic agents against a wide variety of diseases. Academic Editor: Greta Varchi Keywords: anticancer; anti-inflammatory; antimicrobial; quinoxaline sulfonamides; synthesis Received: 25 May 2021 Accepted: 15 June 2021 Published: 19 June 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Heterocyclic scaffolds hold a pivotal place in medicinal chemistry and are one of the published maps and institutional affil- largest areas of research in organic chemistry due to their wide spectrum of biological iations. activities. Therefore, continuous efforts have been undertaken to explore their therapeutic potential in the field of design and development of new drugs. Quinoxaline 1 is a privileged, ubiquitous and versatile nitrogen-containing heterocyclic motif, which exhibits a broad spectrum of medicinal, pharmacological and pharmaceutical applications. Quinoxaline, also known as benzopyrazine, was formed by the combination of pyrazine 2 and benzene 3 Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. rings at the carbons 2 and 3 of the pyrazine ring (Figure1)[ 1–5]. Quinoxaline derivatives are This article is an open access article of relevant interest in medicinal chemistry because of a wide range of pharmacological and distributed under the terms and biological activities, such as antitumor, anticancer [6–12], antidiabetic [13–17], antimycobac- conditions of the Creative Commons terium tuberculosis [18,19], antimicrobial [20–22], antidepressant [23], anthelmintic [24], Attribution (CC BY) license (https:// analgesic [25–31], anti-inflammatory [11,32–36], antiviral [37–43], antifungal [44–49], anti- creativecommons.org/licenses/by/ malarial [50–55], antibacterial [56–63], antioxidant [14,64,65], antithrombotic [66,67] and 4.0/). antiprotozoal [54,68].

Appl. Sci. 2021, 11, 5702. https://doi.org/10.3390/app11125702 https://www.mdpi.com/journal/applsci Appl. Sci. 2021,, 11,, xx FORFOR PEERPEER REVIEWREVIEW 2 of 25

tidepressanttidepressant [23],[23], anthelminticanthelmintic [24],[24], analgesicanalgesic [25–31],[25–31], anti-inflammatoryanti-inflammatory [11,[11, 32–36],32–36], an-an- Appl. Sci. 2021, 11, 5702 tiviraltiviral [37–43],[37–43], antifungalantifungal [44–49],[44–49], antimalarialantimalarial [50–55],[50–55], antibacterialantibacterial [56–63],[56–63], antioxidantantioxidant2 of 24 [14,[14, 64–65],64–65], antithromboticantithrombotic [66,67][66,67] andand antiprotozoalantiprotozoal [54,[54, 68].68]. N N

N N

1 2 3

FigureFigure 1. 1. StructuresStructures of of quinoxaline, quinoxaline, pyrazinepyrazine andand benzene. benzene.

DifferentDifferent quinoxaline-based drugs have been playing playing a a main main role role in in the the therapy therapy and and treatmenttreatment ofofof various variousvarious diseases, diseases,diseases, such suchsuch as varenicline asas vareniclinevarenicline4 (aids in4 smoking(aids(aids inin cessation), smokingsmoking brimonidine cessation),cessation), brimonidine5 (anti-glaucoma 5 (anti-glaucoma(anti-glaucoma activity), quinacillin activity),activity),6 (antibacterial quinacillinquinacillin 6 activity) (antibacterial(antibacterial and XK469 activity)activity) NSC andand7 (selective XK469XK469 β NSCtopoisomerase 7 (selective(selective II topoisomerasetopoisomerasepoison) (Figure IIIIβ2 )[poison)poison)69–71 ]. (Figure(Figure 2)2) [69–71].[69–71].

S CO2H Br O H 2 H Br O N N H H N O COOH N N N N N NH N NH H O N O N N Cl N O N N CO2H 4 5 6 7 5 6 Figure 2. Structures of quinoxaline drugs 4–7.4–7.

SulfonamidesSulfonamides werewere firstfirst characterizedcharacterized in in 1932 1932 and and are are organic organic chemical chemical frameworks frameworks in 1 2 which a sulfonyl group is linked to an amine group (-SO -NR R )[1 722 ]. The sulfonamide inin whichwhich aa sulfonylsulfonyl groupgroup isis linkedlinked toto anan amineamine groupgroup 2(-SO(-SO22--NR1R2)) [72].[72]. TheThe sulfona-sulfona- midegroup group is a key is moietya key moiety that plays that aplays paramount a paramount role in role both in medicinal both medicinal chemistry chemistry and organic and organicchemistry chemistry due to their due immenseto their immense biological biologic action.al A action. series ofA therapeuticseries of therapeutictherapeutic agents contain agentsagents a containsulfonamide a sulfonamide moiety in theirmoiety chemical in their structures chemical [73 structures–79]. Particular [73–79]. examples Particular are antibioticsexamples which are used on a large scale for many clinical purposes [80]. Heterocyclic sulfonamides are antibiotics which are used on a large scale for many clinical purposes [80]. Heterocy- exhibit different biological activities, such as antibacterial [81–83], anti-inflammatory [84], clic sulfonamides exhibit different biological activities, such as antibacterial [81–83], an- antibacterial [85], antimicrobial [86], antifungal [87], antiprotozoal [88], antiviral [89], anti- ti-inflammatoryti-inflammatory [84],[84], antibacterialantibacterial [85],[85], antimicrobialantimicrobial [86],[86], antifungalantifungal [87],[87], antiprotozoalantiprotozoal malarial [90], antitumor [91–93], carbonic anhydrase inhibitors [94–99], antidiabetic [100], [88],[88], antiviralantiviral [89],[89], antimalarialantimalarial [90],[90], antitumorantitumor [91–93],[91–93], carboniccarbonic anhydraseanhydrase inhibitorsinhibitors anticonvulsant, [101], anti-glaucoma [95,97], anti-obesity [102], diuretic [103–105], hy- [94–99],[94–99], antidiabeticantidiabetic [100],[100], anticonvulsant,anticonvulsant, [1[101], anti-glaucoma [95,97], anti-obesity [102], poglycemic [95,97], anti-neuropathic pain [106], matrix metalloproteinase and bacterial diuretic [103–105], hypoglycemic [95,97], anti-neuropathic pain [106], matrix metallo- protease inhibitors [107,108]. The sulfonamide moiety is a basic component of drugs such proteinase and bacterial protease inhibitors [107,108]. The sulfonamide moiety is a basic as sulfamethazine 8 (antibacterial), chlortalidone 9 (diuretic), sulfametopyrazine 10 (chronic component of drugs such as sulfamethazine 8 (antibacterial), chlortalidone 9 (diuretic), bronchitis, urinary tract infections and malaria), chlorpropamide 11 (treats diabetes mellitus sulfametopyrazine 10 (chronic bronchitis, urinaryinary tracttract infectionsinfections andand malaria),malaria), chlor-chlor- type 2), ethoxzolamide 12 (carbonic anhydrase inhibitor) and mafenide 13 (antimicrobial propamide 11 (treats diabetes mellitus type 2), ethoxzolamide 12 (carbonic anhydrase propamideagent used to11 treat(treats severe diabetes burns) mellitus (Figure 3type)[109 2),]. ethoxzolamide 12 (carbonic anhydrase inhibitor) and mafenide 13 (antimicrobial agent used to treat severe burns) (Figure 3) inhibitor)Hybrid and structures mafenide formulated 13 (antimicrobial by the combinationagent used to of treat quinoxaline severe burns) and sulfonamide (Figure 3) [109]. [109].moieties display novelty and versatility and possess a consistent therapeutic potential against most diseases. The general structure of quinoxaline sulfonamide 14, sulfaquinxaline 15 (antimicrobial and a coccidiosis for veterinary use) and chloroquinoxaline sulfonamide 16 (topoisomerase-IIα and a topoisomerase-IIβ poison) are depicted in Figure4[110]. The significance of quinoxline sulfonamide derivatives in medicinal chemistry as therapeutic agents is clearly displayed by the patents. The patented sulfonamide derivatives, such as substituted quinoxaline-2,3-diones 17 (glutamate receptor antagonists) [111], quinoxaline-containing pyridine-3-sulfonamide derivative 18 (used as PI3K inhibitors) [112], amidophenyl-sulfonylamino-quinoxaline compounds 19 (CCK2 modulators useful in the treatment of CCK2 mediated diseases) [113], quinoxaline compounds 20 (for the treat- Appl. Sci. 2021, 11, 5702 3 of 24

ment of autoimmune disorders and/or inﬂammatory diseases and cardiovascular diseases, etc.) [114], dichlorophenyl moiety-containing quinoxaline sulfonamide 21 (useful for the treatment of disease states mediated by CCK2 receptor activity) [115] and benzimidazole moiety-based quinoxaline benzene sulfonamide scaffold 22 (phosphatidylinositol 3-kinase inhibitors) [116], 2-chloro-5-methoxyphenylamino based quinoxaline sulfonamide derivative 23 (phosphatidylinositol 3-kinase inhibitors) [117], substituted quinoxaline compound 24 (HCV NS3 protease inhibitors) [118], macrocyclic quinoxaline Appl. Sci. 2021, 11, x FOR PEER REVIEW 3 of 25 compound 25 (HCV NS3 protease inhibitors) [119], benzene sulfonamide derivatives of quinoxaline 26 (anticancer agents) [120], tetrahydro quinoxaline derivative 27 (inhibitors of sodium channels/pain disorders) [121], benzene sulfonamide derivatives of quinoxaline 28 (kinase inhibitors,Cl anticancer agents) [122], quinoxaline sulfonamides 29 (PI3K inhibitors, anti-inﬂammatory and autoimmune diseases) [123], substitutedO N aminoquinoxa- O N OH O O line sulfonamidesH30Nand substituted chloroquinoxaline sulfonamidesS31 [124], substitutedN 2 S S 1,2,4-thiadiazole based quinoxaline sulfonamide derivative 32 (inhibitorsN of sodium chan- N O O H Appl. Sci. 2021, 11, x FOR PEER REVIEWH nels) [125] and substituted diphenylHN quinoxaline sulfonamide derivative 33 (inhibitorsO 3 of of25 H2N H2N NAMPT) [126] are depicted in Figure5.O

89 10 Cl O N O N OH O O H2N S N S S N N O O O O HN H O O H O O O O S S H2N S H2N O N N S NH2 NH2 H H N O H2N Cl 89 10

11 12 13 O O Figure 3. Structures of sulfonamide drugs 8–13. O O O O O S S S N N Hybrid structures formulated by theS combinationNH2 of quinoxaline andNH sulfonamide2 H H moieties display novelty and versatilityN O and possess aH consistent2N therapeutic potential Cl against most diseases. The general structure of quinoxaline sulfonamide 14, sulfaquinxaline 15 (antimicrobial and a coccidiosis for veterinary use) and chloroquinoxaline sul- 11 fonamide 16 (topoisomerase-IIα and12 a topoisomerase-IIβ poison) are 13 depicted in Figure 4 [110]. Figure 3. StructuresStructures of sulfonamide drugs 8–138–13..

Hybrid structures formulated byNH the combination of quinoxaline and sulfonamide 2 NH moieties display novelty and versatility and possess a consistent therapeutic potential2 O O against most diseases. The general structure of quinoxalineCl sulfonamide 14, sulfaquinxa- N S N line 15 (antimicrobial and a coccidiosis for veterinary use)N and chloroquinoxaline sul- H N fonamide 16 (topoisomerase-IIO α and a topoisomerase-IIβ poison) are depicted in Figure 4 2 S O [110]. N N O S N H N N O H 14 15 NH2 16 NH2 O O Figure 4. Structures of quinoxaline sulfonamide drugs 1414–16.Cl–16. N S N O N H2N The significance of quinoxline sulfonamide derivatives in medicinalO chemistry as therapeutic agents is clearly displayedS by the patents. The patented sulfonamide deriva- N N O S N tives, such as substitutedH quinoxaline-2,3-diones 17 (glutamateN N receptorO antagonists) [111], quinoxaline-containing pyridine-3-sulfonamide derivative 18H (used as PI3K inhib- 14 15 16 itors) [112], amidophenyl-sulfonylamino-quinoxaline compounds 19 (CCK2 modulators usefulFigure in 4. the Structures treatment of quinoxaline of CCK2 mediated sulfonamide diseases) drugs 14–16.[113], quinoxaline compounds 20 (for the treatment of autoimmune disorders and/or inflammatory diseases and cardiovascular diseases,The significance etc.) [114], of dichlorophenylquinoxline sulfonamide moiety-containing derivatives quinoxaline in medicinal sulfonamide chemistry as21 therapeutic(useful for the agents treatment is clearly of diseasedisplayed states by methediated patents. by The CCK2 patented receptor sulfonamide activity) [115] deriva- and tives,benzimidazole such as substitutemoiety-basedd quinoxaline-2,3-diones quinoxaline benzene 17sulfonamide (glutamate scaffold receptor 22 antagonists) (phosphati- [111],dylinositol quinoxaline-containing 3-kinase inhibitors) pyridine-3-sulfonamide [116], 2-chloro-5-methoxyphenylamino derivative 18 (used based as quinoxalinePI3K inhibitors)sulfonamide [112], amidophenyl-sulf derivative 23 (phosphatidylinositolonylamino-quinoxaline 3-kinase compounds inhibitors) 19 (CCK2 [117], modulatorssubstituted usefulquinoxaline in the compoundtreatment of 24 CCK2 (HCV mediated NS3 protease diseases) inhibitors) [113], quinoxaline [118], macrocyclic compounds quinoxaline 20 (for thecompound treatment 25 of(HCV autoimmune NS3 protease disorders inhibitors) and/or [119], inflammatory benzene sulfonamidediseases and derivatives cardiovascu- of larquinoxaline diseases, 26etc.) (anticancer [114], dichlorophenyl agents) [120], moiety-containingtetrahydro quinoxaline quinoxaline derivative sulfonamide 27 (inhibitors 21 (usefulof sodium for thechannels/pain treatment of disorders) disease states [121], me benzenediated bysulfonamide CCK2 receptor derivatives activity) of [115]quinoxa- and benzimidazole moiety-based quinoxaline benzene sulfonamide scaffold 22 (phosphatidylinositol 3-kinase inhibitors) [116], 2-chloro-5-methoxyphenylamino based quinoxaline sulfonamide derivative 23 (phosphatidylinositol 3-kinase inhibitors) [117], substituted quinoxaline compound 24 (HCV NS3 protease inhibitors) [118], macrocyclic quinoxaline compound 25 (HCV NS3 protease inhibitors) [119], benzene sulfonamide derivatives of quinoxaline 26 (anticancer agents) [120], tetrahydro quinoxaline derivative 27 (inhibitors of sodium channels/pain disorders) [121], benzene sulfonamide derivatives of quinoxa- Appl. Sci. 2021, 11, x FOR PEER REVIEW 4 of 25

line 28 (kinase inhibitors, anticancer agents) [122], quinoxaline sulfonamides 29 (PI3K inhibitors, anti-inflammatory and autoimmune diseases) [123], substituted amino- quinoxaline sulfonamides 30 and substituted chloroquinoxaline sulfonamides 31 [124], Appl. Sci. 2021, 11, 5702 substituted 1,2,4-thiadiazole based quinoxaline sulfonamide derivative 32 (inhibitors4 of of 24 sodium channels) [125] and substituted diphenyl quinoxaline sulfonamide derivative 33 (inhibitors of NAMPT) [126] are depicted in Figure 5.

Ra O O O O O N R HN NH O Rb O S HN S N NH O S NH O O O N N N O R2 N N N R O 1 O2N

17 18 19 O O O NH R1 R2 N HN O H Cl NH HN S N NH Cl Cl HN Br O O S O N N N NH N O S O 22 R3 N 21 20

N O S O H NH2 O O HN N H O O H O

NH R1 N N S R2 N

N S O H O N O O O N R1 N N R3 X N O N 24 O 23 25

F N F Cl F MeO F N O O N NH N N F3C OMe S S O N O O N N O F H S N O O F O S O O S 26 N N 27 28

O R1 R1 O S O O S O N NH O N NH N NH

N NH N N NH N Cl O S R2 O O 30 29 31 F C 3 Cl O H N 2 S N O N N H N N N N N H O N N S O S O 33 32 Figure 5. Structures of patented quinoxaline sulfonamides 1717–33.–33.

2. Synthesis and Biological Activities Standard reference works have shown that the orthro-phenylenediamine (OPD) can be condensed with dicarboxylic acids, diketones, α-halo-ketones and esters to give quinoxalines. The development of quinoxaline sulfonamide chemistry is linked with the presence of amino (-NH2) and sulfonyl chloride (-SO2Cl) groups in the reacting species. Commonly, quinoxaline sulfonamides can be available via general transformation of substituted amines, Appl. Sci. 2021, 11, x FOR PEER REVIEW 5 of 25

2. Synthesis and Biological Activities Standard reference works have shown that the orthro-phenylenediamine (OPD) can be condensed with dicarboxylic acids, diketones, α-halo-ketones and esters to give Appl. Sci. 2021, 11, 5702 5 of 24 quinoxalines. The development of quinoxaline sulfonamide chemistry is linked with the presence of amino (-NH2) and sulfonyl chloride (-SO2Cl) groups in the reacting species. Commonly, quinoxaline sulfonamides can be available via general transformation of substitutedwith the quinoxaline amines, with containing the quinoxaline sulfonyl chloride containing functionality sulfonyl chloride and vice versa,functionality as depicted and vicein Figure versa,6. as depicted in Figure 6.

O O O O S N R S N Cl RNH N 2 H N N

H H2N N O R N N RSCl S O O N O N Figure 6. General preparation of quinoxaline sulfonamides.

2.1.2.1. Benzothiazole Benzothiazole Quinoxaline Quinoxaline Sulfonamide Sulfonamide Derivatives Derivatives with Diuretic Activity MedicationsMedications designed designed to to increase increase the excret excretionion of water and salt in urine are termed asas diuretics. DiureticsDiuretics are are used used as as therapeutics therapeutics in liverin liver cirrhosis, cirrhosis, epilepsy, epilepsy, edema, edema, hyperten- hy- pertensions,sions, heart failure,heart failure, hypercalciuria, hypercalciuria, diabetes diabetes insipidus insipidus and in and some in kidneysome kidney diseases. diseases. Their Theirmechanism mechanism of action of action on distinct on distinct sites of sites nephrons of nephrons involves involves the production the production of diuresis of diu- and resisinhibition and inhibition of sodium of ions sodium re-absorption ions re-absorption in the renal in tubulesthe renal of tubules the kidney. of the kidney. AA new new multistep synthetic methodology methodology was was developed for for the synthesis of a novel promising classclass ofof substituted substituted quinoxaline quinoxaline sulfonamides sulfonamides as diureticas diuretic agents, agents, assessed assessedin vivo in vivoby Husain by Husain and coworkersand coworkers [127]. [ The127]. condensation The condensation of o-phenylene of o-phenylene diamine diamine34 with 34 pyruvic with pyruvicacid 35 in acid methanol 35 in methanol produced produced 3-methylquinoxaline-2 3-methylquinoxaline-2H-one 36Hwith-onean 36 80%with yield an 80% that yield was thatfurther was reacted further with reacted substituted with substituted aldehydes aldehydes37 in the presence37 in the ofpresence piperidine of piperidine to afford the to affordsubstituted the quinoxalinesubstituted derivatives quinoxaline38. Thederivatives condensation 38. of 2-amino-benzothiazole-6-The condensation of 2-amino-benzothiazole-6-sulfonamidesulfonamide (41) with 38 in ethanol yielded (41) with the ﬁnal 38 in quinoxaline ethanol yielded sulfonamide the final derivatives quinoxa- line42 in sulfonamide moderate to derivatives good yield 42 (60–82%) in moderate (Scheme to good1)[ yield127]. (60–82%) The derivatives (Scheme with 1) [127]. electron- The derivativesdonating groups with electron-donating showed the maximum groups yield, showed while the the maximum electron-withdrawing yield, while the groups electron-withdrawingresulted in a minimum groups yield. resulted in a minimum yield. The Lipschitz method was adopted to determine the diuretic activity of the thiazole moiety-based quinoxaline sulfonamide hybrids. Fifty-four healthy adult Wistar albino rats (180–200 g) were selected and divided into nine groups, and these were acclimatized in standard environmental conditions for one week. The thiazole moiety-containing quinoxaline sulfonamide derivative 43 showed a remarkably high diuretic activity and Lipschitz value (1.13 and 1.28 values, respectively) compared to the standard reference drugs, acetazolamide and urea. The derivative 44 exhibited a moderate diuretic activity (value of 0.78) and Lipstchitz value (0.88). The structural motif 45 exhibited the least diuretic action among the three compounds (value of 0.56) and a Lipschitz value of 0.63 (Table1). These results showed that diuretic activity is directly proportional to the Lipschitz value. The SAR showed that the presence of a strong electron-donating group (EDG), such as methoxy, on the benzene ring of scaffold 43 increases the diuretic activity, while the presence of strong electron-withdrawing group (EWG), such as an -NO2 group, decreases the diuretic activity of the analog 45. The presence of an -N(CH3)2 moiety on the benzene ring of derivative 44 induced a moderate diuretic effect (Figure7). The SAR study revealed that the diuretic activity decreased in order of –OCH3 > -N(CH3)2 > -NO2. This indicated that EDG increases the diuretic activity, while EWG decreases the diuretic activity [127]. Appl. Sci. 2021, 11, x FOR PEER REVIEW 6 of 25

H H H N O NH2 O N O Ethanol R1 + + O Piperidine R N 1 NH2 CH O OH N 3 R R 34 35 36 37 38 80% Appl. Sci. 2021, 11, 5702 6 of 24 Appl. Sci. 2021, 11, x FOR PEER REVIEW 6 of 25 NH2 N Ethanol Br 2 NH2 H2N + KSCN H N S 2 S S O O O O H 39 40 H H 41 N O NH2 O N O R1 R Ethanol 80%R1 + + O Piperidine R N 1 NH2 CH O OH N 3 R R 34 35 36 37 N 38 80% N H N 2 S S NH2 N Ethanol Br O O HN N 2 NH2 H2N + KSCN H N S 2 S S 42 OR =O H, Cl, OCH3, NO2, N(CH3)2 R1 = H, OCH3 O O 39 40 41 60-82% R1 R 80% Scheme 1. Synthesis of sulfonamide derivatives 42.

The Lipschitz method was adopted to determine the diuretic activity of the thiazole N moiety-based quinoxaline sulfonamide hybrids. Fifty-four healthy adultN Wistar albino H N rats (180–200 g) were selected and divided into nine groups,2 S and theseS were acclimatized in standard environmental conditions for one week. O O HN N The thiazole moiety-containing quinoxaline sulfonamide derivative 43 showed a remarkably high diuretic activity and Lipschitz value (1.13 and42 1.28 values, respectively) R = H, Cl, OCH3, NO2, N(CH3)2 R1 = H, OCH3 compared to the standard reference drugs, acetazolamide and urea. The derivative 44 60-82% exhibited a moderate diuretic activity (value of 0.78) and Lipstchitz value (0.88). The Scheme 1. Synthesis of sulfonamide derivatives 42. structuralScheme motif 1. 45Synthesis exhibited of sulfonamide the least diuretic derivatives action42. among the three compounds (value of 0.56) and a Lipschitz value of 0.63 (Table 1). These results showed that diuretic activity TableThe 1. Diuretic Lipschitz activity method of benzothiazole was adopted quinoxaline to determin sulfonamidee the diuretic derivatives activity43– 45of. the thiazole is directly proportional to the Lipschitz value. The SAR showed that the presence of a moiety-based quinoxaline sulfonamide hybrids. Fifty-four healthy adult Wistar albino strong electron-donating groupUrinary (EDG), Excretion such as methoxy, on the benzene ring of scaffold rats Compound(180–200 g) were selected and divided into nineDiuretic groups,Activity and these were Lipschitz acclimatized Value 43 increases the diuretic activity,Percentage while the presence of strong electron-withdrawing in standard environmental conditions for one week. group (EWG), such as an -NO2 group, decreases the diuretic activity of the analog 45. The The43 thiazole moiety-containing 176.66 quinoxaline sulfonamide 1.13 derivative 43 1.28 showed a presence44 of an -N(CH3)2 moiety 121.42on the benzene ring of derivative 0.78 44 induced a 0.88 moderate remarkably high diuretic activity and Lipschitz value (1.13 and 1.28 values, respectively) diuretic effect45 (Figure 7). The SAR 87.5 study revealed that the 0.56 diuretic activity decreased 0.63 in comparedAcetazolamide to the standard reference 155.17 drugs, acetazolamide 1.0 and urea. The derivative 1.13 44 order of –OCH3 > -N(CH3)2 > -NO2. This indicated that EDG increases the diuretic activity, exhibitedUrea a moderate diuretic activity 136.6 (value of 0.78) and 0.88 Lipstchitz value 1.0(0.88). The while EWG decreases the diuretic activity [127]. structural motif 45 exhibited the least diuretic action among the three compounds (value of 0.56) and a Lipschitz value of 0.63 (Table 1). These results showed that diuretic activity is directlyO proportional to the Lipschitz vaNlue. The SAR showed that the presenceNO2 of a strong electron-donating group (EDG), such as methoxy, on the benzene ring of scaffold 43 increases the diuretic activity, while the presence of strong electron-withdrawing N group (EWG), such as an -NON2 group, decreases the diuretic activityN of the analog 45. The N presence of an -N(CH3)2 moiety onN the benzene ring of derivative 44N induced a moderate H N H N H2N S 2 S S diuretic effect (Figure2 S 7). TheS SAR study revealed thatS the diuretic activity decreased in O O HN N O O HNorder N of –OCH3 > O-N(CHO 3)2 > -NOHN2. This N indicated that EDG increases the diuretic activity, while EWG decreases the diuretic activity [127].

44 45 NO 43 O N 2 Figure 7. Substituted quinoxal quinoxalineine benzothiazole sulfonamide derivative 4343–45.–45.

N 2.2. Quinoxaline SulfonamidesN with Antibacterial Activity N N N N Alavi et al. reported a facile, efﬁcient, solventH and2N catalyst-free green protocol for the H2N H2N S S S synthesis of quinoxalineS sulfonamideS derivatives, whichS were screened for their antibac- O O HN N O O HNterial N activity againstO O different Gram-positiveHN N and Gram-negative bacterial strains. The quinoxaline sulfonyl chloride (QSC) 48 was synthesized in 85% yields by the treatment of methoxyphenyl quinoxaline 46 with chlorosulfonic acid 47. The QSC scaffold 48 was reacted with substituted aromatic44 amines in neat and ecofriendly45 conditions to afford 43 substituted quinoxaline sulfonamides of the type 49 in good to excellent yield (Scheme2). Figure 7. Substituted quinoxaline benzothiazole sulfonamide derivative 43–45. Appl. Sci. 2021, 11, x FOR PEER REVIEW 7 of 25

Table 1. Diuretic activity of benzothiazole quinoxaline sulfonamide derivatives 43–45.

Urinary Excretion Compound Diuretic Activity Lipschitz Value Percentage 43 176.66 1.13 1.28 44 121.42 0.78 0.88 45 87.5 0.56 0.63 Acetazolamide 155.17 1.0 1.13 Urea 136.6 0.88 1.0

2.2. Quinoxaline Sulfonamides with Antibacterial Activity Alavi et al. reported a facile, efficient, solvent and catalyst-free green protocol for the synthesis of quinoxaline sulfonamide derivatives, which were screened for their antibacterial activity against different Gram-positive and Gram-negative bacterial strains. Appl. Sci. 2021, 11, 5702 The quinoxaline sulfonyl chloride (QSC) 48 was synthesized in 85% yields by the 7treat- of 24 ment of methoxyphenyl quinoxaline 46 with chlorosulfonic acid 47. The QSC scaffold 48 was reacted with substituted aromatic amines in neat and ecofriendly conditions to afford substituted quinoxaline sulfonamides of the type 49 in good to excellent yield Aromatic(Scheme 2). amines Aromatic with EDG,amines such with as EDG, methyl such and as methoxy, methyl reactedand methoxy, in 3–10 minreacted and in lead 3–10 to productsmin and lead with to a higherproducts yield, with while a higher aromatic yield, amines while aromatic with EWG amines afforded with products EWG afforded with a lowproducts yield. with Aromatic a low aminesyield. Aromatic with strongly amines EWG, with such strongly as nitro, EWG, do notsuch react as nitro, in the do below not mentionedreact in the conditionsbelow mentioned [128]. conditions [128].

N ClSO3H N N NRR1 47 O O O O NaHCO3 S S R1 N N Cl N N neat R O O O 46 48 49 85% 85%

Green effeicient and solvent free approach to afford derivatives in good to excellent 74-92% yield

R = H, C2H5; R1 = Aryl

Scheme 2. Synthesis of substituted quinoxaline sulfonamide derivatives, withwith structurestructure 4949..

The substitutedsubstituted 4-methoxyphenyl4-methoxyphenyl quinoxalinequinoxaline sulfonamidesulfonamide50 50and and substituted substituted 2- methoxyphenyl2-methoxyphenyl quinoxaline quinoxaline sulfonamide sulfonamide derivative derivative51 showed 51 showed the best the antibacterialbest antibacterial activityactivity against againstS. Aureus S. Aureus,, having having a zone a of zone inhibition of inhibition (ZOI) of (ZOI) 20 mm of and20 mm 22 mm, and respectively, 22 mm, re- whichspectively, is more which than is themore standard than the chloramphenicol standard chloramphenicol drug (ZOI 19drug mm) (ZOI but 19 less mm) than but refer- less encethan ampicillinreference ampicillin drug (ZOI 28drug mm). (ZOI The 28 substituted mm). The naphthalenesubstituted naphthalene quinoxaline sulfonamidequinoxaline derivativessulfonamide52 derivativesexhibited the52 exhibited highest antibacterial the highest antibacterial activity against activityE. coli against, with a E. ZOI coli value, with ofa ZOI 18 mm value when of 18 compared mm when to compared the standard to the drug, standard ampicillin drug, (ZOI ampicillin 15 mm), (ZOI but less15 mm), than thebut referenceless than chloramphenicolthe reference chloramphenicol drug (ZOI 19 mm)drug(Table (ZOI 219). Amm) moderate (Table antibacterial2). A moderate activity anti- wasbacterial observed activity for thewas substituted observed chlorophenylfor the substituted quinoxaline chlorophenyl sulfonamides quinoxaline53 and 54 sulfona-against Gram-positivemides 53 and 54S. Aureusagainstand Gram-positive Gram-negative S. AureusE. coli. andThe Gram-negative unsubstitutedphenyl E. coli. quinoxalineThe unsub- sulfonamidestituted phenyl derivative quinoxaline55 showed sulfonamide the least derivative antibacterial 55 showed activity the against least antibacterialS. Aureus and ac- E.tivity coli ,against exhibiting S. Aureus a ZOI ofand 5 mm E. coli and, exhibiting 5> mm, respectively, a ZOI of 5 when mm comparedand 5> mm, to therespectively, reference drugs,when compared chloramphenicol to the reference and ampicillin, drugs, exhibiting chloramphenicol ZOI values and of ampicillin, 19 mm and exhibiting 28 mm against ZOI S.values Aureus of 19and mm 22 and mm 28 and mm 15 against mm against S. AureusE. coli and. The 22 mm SAR and revealed 15 mm that against the presence E. coli. The of electron-richSAR revealed groupsthat the on presence the aminophenyl of electron-r ringich showedgroups on the the highest aminophenyl antibacterial ring showed activity for derivatives 50–52, whereas the presence of the electron-withdrawing groups on the the highest antibacterial activity for derivatives 50–52, whereas the presence of the elec- aminophenyl ring, such as a chloro atom (weak EWD group), in 53 and 54 scaffolds led tron-withdrawing groups on the aminophenyl ring, such as a chloro atom (weak EWD to a moderate antibacterial activity, while the least antibacterial activity was observed for the unsubstituted derivative 55 (Figure8)[ 128]. The results showed that electron-donating group’s substitution on the quinoxaline sulfonamide scaffolds contribute positively to increase the antibacterial activity.

Table 2. Antibacterial activity of quinoxaline benzene sulfonamide derivatives 50–55.

Antibacterial Activity (DMSO, 4 mg mL−1) Diameter of Zone of Inhibition (mm) Compound S. Aureus E. coli 50 20 9 51 22 11 52 17 18 53 15 12 54 11 13 55 5 5> Chloramphenicol 19 22 Appl. Sci. 2021, 11, x FOR PEER REVIEW 8 of 25

group), in 53 and 54 scaffolds led to a moderate antibacterial activity, while the least an- Appl. Sci. 2021, 11, 5702 tibacterial activity was observed for the unsubstituted derivative 55 (Figure 8) [128].8 The of 24 results showed that electron-donating group’s substitution on the quinoxaline sulfonamide scaffolds contribute positively to increase the antibacterial activity.

HO O O O HN S NH NH O O SO O SO O N N O N N

N N 50 51 52

Cl NH NH NH O SO O SO O SO O O O N N N

N N N 53 54 55 Figure 8. SubstitutedSubstituted quinoxaline benzene sulfonamide derivatives 50–55.50–55.

Table 2. AntibacterialIngle etactivity al. synthesized of quinoxaline antimicrobial benzene sulfonamide quinoxaline derivatives sulfonamide 50–55. derivatives by ap- plying a convenient and an expeditious methodology. In this synthetic strategy, the nu- cleophilic substitutionAntibacterial was performed activity by attacking (DMSO, the 4 electrophilicmg mL−1) center (S) of chloro sulfonic acid 47 by the benzene of diphenylDiameter quinoxalineof Zone of Inhibition56 to furnish (mm) the intermediate Compound 2,3-diphenylquinoxaline-6-sulfonylS. Aureus chloride 57, which further refluxed E. coli with the substituted primary amine50 under basic conditions20 to deliver the final product 9 diphenyl quinoxaline sulfonamide51 58 in moderate to22 good (69–83%) yield (Scheme3). The 11 aromatic amines with EWG, such52 as nitro, lead to the17 final products in a higher yield, while 18 the aromatic amines with EDG,53 such as methyl and15 methoxy, etc, lead to final products 12 in low yield [129]. 59 The quinoxaline54 sulfonamide11 analogs displayed the highest 13 antibacterial activity, exhibiting a ZOI value of 10 mm against S. aureus and 8 mm against E. coli at a concentration 55 5 5> of 100 µg (microgram), while the quinoxaline sulfonamide hybrid 60 showed moderate Chloramphenicol 19 22 antibacterial activity, with a ZOI of 7 mm and 6 mm at a concentration of 100 µg against S. aureus and E. coli, respectively (Table3). The moderate antibacterial activity was observed for derivativeIngle et al.61 synthesizedthat exhibited antimicrobial a ZOI value quinoxaline of 6 mm against sulfonamideS. aureus derivativesat a concentration by ap- plyingof 100 µag, convenient and derivative and an62 expeditiousexhibited the methodology. least antibacterial In this activity synthetic by inducingstrategy, athe 2 mmnu- cleophilicZOI value substitution at the concentration was performed of 100 µ gby against attackingE. coli the, when electrophilic compared center with (S) the of standard chloro sulfonicdrug azithromycin acid 47 by the (ZOI benzene value of of 12 diphenyl mm and quinoxaline 10 mm against 56 toS. furnish aureus andthe intermediateE. coli at the 2,3-diphenylquinoxaline-6-sulfonylconcentration of 100 µg). The SAR revealedchloride that57, which the maximum further refluxed antibacterial with activity the substi- was tutedobserved primary in the amine presence under of a strongbasic EWDconditions group to (chloro deliver atom) the on final the ringproduct of analogue diphenyl59, quinoxalinewhile the introduction sulfonamide of a 58m-OH in moderate and p-OH to group good on (69–83%) the ring produced yield (Scheme a moderate 3). The activity aro- for compounds 60 and 61. The derivative 62 exhibited the least antibacterial activity due to the presence of an electron-denoting methoxy group at the phenyl ring (Figure9). The presence of EWG showed the highest antibacterial activity as compared to the presence of EDG, which displayed moderate to low antibacterial activity [129]. Appl. Sci. 2021, 11, x FOR PEER REVIEW 9 of 25

Appl. Sci. 2021, 11, 5702 matic amines with EWG, such as nitro, lead to the final products in a higher yield, 9while of 24 the aromatic amines with EDG, such as methyl and methoxy, etc, lead to final products in low yield [129].

O O O RNH NHR N 2 N S 47 N S Cl O

N N 10% NaOH N

58 56 57

Expeditious and convenient synthetic approch to afford products in moderate to good (69–83%) yield

R = , , , NO2 OH HO Cl , , , O , Cl OH O

SchemeScheme 3.3. SynthesisSynthesis ofof substitutedsubstituted quinoxalinequinoxaline sulfonamidesulfonamide derivativesderivatives withwith structurestructure58 58..

TableThe 3. Antibacterial quinoxaline activity sulfonamide of quinoxaline-based analogs 59 displayed substituted the benzene highest sulfonamide antibacterial derivatives. activity, exhibiting a ZOI value of 10 mm against S. aureus and 8 mm against E. coli at a concen- Zone of Inhibition (mm) at 100 µg tration ofCompound 100 µg (microgram), while the quinoxaline sulfonamide hybrid 60 showed moderate antibacterial activity, with a ZOIS. aureus of 7 mm and 6 mm at a concentration E. coli of 100 µg against S. aureus59 and E. coli, respectively 10 (Table 3). The moderate antibacterial 8 activity was observed60 for derivative 61 that exhibited 7 a ZOI value of 6 mm against 6 S. aureus at a concentration61 of 100 µg, and derivative 62 6 exhibited the least antibacterial 7 activity by Appl. Sci. 2021, 11, x FOR PEER REVIEW 62 9 2 10 of 25 inducing a 2 mm ZOI value at the concentration of 100 µg against E. coli, when compared Azithromycin 12 10 with the standard drug azithromycin (ZOI value of 12 mm and 10 mm against S. aureus and E. coli at the concentration of 100 µg). The SAR revealed that the maximum antibac- H Oterial activity was observed in the presence of a strongH O EWD group (chloro atom) on the Cl N HO N Sring of analogueN 59, while the introduction of a m-OHS and p-OH Ngroup on the ring produced a moderate activity for compounds 60 and 61. The derivative 62 exhibited the least O O antibacterial activity due to the presence of an electron-denoting methoxy group at the phenyl ringN (Figure 9). The presence of EWG showed the highest Nantibacterial activity as compared to the presence of EDG, which displayed moderate to low antibacterial activity [129]. 59 60

H O N S N H O O O N HO S N N O N 61

62 Figure 9. Substituted quinoxaline sulfonamide derivatives 5959–62–62.

TableTalari 3. Antibacterial and coworkers activity developed of quinoxaline-based a novel synthetic substituted strategy benzene for su thelfonamide synthesis derivatives. of indole- based quinoxaline sulfonamides. These sulfonamide derivatives were evaluated for their Zone of Inhibition (mm) at 100 μg antimicrobialCompound activity against different bacterial and fungal strains. Indole quinoxaline ana- S. aureus E. coli 59 10 8 60 7 6 61 6 7 62 9 2 Azithromycin 12 10

Talari and coworkers developed a novel synthetic strategy for the synthesis of indole-based quinoxaline sulfonamides. These sulfonamide derivatives were evaluated for their antimicrobial activity against different bacterial and fungal strains. Indole quinoxaline analogue 64 was afforded by the reaction of OPD 34 with 5-bromoisatin 63 heated to reflux for 30 min. The scaffold 64 was refluxed with chlorosulfonic acid 47 to obtain the quinoxaline sulfonyl chloride 65 that was further treated with substituted amines in anhydrous acetone and pyridine to furnish final quinoxaline sulfonamides 66 via dehydrohalogenation in a low to moderate (20–47.5%) yield (Scheme 4) [130].

Br Br Br N O N Br Reflux N 47 Cl RNH2 RHN N 34 O S N N S N 30 min H H N N N O O O O H H 66 63 65 64

This synthetic approach deliver final products in low to moderate (20–47.5%) yield

O S NH H Cl S N R = Cl H2N H2N N H N H2N N N F H 2 H O O Br Scheme 4. Synthesis of substituted quinoxaline sulfonamide derivatives with structure 66. Appl. Sci. 2021, 11, x FOR PEER REVIEW 10 of 25

H O H O Cl N HO N S N S N O O N N

59 60

H O N S N H O O O N HO S N N O N 61

62 Figure 9. Substituted quinoxaline sulfonamide derivatives 59–62.

Table 3. Antibacterial activity of quinoxaline-based substituted benzene sulfonamide derivatives.

Zone of Inhibition (mm) at 100 μg Compound S. aureus E. coli 59 10 8 60 7 6 61 6 7 62 9 2 Azithromycin 12 10 Appl. Sci. 2021, 11, 5702 10 of 24 Talari and coworkers developed a novel synthetic strategy for the synthesis of indole-based quinoxaline sulfonamides. These sulfonamide derivatives were evaluated for their antimicrobial activity against different bacterial and fungal strains. Indole quinoxa- logueline analogue64 was afforded 64 was afforded by the reaction by the reaction of OPD 34of OPDwith 34 5-bromoisatin with 5-bromoisatin63 heated 63 toheated reflux to for 30reflux min. for The 30 scaffold min. The64 scaffoldwas refluxed 64 was with refluxed chlorosulfonic with chlorosulfonic acid 47 to acid obtain 47 theto obtain quinoxaline the sulfonylquinoxaline chloride sulfonyl65 that chloride was further 65 that treated was further with substitutedtreated with amines substituted in anhydrous amines in acetone an- andhydrous pyridine acetone to furnish and pyridine final quinoxaline to furnish sulfonamidesfinal quinoxaline66 via sulfonamides dehydrohalogenation 66 via dehy- in a lowdrohalogenation to moderate (20–47.5%)in a low to moderate yield (Scheme (20–47.5%)4)[130 yield]. (Scheme 4) [130].

Br Br Br N O N Br Reflux N 47 Cl RNH2 RHN N 34 O S N N S N 30 min H H N N N O O O O H H 66 63 65 64

This synthetic approach deliver final products in low to moderate (20–47.5%) yield

O S NH H Cl S N R = Cl H2N H2N N H N H2N N N F H 2 H O O Br SchemeScheme 4. 4.Synthesis Synthesis ofof substitutedsubstituted quinoxaline sulfonamide sulfonamide derivatives derivatives with with structure structure 66.66 .

Some of the synthesized quinoxaline sulfonamide derivatives were screened for antimicrobial activities against some bacterial and fungal strains. The quinoxaline sulfonamide 67 showed the most potent antibacterial and antifungal activity, with ZOI values of 14 mm, 14 mm, 16 mm, 17 mm and 17 mm against S. aureus, B. pimilis, E. coli A. niger and P. notatum, respectively at 50 µg/mL (Table4). The quinoxaline sulfonamide derivative 68 demonstrated a moderate activity, exhibiting ZOI values of 13 mm against S. aureus, 14 mm against B. pimilis, 15 mm against E. coli and 12 mm against A. niger at 50 µg/mL. The derivative 69 exhibited the lowest ZOI values of 10 mm against B. pimilis and 10 mm against A. niger at 50 µg/mL. The reference standard streptomycin at 50 µg/mL exhibited a ZOI of 18 mm, 20 mm and 20 mm against S. aureus, B. pimilis and E. coli strains, respectively. Miconazole nitrate exhibited, instead, 23 mm and 20 mm ZOI values at 50 µg/mL against A. niger and P. notatum strains. The SAR showed that the introduction of a bromophenyl moiety on the sulfonamide increased the antimicrobial activity of 67, while thioamide functionality was incorporated in analogue 68 to induce a moderate antimicrobial activity. The acetophenone moiety-containing derivative 69 displayed the least antimicrobial activity (Figure 10). The SAR study indicated that the antimicrobial activity decreased in the order Bromo > Thiamide > Acetyl. The results in the Table4 showed that the structural motif 67 displayed a broad spectrum antimicrobial therapeutic potential against different bacterial and fungal strains than the reference standard drugs [130].

Table 4. Antimicrobial activity of quinoxaline-substituted benzene sulfonamide derivatives 67–69.

Zone of Inhibition (mm) Compound Antibacterial Antifungal S. aureus B. pimilis E.coli A. nigar P. notatum 67 14 14 16 17 17 68 13 14 15 12 - 69 - 11 - 10 - Streptomycin 18 20 20 - - Miconazole - - - 23 20 nitrate Appl. Sci. 2021, 11, x FOR PEER REVIEW 11 of 25

Some of the synthesized quinoxaline sulfonamide derivatives were screened for antimicrobial activities against some bacterial and fungal strains. The quinoxaline sulfonamide 67 showed the most potent antibacterial and antifungal activity, with ZOI values of 14 mm, 14 mm, 16 mm, 17 mm and 17 mm against S. aureus, B. pimilis, E. coli A. niger and P. notatum, respectively at 50 µg/mL (Table 4). The quinoxaline sulfonamide derivative 68 demonstrated a moderate activity, exhibiting ZOI values of 13 mm against S. aureus, 14 mm against B. pimilis, 15 mm against E. coli and 12 mm against A. niger at 50 µg/mL. The derivative 69 exhibited the lowest ZOI values of 10 mm against B. pimilis and 10 mm against A. niger at 50 µg/mL. The reference standard streptomycin at 50 µg/mL exhibited a ZOI of 18 mm, 20 mm and 20 mm against S. aureus, B. pimilis and E. coli strains, respectively. Miconazole nitrate exhibited, instead, 23 mm and 20 mm ZOI values at 50 µg/mL against A. niger and P. notatum strains. The SAR showed that the introduction of a bromophenyl moiety on the sulfonamide increased the antimicrobial activity of 67, while thioamide functionality was incorporated in analogue 68 to induce a moderate antimicrobial activity. The acetophenone moiety-containing derivative 69 displayed the least antimicrobial activity (Figure 10). The SAR study indicated that the antimicrobial activity decreased in the order Bromo > Thiamide > Acetyl. The results in the Table 4 Appl. Sci. 2021, 11, 5702 showed that the structural motif 67 displayed a broad spectrum antimicrobial therapeutic11 of 24 potential against different bacterial and fungal strains than the reference standard drugs [130].

Br Br N N Br S O O S N N S N N H N N H N H 2 O O H H 68 67

O Br H O N N N S H O N N H 69 Figure 10. Substituted quinaxoline sulfonamide derivatives 67–6967–69.

Appl. Sci. 2021, 11, x FOR PEER REVIEW 12 of 25 TableAn 4. Antimicrobial efﬁcient pathway activity was of quinoxaline-su adopted by Sharafbstituted El-Din benzene et al. sulfonamide to afford substituted derivatives quinox- 67–69. aline sulfonamide derivatives, and they analyzed these designed scaffolds for antibacterial therapeutic potential by the agar diffusion method.Zone of The Inhibition 1,4-dihydroquinoxaline-2,3-dione (mm) (1,4-dihydroquinoxa71) wasCompound prepared byline-2,3-dione condensation ( of71)Antibacterial34 waswith prepared oxalic acid by70 condensation. In the nextAntifungal step, of 34 reaction with oxalic with chlorosulfonicacid 70. In the acidnext (47step,) at reaction 0–5S. aureus◦C furnished with B. chlorosulfonic pimilis the quinoxaline E.coli acid scaffold(47 A.) atnigar 0–5 with °C chlorosulfonyl P.furnished notatum the moietyquinoxaline72, which67 scaffold was with combined chlorosulfonyl14 with different moiety14 amino 72, which compounds,16 was combined17 such as amines,with 17different amino acids,amino morpholine compounds,68 and such piperazine, as amines,13 to amino produce 14acids, ﬁnal morpholine quinoxaline15 and sulfonamide12 piperazine, derivatives to -produce 73 infinal good quinoxaline yield69 (61–66%) sulfonamide (Scheme derivatives- 5)[131]. 7311 in good yield- (61–66%)10 (Scheme 5) [131]- . Streptomycin 18 20 20 - - O O O O MiconazoleH nitrate - H - - 23 H 20 O OH N O S N O S N O 4 N HCl 47 Cl Amino acid, Morpholine R 34 O OH reflux An efficientN O pathway was adoptedN ObyAmine, Sharaf Piperazine El-Din et al. to affordN substitutedO quinoxalineH sulfonamide derivatives,H and they analyzed these designed scaffoldsH for an- 70 71 72 73 61-66% tibacterial therapeutic potential by the agar diffusion method. The

- R = NHC3H7, NHC3H6OH, NHCH2CO2H, NH (COOH-C6H4), morpholine, piperazine

Scheme 5. SynthesisSynthesis of of quinoxaline-2,3 ( (11H,4,4HH)) dionedione sulfonamidesulfonamide derivativederivative withwith structurestructure73 73..

The quinoxaline sulfonamide 74 displayed the highest antibacterial activity, with aa zone ofof inhibitioninhibition (ZOI) (ZOI) of of 15 15 mm mm and and 10 mm10 mm against againstS. aureus S. aureusand E.and coli E., respectively, coli, respectively, while thewhile reference the reference drug, sulfadiazine,drug, sulfadiazine, gave a gave ZOI ofa ZOI 14 mm of 14 and mm 13 mmand zone13 mm diameter zone diameter against S.against aureus S.and aureusE. coli and(Table E. coli5). (Table The derivative 5). The derivative75 showed 75 showed equipotent equipotent antibacterial antibacterial activity (ZOIactivity of 14(ZOI mm) of against14 mm)S. against aureus S.in aureus comparison in comparison with the with reference the reference drug (ZOI drug of 14(ZOI mm), of but14 mm), less antibacterial but less antibacterial activity (ZOI activity of 8 mm) (ZOI against of 8 mm)E. coli againstthan the E. referencecoli than the drug reference (ZOI of 13drug mm). (ZOI A of moderate 13 mm). activity A moderate was observed activity was for theobserved quinoxaline for the sulfonamide quinoxaline derivativesulfonamide76 thatderivative led to a76 ZOI that of led 12 mmto a andZOI 10 of mm12 mm against andS. 10 aureus mm againstand E. coliS. ,aureus respectively. and E. Compoundcoli, respec- 77tively.exhibited Compound the lowest 77 exhibited antibacterial the lowest activity, antibacterial showing aactivity, ZOI of showing 10 mm against a ZOI ofS. 10 aureus mm withagainst respect S. aureus to the with reference respectdrug to the sulfadiazine, reference drug but sulfadiazine, it did not exhibit but it any did activitynot exhibit against any E. coli. The SAR studies demonstrated that the presence of a propanol or benzoic acid activity against E. coli. The SAR studies demonstrated that the presence of a propanol or moiety on the sulfonamide analogs 74 and 75 displayed an excellent and slightly higher benzoic acid moiety on the sulfonamide analogs 74 and 75 displayed an excellent and or equipotent antibacterial activity in comparison with the reference drug sulfadiazine, slightly higher or equipotent antibacterial activity in comparison with the reference drug sulfadiazine, while the presence of a sulfonyl glycine moiety was responsible for the moderate activity of the derivative 76. The morpholine moiety in analog 77 was responsible for the least antibacterial activity against Gram-positive and negative bacterial strains. (Figure 11) [131].

H H N O N O O O O S N O HO S N O N H N H H O H O HO 75 74

HO O H N O S O N O O N S H O NH N O H O O HN 76 O 77 Figure 11. Quinaxoline sulfonamide derivatives 74–77. Appl. Sci. 2021, 11, x FOR PEER REVIEW 12 of 25

1,4-dihydroquinoxaline-2,3-dione (71) was prepared by condensation of 34 with oxalic acid 70. In the next step, reaction with chlorosulfonic acid (47) at 0–5 °C furnished the quinoxaline scaffold with chlorosulfonyl moiety 72, which was combined with different amino compounds, such as amines, amino acids, morpholine and piperazine, to produce final quinoxaline sulfonamide derivatives 73 in good yield (61–66%) (Scheme 5) [131].

H O O H O O H O OH N O S N O S N O 4 N HCl 47 Cl Amino acid, Morpholine R 34 O OH reflux N O N O Amine, Piperazine N O H H H 70 71 72 73 61-66%

- R = NHC3H7, NHC3H6OH, NHCH2CO2H, NH (COOH-C6H4), morpholine, piperazine

Scheme 5. Synthesis of quinoxaline-2,3 (1H,4H) dione sulfonamide derivative with structure 73.

Appl. Sci. 2021, 11, 5702 The quinoxaline sulfonamide 74 displayed the highest antibacterial activity, 12with of 24 a zone of inhibition (ZOI) of 15 mm and 10 mm against S. aureus and E. coli, respectively, while the reference drug, sulfadiazine, gave a ZOI of 14 mm and 13 mm zone diameter whileagainst the S. presence aureus and of aE. sulfonyl coli (Table glycine 5). The moiety derivative was responsible 75 showed for equipotent the moderate antibacterial activity ofactivity the derivative (ZOI of 1476 mm). The against morpholine S. aureus moiety in comparison in analog 77withwas the responsible reference drug for the (ZOI least of antibacterial14 mm), but activity less antibacterial against Gram-positive activity (ZOI and of negative 8 mm) bacterialagainst E. strains. coli than (Figure the reference11)[131]. drug (ZOI of 13 mm). A moderate activity was observed for the quinoxaline sulfonamide Tablederivative 5. Antibacterial 76 that led activity to a ZOI of quinaxoline of 12 mm sulfonamide and 10 mm derivatives against S.74 aureus–77. and E. coli, respectively. Compound 77 exhibited the lowest antibacterial activity, showing a ZOI of 10 mm against S. aureus with respectAntibacterial to the reference Activity drug (20 sulfadiazine, mg/mL) but it did not exhibit any activity against E. coli. The SAR studies demonstratedZone Diameterthat the presence (mm) of a propanol or Compound benzoic acid moiety on the sulfonamideS. aureusanalogs 74 and 75 displayed E. an coli excellent and slightly higher or equipotent antibacterial activity in comparison with the reference drug 74 15 10 sulfadiazine, 75while the presence of a sulfon 14yl glycine moiety was responsible 8 for the moderate activity76 of the derivative 76. The 12morpholine moiety in analog 10 77 was responsible for the 77least antibacterial activity against 10 Gram-positive and negative - bacterial strains. (FigureSulfadiazine 11) [131]. 14 13

H H N O N O O O O S N O HO S N O N H N H H O H O HO 75 74

HO O H N O S O N O O N S H O NH N O H O O HN 76 O 77 FigureFigure 11.11. QuinaxolineQuinaxoline sulfonamidesulfonamide derivativesderivatives 7474–77–77..

Potey et al. described a new synthetic approach for the synthesis of libraries of quinoxaline sulfonamides and studied their antimicrobial activities. The starting 2,3- diphenylquinoxaline (56) was prepared in an excellent yield by condensation of o-phenylenediamine (OPD) (34) and diketone 78. Then, quinoxaline 56 was treated with chlorosulfonic acid 47 at room temperature to afford the quinoxaline sulfonyl chloride 57 that reacted with primary and secondary amines to furnish quinoxaline sulfonamides 79 and 80 in good to excellent yield (Scheme6)[132]. The prepared derivatives were tested against some Gram-positive and negative bacterial strains (Table6). Among all these derivatives, the quinoxaline sulfonamide 81 exhibited an excellent antibacterial activity, with a ZOI of 30 mm and 24 mm against P. vulgaries and Enterobacteria, respectively. A moderate activity was observed for 82, with a ZOI value of 18 mm against S. aureus, 18 mm against Enterobacteria, 16 mm against V. cholorie, 16 mm against E. coli and 16 mm against P. vulgaries. Compound 83 showed the least antibacterial activity, exhibiting a ZOI of 8 mm, 8 mm, 6 mm, 6 mm and 8 mm against S. aureus, Enter- obacteria, V. cholera, E. coli and P. vulgaries, respectively. The SAR showed that ortho-OH on the phenylsulfonamide moiety increased the antibacterial activity of the quinoxaline sulfonamide 81, while the presence of a 2-chlorophenyl substituent was responsible for the moderate activity of the scaffold 82. The introduction of a methoxyphenyl group into the quinoxaline sulfonamide derivative 83 decreased the antibacterial activity (Figure 12)[132]. Appl. Sci. 2021, 11, x FOR PEER REVIEW 13 of 25

Table 5. Antibacterial activity of quinaxoline sulfonamide derivatives 74–77.

Antibacterial Activity (20 mg/mL) Zone Diameter (mm) Compound S. aureus E. coli 74 15 10 75 14 8 76 12 10 77 10 - Sulfadiazine 14 13

Appl. Sci. 2021, 11, 5702 chlorosulfonic acid 47 at room temperature to afford the quinoxaline sulfonyl chloride13 of 57 24 that reacted with primary and secondary amines to furnish quinoxaline sulfonamides 79 and 80 in good to excellent yield (Scheme 6) [132].

O O O N S R C2H5OH 47 RNH2 N 34 + 56 57 H O Δ, 1.5 h N

NHRR 80 78 1 O O N S R N R N 1

R = -H, -C6H5, -(NO2-C6H4), -(OH-C6H4), -(OCH3-C6H5-COCH3, -CSNHNH2, -N3, -CH(Cl-C6H4), R1 = C6H5

Scheme 6. Synthesis of 2,3-diphenylquinox 2,3-diphenylquinoxalinealine sulfonamide derivatives 79 and 80.

TableThe 6. Antimicrobialprepared derivatives activity of quinoxalinewere tested derivatives against 81some–83. Gram-positive and negative bacterial strains (Table 6). Among all these derivatives, the quinoxaline sulfonamide 81 Antimicrobial Activity exhibited an excellent antibacterial activity, with a ZOI of 30 mm and 24 mm against P. vulgaries and Enterobacteria, respectively.Zone of Inhibition A moderate (mm) activity was observed for 82, with a Gram-PositiveZOI value of 18 mm against S. aureus, 18 mm against Enterobacteria, 16 mm against V. Compound Gram-Negative Bacteria cholorie,Bacteria 16 mm against E. coli and 16 mm against P. vulgaries. Compound 83 showed the leastS. aureusantibacterial activity, Enterobacteria exhibiting a ZOI V. choleraof 8 mm, 8 mm, E. coli6 mm, 6 mm P. vulgarisand 8 mm against S. aureus, Enterobacteria, V. cholera, E. coli and P. vulgaries, respectively. The SAR 81 19 24 2 22 30 Appl. Sci. 2021, 11, x FOR PEER REVIEWshowed that ortho-OH on the phenylsulfonamide moiety increased the antibacterial14 of ac- 25 82 18 18 16 16 16 83tivity of 8 the quinoxaline sulfonamide 8 81, while 6the presence of 6a 2-chlorophenyl 8 substituent was responsible for the moderate activity of the scaffold 82. The introduction of a methoxyphenyl group into the quinoxaline sulfonamide derivative 83 decreased the an- O O O tibacterial activity (Figure 12)O [132].O Cl O O N S N N S N S H N N OH H H N N N

81 82 83 Figure 12. Substituted quinaxoline sulfonamide derivatives 81–8381–83.

Table2.3. Synthesis 6. Antimicrobial of Quinoxaline activity Sulfonamideof quinoxaline Derivative derivatives with 81–83 Neuropharmacological. Activity

The activity which determinesAntimicrobial how drugs Activity or therapeutic agents affect the cellular functions in the nervous system is called neuropharmacological activity. The neuropharma- Zone of Inhibition (mm) cological effects, such as analgesia, sedation, convulsion, anxiety, memory and psychosis, Gram-Positive andCompound the neural mechanisms through which the drugsGram-Negative inﬂuence behaviorBacteria were studied in neuropharmacology.Bacteria Olayiwola et al.S. aureus reported theEnterobacteria green microwave V. synthetic cholera route E. coli to quinonoxaline P. vulgaris sul- fonamide81 with neuropharmacological19 activity.24 The 2,3-quinoxalinedione2 22 71 was furnished30 in an excellent82 yield (99%)18 by the condensation18 of 34 and16 oxalic acid16 dihydrate (7016) using microwave83 radiations. The8 scaffold 71 was8 treated with 476 to obtain quinoxaline-6-sulfonyl6 8 chloride 72 at 88% yield, followed by the reaction with dibenzyloamine in anhydrous 2.3.dimethylformamide Synthesis of Quinoxaline (DMF) Sulfonamide to give corresponding Derivative quinoxalinewith Neuropharmacological sulfonamide 84 Activityat 75% yield (Scheme7)[133]. The activity which determines how drugs or therapeutic agents affect the cellular functions in the nervous system is called neuropharmacological activity. The neuropharmacological effects, such as analgesia, sedation, convulsion, anxiety, memory and psychosis, and the neural mechanisms through which the drugs influence behavior were studied in neuropharmacology. Olayiwola et al. reported the green microwave synthetic route to quinonoxaline sulfonamide with neuropharmacological activity. The 2,3-quinoxalinedione 71 was furnished in an excellent yield (99%) by the condensation of 34 and oxalic acid dihydrate (70) using microwave radiations. The scaffold 71 was treated with 47 to obtain quinoxaline-6-sulfonyl chloride 72 at 88% yield, followed by the reaction with dibenzyloamine in anhydrous dimethylformamide (DMF) to give corresponding quinoxaline sulfonamide 84 at 75% yield (Scheme 7) [133].

. O O H 70 (PhCH ) NH S N O 47 2 2 N 34 71 72 DMF MWI 99 % N O H

84 75 %

Scheme 7. Synthesis of quinoxaline sulfonamide 84.

The obtained derivative 84 was analyzed for its neuropharmacological effects, such as anxiolytic, anticonvulsant and total locomotor activity, in mice (Table 7). It showed maximum inhibition of locomotor activity (sedative action) at 40 mg/kg. As for anxiolytic activity, 84 exhibited a maximum action at 2.5 mg/kg, having 67.3% time in open arm and 81.0% entry into open arm, and the index of open arm avoidance was 25.9 when compared with diazepam at 1 mg/kg (53.3% = time in open arm, 82.4% = entry into open arm and 32.2 = index of open arm avoidance). As for anticonvulsant activity, 84 displayed a protection effect of 100% against both leptazol at 80 mg/kg and strychnine at 2.0 mg/kg Appl. Sci. 2021, 11, x FOR PEER REVIEW 14 of 25

O O O O O Cl O O N S N N S N S H N N OH H H N N N

81 82 83 Figure 12. Substituted quinaxoline sulfonamide derivatives 81–83.

Table 6. Antimicrobial activity of quinoxaline derivatives 81–83.

Antimicrobial Activity Zone of Inhibition (mm) Gram-Positive Compound Gram-Negative Bacteria Bacteria S. aureus Enterobacteria V. cholera E. coli P. vulgaris 81 19 24 2 22 30 82 18 18 16 16 16 83 8 8 6 6 8

2.3. Synthesis of Quinoxaline Sulfonamide Derivative with Neuropharmacological Activity The activity which determines how drugs or therapeutic agents affect the cellular functions in the nervous system is called neuropharmacological activity. The neuropharmacological effects, such as analgesia, sedation, convulsion, anxiety, memory and psychosis, and the neural mechanisms through which the drugs influence behavior were studied in neuropharmacology. Olayiwola et al. reported the green microwave synthetic route to quinonoxaline sulfonamide with neuropharmacological activity. The 2,3-quinoxalinedione 71 was furnished in an excellent yield (99%) by the condensation of 34 and oxalic acid dihydrate (70) using microwave radiations. The scaffold 71 was treated with 47 to obtain quinoxa- Appl. Sci. 2021, 11, 5702 line-6-sulfonyl chloride 72 at 88% yield, followed by the reaction with dibenzyloamine14 of in 24 anhydrous dimethylformamide (DMF) to give corresponding quinoxaline sulfonamide 84 at 75% yield (Scheme 7) [133].

. O O H 70 (PhCH ) NH S N O 47 2 2 N 34 71 72 DMF MWI 99 % N O H

84 75 %

Scheme 7. Synthesis of quinoxaline sulfonamide 84.84.

TheThe obtained obtained derivative derivative 8484 was analyzed for its neuropharmacological effects, such asas anxiolytic, anticonvulsant anticonvulsant and and total total locomotor locomotor activity, activity, in mice (Table7 7).). ItIt showedshowed maximummaximum inhibition of locomotor activity (sedative action)action) atat 4040 mg/kg.mg/kg. As As for for anxiolytic anxiolytic activity,activity, 8484 exhibitedexhibited a a maximum maximum action action atat 2.5 2.5 mg/k mg/kg,g, having having 67.3% 67.3% time time in open in open arm armand 81.0%and 81.0% entry entry into open into openarm, arm,and the and index the indexof open of openarm avoidance arm avoidance was 25.9 was when 25.9 whencom- paredcompared with withdiazepam diazepam at 1 mg/kg at 1 mg/kg (53.3% (53.3% = time = timein open in openarm, arm,82.4% 82.4% = entry = entry into open into open arm arm and 32.2 = index of open arm avoidance). As for anticonvulsant activity, 84 displayed and 32.2 = index of open arm avoidance). As for anticonvulsant activity, 84 displayed a a protection effect of 100% against both leptazol at 80 mg/kg and strychnine at 2.0 mg/kg protection effect of 100% against both leptazol at 80 mg/kg and strychnine at 2.0 mg/kg after 60 min at 25 mg/kg dose, when compared with phenobarbitone sodium, having a 90% protection effect at 20 mg/kg dose against both leptazol at 80 mg/kg and strychnine at 2.0 mg/kg after 60 min [133].

Table 7. Neuropharmacological activity of quinoxaline-based substituted benzene sulfonamide derivatives.

Neuropharmacological Effect Reference Compound Activity Inhibition Effect Inhibition Effect Compound Potent sedative at Total locomotor activity -- 40 mg/kg 67.3% = time in open arm 53.3% = time in open arm 81.0% = entry into open 82.4% = entry into open Anxiolytic activity arm, 25.9 = index of open Diazepam arm, 32.2 = index of open arm avoidance arm avoidance 84 Dose = 2.5 mg/kg Dose = 1 mg/kg Protection effect = 90% Protection effect = 100% against both Leptazol at against Leptazol at 80 mg/kg. and Strychnine Anticonvulsant activity 80 mg/kg and Strychnine Phenobarbitone sodium at 2.0 mg/kg after at 2.0 mg/kg after 60 min 60 min 15.15 Dose = 25 mg/kg dose Dose = 20 mg/kg

2.4. Quinoxaline Sulfonamide Derivatives with Antileishmanial Activity Barea et al. synthesized quinoxaline sulfonamide derivatives and studied their antileishmanial activities. The 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivative 89 was synthesized in 15–90% yield by the reaction of benzofuroxane 85 and malononitrile 86, using triethylamine as catalyst and DMF as solvent. The scaffold 87 was further treated with substituted sulfonyl chlorides 88 at 0 ◦C to afford quinoxaline sulfonamide derivatives 89 in low yield (13–15%) (Scheme8)[134]. Appl. Sci. 2021, 11, x FOR PEER REVIEW 15 of 25

after 60 min at 25 mg/kg dose, when compared with phenobarbitone sodium, having a 90% protection effect at 20 mg/kg dose against both leptazol at 80 mg/kg and strychnine at 2.0 mg/kg after 60 min [133].

Table 7. Neuropharmacological activity of quinoxaline-based substituted benzene sulfonamide derivatives.

Neuropharmacological Effect Reference Compound Activity Inhibition Effect Inhibition Effect Compound Total locomotor activity Potent sedative at 40 mg/kg - - 53.3% = time in open 67.3% = time in open arm arm 82.4% = entry into Anxiolytic activity 81.0% = entry into open arm, 25.9 = Diazepam open arm, 32.2 = index of open arm avoidance index of open arm avoidance 84 Dose = 2.5 mg/kg Dose = 1 mg/kg Protection effect = Protection effect = 100% against 90% against both Leptazol at 80 mg/kg and Leptazol at 80 mg/kg. Phenobarbitone Anticonvulsant activity Strychnine at 2.0 mg/kg after 60 and Strychnine at 2.0 sodium min mg/kg after 60 min 15.15 Dose = 25 mg/kg dose Dose = 20 mg/kg

2.4. Quinoxaline Sulfonamide Derivatives with Antileishmanial Activity Barea et al. synthesized quinoxaline sulfonamide derivatives and studied their antileishmanial activities. The 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivative 89 was synthesized in 15–90% yield by the reaction of benzofuroxane 85 and malono- Appl. Sci. 2021, 11, 5702 nitrile 86, using triethylamine as catalyst and DMF as solvent. The scaffold 87 was further15 of 24 treated with substituted sulfonyl chlorides 88 at 0 °C to afford quinoxaline sulfonamide derivatives 89 in low yield (13–15%) (Scheme 8) [134].

O O O- - O NC CN S O R R N+ CN Cl Ar + 1 N 86 1 R1 N CN O 88 O O o S R N Triethylamine, DMF R N+ NH Pyridine, 0 C + 2 2 2 R2 N N Ar - H O O- 85 87 15-90% 89 13-15%

R1 = R2 = H, CH3, Cl, Ar = 2-naphthyl, o-nitrophenyl, p-nitrophenyl

SchemeScheme 8. 8.Synthesis Synthesis of of substituted substituted quinoxalinequinoxaline sulfonamide derivatives derivatives 89.89 .

TheThe synthesized synthesized derivativesderivatives were evaluated evaluated against against LeishmaniaLeishmania amazonensis amazonensis strainstrain MHOM/BR/76/LTBMHOM/BR/76/LTB in in infected infected macrophages macrophages (Table (Table 8)8 )The The quinoxaline quinoxaline sulfonamide sulfonamide 92 92 displayeddisplayed a a potent potent antileishmanialantileishmanial activity (IC (IC5050 == 3.1 3.1 µM),µM), although although 15-fold 15-fold less less active active thanthan the the standard standard drug drug amphotericin amphotericin B. B. The The quinoxaline quinoxaline sulfonamide sulfonamide analog analog91 displayed91 dis- aplayed moderate a moderate antileishmanial antileishmanial activity activity (IC50 (IC= 16.350 = 16.3µM), µM), comparable comparable to to that that observed observedfor 90for (IC 9050 (IC=50 20.3 = 20.3µ M).µM). The TheSAR SAR demonstrated that that the the presence presence of aof 2-naphtyl a 2-naphtyl moiety moiety on on the sulfonamide motif and a methyl group on the quinoxaline in 90 led to a potent antileishmanial activity, while a 2-naphtyl moiety and the electronegative chlorine atom was responsible for the moderate antileishmanial activity of scaffold 91. The highest antileishmanial activity was observed for 92 with the o-nitrophenyl group and chlorine atom (Figure 13)[134].

Appl. Sci. 2021, 11, x FOR PEER REVIEWTable 8. Antileishmanial activity of quinoxaline-1,4-dioxide sulfonamide derivatives 90–92. 16 of 25

Antileishmanial Activity

Compound IC50 (µM) the sulfonamide motif and a methyl group on the quinoxaline in 90 led to a potent an- 90 20.3 tileishmanial activity,91 while a 2-naphtyl moiety and the electronegative 16.3 chlorine atom was responsible for the92 moderate antileishmanial activity of scaffold 3.1 91. The highest antileishmanial activityAmphotericin was observed B for 92 with the o-nitrophenyl 0.2 group and chlorine atom (Figure 13) [134].

NO O- O- 2 - H H O + + H N N N N N N+ S S S O O O O + + O O NC N NC N Cl NC N+ Cl - - O O O- 90 91 92 Figure 13. Structure of quinoxaline-1,4-dioxide sulfonamide derivativesderivatives 9090–92–92..

Table2.5. Synthesis 8. Antileishmanial of Quinoxaline activity Moiety-Based of quinoxaline-1,4-dioxide Benzene Sulfonamides sulfonamide with derivatives Antitumor 90–92. Activity A mass or lump of tissue that is formed by an accumulation of abnormal cells, resem- Antileishmanial Activity bling swelling and varying from a tiny nodule to a large mass, is speciﬁed as a tumor. Not Compound IC50 (μM) all tumors are cancerous; some are benign (non-cancerous), premalignant (having potential to become cancerous)90 and some are malignant (cancerous). A20.3 chemotherapeutic agent which has the ability91 to prevent or inhibit the formation or growth16.3 of tumors is termed as antitumor. 92 3.1 FarragAmphotericin et al. developed B a novel synthetic strategy to furnish 0.2 novel sulfamoyl phenyl carbamoyl quinoxaline hybrid structures. In the ﬁrst step, quinoxaline-2,3-dicarboxylic 2.5. Synthesis of Quinoxaline Moiety-Based Benzene Sulfonamides with Antitumor Activity A mass or lump of tissue that is formed by an accumulation of abnormal cells, re- sembling swelling and varying from a tiny nodule to a large mass, is specified as a tumor. Not all tumors are cancerous; some are benign (non-cancerous), premalignant (having potential to become cancerous) and some are malignant (cancerous). A chemotherapeutic agent which has the ability to prevent or inhibit the formation or growth of tumors is termed as antitumor. Farrag et al. developed a novel synthetic strategy to furnish novel sulfamoyl phenyl carbamoyl quinoxaline hybrid structures. In the first step, quinoxaline-2,3-dicarboxylic acid 94 was produced by the treatment of OPD 34 with disodium dihydroxytartarate 93, followed by a reaction with acetic anhydride, which resulted in the formation of quinoxaline anhydride derivative 95. The scaffold 95 was refluxed with substituted sulfonamide 96 in ethanol to afford 3-sulfamoyl phenylcarbamoyl quinoxaline-2-carboxylic acids 97 at 71–78% yield, which further reacted in quinoline-containing copper powder to obtain corresponding quinoxaline sulfonamide scaffold 98. The quinoxaline sulfonamide derivative 98 was also prepared at 68–73% yield by directly heating the anhydride compound 95 with sulfonamide compound 96 under fusing conditions (Scheme 9) [135]. Appl. Sci. 2021, 11, 5702 16 of 24

acid 94 was produced by the treatment of OPD 34 with disodium dihydroxytartarate 93, followed by a reaction with acetic anhydride, which resulted in the formation of quinoxaline anhydride derivative 95. The scaffold 95 was reﬂuxed with substituted sulfonamide 96 in ethanol to afford 3-sulfamoyl phenylcarbamoyl quinoxaline-2-carboxylic acids 97 at 71–78% yield, which further reacted in quinoline-containing copper powder to obtain cor- Appl. Sci. 2021, 11, x FOR PEER REVIEWresponding quinoxaline sulfonamide scaffold 98. The quinoxaline sulfonamide derivative17 of 25 98 was also prepared at 68–73% yield by directly heating the anhydride compound 95 with sulfonamide compound 96 under fusing conditions (Scheme9)[135].

OH NH N COOH 2 HO COONa HCl + HO COONa NH N COOH 2 OH 94 34 93

Ac2O

O O O N S NHR + O N H N Fusion 2 O C2H5OH 96 95

O O O O S S O NHR O NHR Quinoline N N N N H Cu powder H N N COOH 98 97 68-73% 71-78%

NH N N R = H, , N , , NH2 O N N

Scheme 9. Synthesis of quinoxaline moiety-based benzenebenzene sulfonamidessulfonamides withwith structurestructure 9898..

The quinoxaline sulfonamide sulfonamide derivative derivative 9999 displayeddisplayed the the most most potent potent antitumor antitumor ac- activitytivity against against the the liver liver carcinoma carcinoma cell cell line line (IC (IC50 value50 value 0.5 0.5µg µm/L),g m/L), while while moderate moderate an- anti-tumorti-tumor activity activity was was exerted exerted by by 100100 (IC(IC5050 valuevalue 4.75 4.75 µgµg m/L, m/L, Table Table 99).). TheThe quinoxalinequinoxaline sulfonamide structural motif 101 demonstrated the least antitumorantitumor activity, exhibitingexhibiting anan IC50 valuevalue of of 6.79 6.79 µgµg m/L. The The SAR SAR described described th thatat the the presence presence of a carboxylic acid group on thethe quinoxalinequinoxaline was was responsible responsible for for the the potent potent antitumor antitumor activity activity of 99 of, while99, while its absence its ab- insence100 inled 100 to aled moderate to a moderate activity. activity. The absence The absence of the isoxazoleof the isoxazole in 101 inproduced 101 produced the worst the actionworst action herein herein (Figure (Figure 14)[135 14)]. [135].

O O OO O O O O S S S O NH O N N O N N 2 H H N N N N N N H H H N N COOH N 101 99 100 Figure 14. Substituted quinoxaline sulfonamide derivatives 99–101. Appl. Sci. 2021, 11, x FOR PEER REVIEW 17 of 25

OH NH N COOH 2 HO COONa HCl + HO COONa NH N COOH 2 OH 94 34 93

Ac2O

O O O N S NHR + O N H N Fusion 2 O C2H5OH 96 95

O O O O S S O NHR O NHR Quinoline N N N N H Cu powder H N N COOH 98 97 68-73% 71-78%

NH N N R = H, , N , , NH2 O N N

Appl. Sci. 2021, 11, 5702 17 of 24 Scheme 9. Synthesis of quinoxaline moiety-based benzene sulfonamides with structure 98.

The quinoxaline sulfonamide derivative 99 displayed the most potent antitumor ac- Tabletivity 9.againstAnti-tumor the liver activity carcinoma of quinoxaline cell sulfonamidesline (IC50 value99– 1010.5. µg m/L), while moderate anti-tumor activity was exerted by 100 (IC50 value 4.75 µg m/L, Table 9). The quinoxaline Antitumor Activity sulfonamide structural motif 101 demonstrated the least antitumor activity, exhibiting an Compound IC (µg m/L) Appl. Sci. 2021, 11, x FOR PEER REVIEW50 50 18 of 25 IC value of 6.79 µg m/L. The SAR described that the presence of a carboxylic acid group on the quinoxaline was99 responsible for the potent antitumor activity0.5 of 99, while its absence in 100 led to a 100moderate activity. The absence of the isoxazole4.75 in 101 produced the 101 6.79 worst action herein (Figure 14) [135].

Table 9. Anti-tumor activity of quinoxaline sulfonamides 99–101. O O OO O O O O S S S O NH O N N O AntitumorN NActivity 2 H H N N CompoundN IC50N (μg m/L) N N H H 99 H 0.5 N N COOH N 100 4.75 101 1016.79 99 100 FigureIngle 14. Substituted and coworkers quinoxaline reported sulfonamide the synthesi derivativesderivativess of new 9999–101–101 anticancer.. quinoxaline sulfonamide derivatives. The 2,3-diphenylquinoxaline derivative 56 was treated with electro- Ingle and coworkers reported the synthesis of new anticancer quinoxaline sulfonamide philic compound 47 to produce 2,3-diphenyl quinoxaline-6-sulfonylchloride 57 that fur- derivatives. The 2,3-diphenylquinoxaline derivative 56 was treated with electrophilic com- ther refluxed with primary amines in a basic medium and resulted in the formation of the pound 47 to produce 2,3-diphenyl quinoxaline-6-sulfonylchloride 57 that further reﬂuxed withdesired primary final product, amines in substitu a basicted medium quinoxaline and resulted sulfonamides in the formation 58 at 53–78% of the yield desired (Scheme ﬁnal product,10) [136]. substituted quinoxaline sulfonamides 58 at 53–78% yield (Scheme 10)[136].

O O N S R N 47 R NH2 H 56 57 N 10 % NaOH 102 53-78%

CH3 O S H N NH2 R = H3C , H3C , , , , , , S NO2 N , O2N Cl NO O 2 H N

, O , , , N , , O

Scheme 10.10. Synthesis of quinoxaline sulfonamidesulfonamide derivativesderivatives 102102..

These synthesizedsynthesized quinoxalinequinoxaline sulfonamide sulfonamide derivatives derivatives were were tested tested for for their their cytotoxi- cyto- citytoxicityin vitro in vitroagainst against various various cancer cancer cell lines, cell lines, such assuch leukemia, as leukemia, non-small non-small cell lung cell cancer, lung coloncancer, cancer, colon cancer, CNS cancer, CNS canc melanoma,er, melanoma, ovarian ovarian cancer, cancer, renal cancer, renal cancer, prostate prostate cancer can- and breastcer and cancer breast cell cancer lines. Amongcell lines. all the Among synthesized all the derivatives, synthesized the chlorophenyl-containingderivatives, the chloro- moietyphenyl-containing quinoxaline sulfonamidemoiety quinoxaline103 and thesulfonamide pyridine moiety-containing 103 and the pyridine quinoxaline moie- sul- fonamidety-containing104 (Figurequinoxaline 15) exhibited sulfonamide the greatest 104 (Figure anticancer 15) exhibited activities the against greatest various anticancer above mentionedactivities against cancer various cell lines above [136 ].mentioned cancer cell lines [136].

Cl O O O O N S N S N N N H H N N

103 104

Appl. Sci. 2021, 11, x FOR PEER REVIEW 18 of 25

Table 9. Anti-tumor activity of quinoxaline sulfonamides 99–101.

Antitumor Activity Compound IC50 (μg m/L) 99 0.5 100 4.75 101 6.79

Ingle and coworkers reported the synthesis of new anticancer quinoxaline sulfonamide derivatives. The 2,3-diphenylquinoxaline derivative 56 was treated with electrophilic compound 47 to produce 2,3-diphenyl quinoxaline-6-sulfonylchloride 57 that further refluxed with primary amines in a basic medium and resulted in the formation of the desired final product, substituted quinoxaline sulfonamides 58 at 53–78% yield (Scheme 10) [136].

O O N S R N 47 R NH2 H 56 57 N 10 % NaOH 102 53-78%

CH3 O S H N NH2 R = H3C , H3C , , , , , , S NO2 N , O2N Cl NO O 2 H N

, O , , , N , , O

Scheme 10. Synthesis of quinoxaline sulfonamide derivatives 102.

These synthesized quinoxaline sulfonamide derivatives were tested for their cytotoxicity in vitro against various cancer cell lines, such as leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer cell lines. Among all the synthesized derivatives, the chloro- Appl. Sci. 2021, 11, 5702 phenyl-containing moiety quinoxaline sulfonamide 103 and the pyridine 18moie- of 24 ty-containing quinoxaline sulfonamide 104 (Figure 15) exhibited the greatest anticancer activities against various above mentioned cancer cell lines [136].

Cl O O O O N S N S N N N H H Appl. Sci. 2021, 11, x FOR PEER REVIEW 19 of 25 N N

103 104 Figure 15. Substituted quinoxaline sulfonamide derivatives 103–104. Figure 15. Substituted quinoxaline sulfonamide derivatives 103–104. 2.6. Synthesis of Quinoxaline-Based Benzene Sulfonamide Derivatives with Anti-Inflammatory 2.6.ActivitySynthesis of Quinoxaline-Based Benzene Sulfonamide Derivatives with Anti-Inflammatory Activity The propertyproperty ofof aa substance substance or or drug drug that that reduces reduces inflammation inflammation or or swelling swelling is specified is speci- asfied anti-inflammatory. as anti-inflammatory. In other In words, other nonsteroidal words, nonsteroidal anti-inflammatory anti-inflammatory drugs (NSAIDs) drugs are drugs(NSAIDs) that are help drugs reduce that inflammation, help reduce whichinflammation, often helps which to relieve often helps pain. NSAIDsto relieve can pain. be veryNSAIDs effective, can be and very some effective, of the and NSAIDS some areof the high-dose NSAIDS aspirin, are high-dose ibuprofen aspirin, (Advil, ibuprofen Motrin, Midol)(Advil, andMotrin, naproxen Midol) (Aleve, and napr Naprosyn),oxen (Aleve, etc. Naprosyn), etc. Ingle etet al.al. synthesized novel quinoxalinequinoxaline sulfonamidesulfonamide derivativesderivatives andand describeddescribed their anti-inflammatoryanti-inflammatory activity. activity. The The sulfonation sulfonation of of 2,3 2,3 diphenylquinoxaline diphenylquinoxaline56 was56 was carried car- outried byout the by electrophilic the electrophilic agent agent47 to 47 produce to produce quinoxaline quinoxaline sulfonyl sulfonyl chloride chloride57 at 76%57 at yield 76% thatyield was that further was further treated treated with aliphatic with aliphatic and aromatic and aromatic substituted substituted amines toamines obtain to the obtain final quinoxalinethe final quinoxaline sulfonamides sulfonamides105 at 59–85% 105 at yield 59–85% (Scheme yield 11(Scheme)[137]. 11) [137].

O O N S 47 R NH2 56 57 R 10 % NaOH N

105 59-85%

O HO O2N O S R = NH2 N NH N3 , , N N , N , N , N , , N 2 , N H H H H H H H

Scheme 11.11. Synthesis of substituted quinoxaline sulfonamidesulfonamide derivativederivative 105105..

The synthesized quinaxoline sulfonamide deri derivativesvatives were tested for their in vivo anti-inﬂammatoryanti-inflammatory activityactivity in in rat rat paw paw edema. edema. The The compounds compounds106 106–108–108 (Figure (Figure 16) 16) exhibited exhib- anti-inﬂammatoryited anti-inflammatory activity, activity, showing showing inhibition inhibition ofedema of edema in thein the range range 1.17–4.04% 1.17–4.04% and and a meana mean paw paw volume volume of of 0.96–0.98 0.96–0.98 mL. mL. Diclofenac Diclofenac sodiumsodium usedused asas referencereference drugdrug showed, instead, 15.15% inhibition of edema after 30 min with a meanmean pawpaw volumevolume ofof 0.850.85 mLmL (Table 1010))[ [137].137].

O O O O O O O N S N S N S NH2 N N H H N N N

106 107 108 Figure 16. Substituted quinaxoline sulfonamide derivatives 106–108.

Appl. Sci. 2021, 11, x FOR PEER REVIEW 19 of 25

Figure 15. Substituted quinoxaline sulfonamide derivatives 103–104.

2.6. Synthesis of Quinoxaline-Based Benzene Sulfonamide Derivatives with Anti-Inflammatory Activity The property of a substance or drug that reduces inflammation or swelling is specified as anti-inflammatory. In other words, nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that help reduce inflammation, which often helps to relieve pain. NSAIDs can be very effective, and some of the NSAIDS are high-dose aspirin, ibuprofen (Advil, Motrin, Midol) and naproxen (Aleve, Naprosyn), etc. Ingle et al. synthesized novel quinoxaline sulfonamide derivatives and described their anti-inflammatory activity. The sulfonation of 2,3 diphenylquinoxaline 56 was carried out by the electrophilic agent 47 to produce quinoxaline sulfonyl chloride 57 at 76% yield that was further treated with aliphatic and aromatic substituted amines to obtain the final quinoxaline sulfonamides 105 at 59–85% yield (Scheme 11) [137].

O O N S 47 R NH2 56 57 R 10 % NaOH N

105 59-85%

O HO O2N O S R = NH2 N NH N3 , , N N , N , N , N , , N 2 , N H H H H H H H

Scheme 11. Synthesis of substituted quinoxaline sulfonamide derivative 105.

The synthesized quinaxoline sulfonamide derivatives were tested for their in vivo anti-inflammatory activity in rat paw edema. The compounds 106–108 (Figure 16) exhibited anti-inflammatory activity, showing inhibition of edema in the range 1.17–4.04% and Appl. Sci. 2021, 11, 5702 a mean paw volume of 0.96–0.98 mL. Diclofenac sodium used as reference drug showed,19 of 24 instead, 15.15% inhibition of edema after 30 min with a mean paw volume of 0.85 mL (Table 10) [137].

O O O O O O O N S N S N S NH2 N N H H N N N

106 107 108 Figure 16. Substituted quinaxoline sulfonamide derivatives 106106–108.–108.

Table 10. Anti-inﬂammatory activity of quinoxaline-based substituted benzene sulfonamide derivatives 104–106.

Anti-Inﬂammatory Activity Mean Paw Volume (mL) ± Compound % Inhibition of Edema SEM 106 0.96 ± 0.058 4.04 107 0.96 ± 0.052 3.82 108 0.98 ± 0.021 1.17 Diclofenac sodium 0.85 ± 0.0085 15.15

3. Conclusions The present review showed the escalating interest of organic and medicinal chemists in the synthesis of quinoxaline scaffolds bearing a sulfonamide moiety to target a variety of diseases. The literature survey cited in this article highlighted and revealed that quinoxaline sulfonamide derivatives show a wide array of biological activities, such as antimicrobial, anti-convulsant, anti-inflammatory, anti-leishmania, anti-tumor and anticancer. Ecofriendly and economical procedures for the synthesis of quinoxaline sulfonamide derivatives were also reported. The structure-based activity findings will be helpful for further modifications on the quinoxaline sulfonamide derivatives. In order to develop future potent therapeutic agents.

Author Contributions: Conceptualization: A.I.; resources: S.H., F.B., H.R., R.Z.; writing—original draft preparation: A.I., S.A.; writing—review and editing: K.K.-M., M.M.; All authors have read and agreed to the published version of the manuscript. Funding: Not applicable. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Data sharing not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References 1. Seitz, L.E.; Suling, W.J.; Reynolds, R.C. Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. J. Med. Chem. 2002, 45, 5604–5606. [CrossRef][PubMed] 2. Brown, D.J.; Taylor, E.C.; Ellman, J.A. The Chemistry of Heterocyclic Compounds; Wiley: Hoboken, NJ, USA, 2004. 3. Saiﬁna, D.F.; Mamedov, V.A. New and modiﬁed classical methods for the synthesis of quinoxalines. Russ. Chem. Rev. 2010, 79, 351–370. [CrossRef] 4. Patidar, A.K.; Jeyakanda, M.; Mobiya, A.K.; Selvam, G. Exploring potential of quinoxaline moiety. Int. J. Pharm. Tech. Res. 2011, 3, 386–392. 5. Tariq, S.; Somakala, K.; Amir, M. Quinoxaline: An insight into the recent pharmacological advances. Eur. J. Med. Chem. 2017, 143, 542–557. [CrossRef][PubMed] 6. Pinheiro, C.A.; Nogueira, M.C.T.; de Souza, M.V.N. Quinoxaline Nucleus: A promising scaffold in anti-cancer drug discovery. Anticancer. Agents Med. Chem. 2016, 16, 1339–1352. [CrossRef][PubMed] Appl. Sci. 2021, 11, 5702 20 of 24

7. Amin, M.K.; Ismail, F.M.M.; Noaman, E.; Soliman, D.H.; Ammar, Y.A. New quinoxaline 1,4-di-N-oxides. Part 1: Hypoxia-selective cytotoxins and anticancer agents derived from quinoxaline 1,4-di-N-oxides. Bioorg. Med. Chem. 2006, 14, 6917–6923. [CrossRef] 8. Kotb, R.; Anwar, A.M.; Soliman, S.M.; Salama, A.M. Synthesis and reactions of some novel quinoxalines for anticancer evaluation. Phosphorus Sulfur 2007, 182, 1119–1130. [CrossRef] 9. Lindsley, C.W.; Zhao, Z.; Leister, W.H.; Robinson, R.G.; Barnett, S.F.; Defeo-Jones, D.; Jones, R.E.; Hartman, G.D.; Huff, J.R.; Huber, H.E.; Duggan, M.E. Allosteric Akt (PKB) inhibitors: Discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 761–764. [CrossRef] 10. Carta, A.; Loriga, M.; Piras, S.; Paglietti, G.; La Colla, P.; Busonera, B.; Collu, G.; Loddo, R. Synthesis of variously substituted 3-phenoxymethyl quinoxalin-2-ones and quinoxalines capable to potentiate in vitro the antiproliferative activity of anticancer drugs in multi-drug resistant cell lines. Med. Chem. 2006, 2, 113–122. 11. Khan, S.A.; Mullick, P.; Pandit, S.; Kaushik, D. Synthesis of hydrazones derivatives of quinoxalinone-prospective antimicrobial and antiinflammatory agents. Acta Pol. Pharm. 2009, 66, 169–172. 12. Piras, S.; Loriga, M.; Paglietti, G. Quinoxaline chemistry. Part XVII. Methyl [4-(substituted 2-quinoxalinyloxy) phenyl] acetates and ethyl N-{[4-(substituted 2-quinoxalinyloxy) phenyl] acetyl} glutamates analogues of methotrexate: Synthesis and evaluation of in vitro anticancer activity. Farmaco 2004, 59, 185–194. [CrossRef][PubMed] 13. Bahekar, R.H.; Jain, M.R.; Gupta, A.A.; Goel, A.; Jadav, P.A.; Patel, D.N.; Prajapati, V.M.; Patel, P.R. Synthesis and antidiabetic activity of 3,6,7-trisubstituted-2-(1H-imidazol-2-ylsulfanyl)quinoxalines and quinoxalin-2-yl isothioureas. Arch. Pharm. 2007, 340, 359–366. [CrossRef][PubMed] 14. Shintre, S.A.; Ramjugernath, D.; Islam, M.; Mopuri, R.; Mocktar, C.; Koorbanally, N.A. Synthesis, in vitro antimicrobial, antioxidant, and antidiabetic activities of thiazolidine–quinoxaline derivatives with amino acid side chains. Med. Chem. Res. 2017, 26, 2141–2151. [CrossRef] 15. Kulkarni, N.V.; Revankar, V.K.; Kirasur, B.N.; Hugar, M.H. Transition metal complexes of thiosemicarbazones with quinoxaline hub: An emphasis on antidiabetic property. Med. Chem. Res. 2012, 21, 663. [CrossRef] 16. Yang, Y.; Zhang, S.; Wu, B.; Ma, M.; Mingming, M.; Xin, C.; Xiangyu, Q.; Minlan, H.; Saghir, H.; Chaojun, J.; Bing, M.; Changjin, Z. An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase. Chem. Med. Chem. 2012, 7, 823–835. [CrossRef] 17. Gupta, D.; Ghosh, N.N.; Chandra, R. Synthesis and pharmacological evaluation of substituted 5-[4-[2-(6, 7-dimethyl-1, 2, 3, 4-tetrahydro-2-oxo-4-quinoxalinyl) ethoxy] phenyl] methylene] thiazolidine-2, 4-dione derivatives as potent euglycemic and hypolipidemic agents. Bioorg. Med. Chem. Lett. 2005, 15, 1019–1022. [CrossRef] 18. Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. Synthesis of new quinoxaline-2-carboxylate 1,4-dioxide derivatives as anti- Mycobacterium tuberculosis agents. J. Med. Chem. 2005, 48, 2019–2025. [CrossRef] 19. Ancizu, S.; Moreno, E.; Solano, B.; Villar, R.; Asunción, B.; Torres, E.; Pérez-Silanes, S.; Aldana, I.; Monge, A. New 3- methylquinoxaline-2-carboxamide 1, 4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents. Biorg. Med. Chem. 2010, 18, 2713–2719. [CrossRef] 20. El-Atawy, A.M.; Ezzat, A.; Hamed, E.A.; Alhadi, M.; Omar, A.Z. Synthesis and antimicrobial activity of some new substituted quinoxalines. Molecules 2019, 24, 4198. [CrossRef] 21. Dharmchand, P.S.; Sanjay, K.D.; Hashim, R.S.; Singhal, G.R. Synthesis and antimicrobial activity of some new quinoxaline derivatives. Pharmaceuticals 2010, 3, 2416–2425. 22. Kim, Y.B.; Kim, Y.H.; Park, J.Y.; Kim, S.K. Synthesis and biological activity of new quinoxaline antibiotics of echinomycin analogueS. Bioorg. Med. Chem. Lett. 2004, 14, 541–544. [CrossRef][PubMed] 23. Sarges, R.; Howard, H.R.; Browne, R.G.; Lebel, L.A.; Seymour, P.A.; Koe, B.K. 4-Amino [1, 2, 4] triazolo [4, 3-a] quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants. J. Med. Chem. 1990, 33, 2240–2254. [CrossRef][PubMed] 24. Sakata, G.; Makino, K.; Kurasawa, Y. Recent progress in the quinoxaline chemistry. Synthesis and biological activity. Heterocycles 1988, 27, 2481–2515. 25. Abu-hashem, A.A.; Gouda, M.A.; Badria, F.A. Synthesis of some new pyrimido[2:2,3]thiazolo[4,5-b]quinoxaline derivatives as anti-inflammatory and analgesic agents. Eur. J. Med. Chem. 2010, 45, 1976–1981. [CrossRef] 26. Wagle, S.; Adhikari, V.A.; Kumari, S.N. Synthesis of some new 2-(3-methyl-7-substituted-2-oxoquinoxalinyl)-5-(aryl)-1,3,4- oxadiazoles as potential non-steroidal anti-inflammatory and analgesic agents. Indian J. Chem. 2008, 47, 439–448. 27. Ismail, M.M.; Ammar, Y.A.; Ibrahim, M.K.; El-Zahaby, H.S.A.; Mahmoud, S.S. Synthesis and pharmacological evaluation of novel quinoxalines as potential nonulcerogenic anti-inflammatory and analgesic agents. Arzneimittelforschung 2005, 55, 738–743. [CrossRef] 28. Dhansay, D.; Kartik, T.N.; Vinay, S.V.; Nagori, K.; Badwaik, H.; Nair, N.; Tripathi, D.K.; Mishra, A. Synthesis and molecular docking study of novel hybrids of 1,3,4-oxadiazoles and quinoxaline as a potential analgesic and anti-inflammatory agents. J. Heterocycl. Chem. 2018, 55, 2901–2910. 29. Gayathri, R.; Suresh, S.; Thirumurthy, R. Synthesis, characterization and pharmacological evaluation of some potent 2-(substituted phenylimino) quinoxaline-3-one for their analgesic activity. J. Chem. Pharm. 2015, 7, 961–966. 30. Alswah, M.; Adel, G.; El-Morsy, A.; El-Gamal, K. Synthesis and biological evaluation of some [1,2,4]triazolo[4,3-a]quinoxaline derivatives as novel anticonvulsant agents. ISRN Org. Chem. 2013, 587054. [CrossRef] Appl. Sci. 2021, 11, 5702 21 of 24

31. Møllerud, S.; Hansen, R.B.; Pallesen, J.; Temperini, P.; Pasini, D.; Bornholt, J.; Nielsen, B.; Mamedova, E.; Chalupnik, P.; Paternain, A.V.; et al. N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4- dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology. ACS Chem. Neurosci. 2019, 10, 4685–4695. 32. Burguete, A.; Pontiki, E.; Hadjipavlou-Litina, D.; Ancizu, S.; Villar, R.; Solano, B.; Moreno, E.; Torres, E.; Pérez, S.; Aldana, I.; Monge, A. Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents. Chem Biol. Drug Des. 2011, 77, 255–267. [CrossRef][PubMed] 33. El-Sabbagh, O.I.; El-Sadek, M.E.; Lashine, S.M.; Yassin, S.H.; El-Nabtity, S.M. Synthesis of new 2 (1H)-quinoxalinone derivatives for antimicrobial and antiinflammatory evaluation. Med. Chem. Res. 2009, 18, 782. [CrossRef] 34. Qing-K, S.; Guo, H.G.; Gao, L.; Mei, J.; Li-Hua Cao, C.; Zhe-Shan, Q. Discovery and evaluation of novel synthetic 5-alkyl-4-oxo- 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents. J. Enzyme Inhib. Med. Chem. 2020, 35, 85–95. 35. Tariq, S.; Ozair, A.; Mohd, A. Synthesis, anti-inflammatory, p38α MAP kinase inhibitory activities and molecular docking studies of quinoxaline derivatives containing triazole moiety. Bioorg. Chem. 2018, 76, 343–358. [CrossRef][PubMed] 36. Manzano, M.T.; Guirado, A.; Martínez-Esparza, M.; Gálvez, J.; García-Peñarrubia, P.; Ruiz-Alcaraz, A.J. 1Quinoxalines potential to target pathologies. Curr. Med. Chem. 2015, 22, 3075–3108. [CrossRef] 37. El-Zahabi, H.S.A. Synthesis, Characterization, and biological evaluation of some novel quinoxaline derivatives as antiviral agents. Arch. Pharm. Chem. Life Sci. 2017, 350, 1–13. [CrossRef] 38. Wilhelmsson, L.M.; Kingi, N.; Bergman, J. Interactions of Antiviral Indolo[2,3-b]quinoxaline Derivatives with DNA. J. Med. Chem. 2008, 51, 7744–7750. [CrossRef] 39. Rongjiao, X.; Tao, G.; Mei, C.; Shijun, S.; He, J.; Xu, T.; Jianga, S.; Xue, W. Synthesis, antiviral and antibacterial activities and action mechanism of penta-1,4-dien-3-one oxime ether derivatives containing a quinoxaline moiety. New J. Chem. 2019, 43, 16461–16467. 40. Fonseca, T.; Gigante, B.; Marques, M.M.; Gilchrist, T.L.; de Clercq, E. Synthesis and antiviral evaluation of benzimidazoles, quinoxalines and indoles from dehydroabietic acid. Bioorg. Med. Chem. 2004, 12, 103–112. [CrossRef][PubMed] 41. Ali, I.; Al-Masoudi, I.; Hassan, H.G.; Al-Masoudi, N. Synthesis and anti-HIV activity of new homo acyclic nucleosides, 1-(pent-4- enyl) quinoxalin-2-ones and 2-(pent-4-enyloxy) quinoxalines. Chem. Hetrocycl. Compd. 2007, 43, 1052–1059. [CrossRef] 42. Shibinskaya, M.O.; Lyakhov, S.A.; Mazepa, A.V.; Andronati, S.A.; Turov, A.V.; Zholobak, N.M.; Spivak, N.Y. Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines. Eur. J. Med. Chem. 2010, 45, 1237–1243. [CrossRef] 43. Loughran, M.H.; Ziying, H.; Wrobel, E.J.; Sarah, D.E.; Gordon, R.; Bruce, F.D.; Ronald, H.N.; Allen, R.B. Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress. Bioorg Med. Chem. Lett. 2016, 26, 3429–3435. [CrossRef][PubMed] 44. Zhang, M.; Zhi-Cheng, D.; Shao-Song, Q.; Jun-Yan, L.; Yu, X.; Ai-Min, L.; Hai-Liang, Z.; Jian-Xin, W.; Yong-Hao, Y. Design, synthesis, antifungal, and antioxidant activities of (E)-6-((2 phenylhydrazono) methyl) quinoxaline derivatives. J. Agric. Food Chem. 2014, 62, 9637–9643. [CrossRef] 45. Waring, M.J.; Taibi, B.H.; Kotchevar, A.T.; Ramdani, A.; Touzani, R.; Elkadiri, S.; Hakkou, A.; Bouakka, M.; Ellis, T. 2,3- Bifunctionalized quinoxalines: Synthesis, DNA interactions and evaluation of anticancer, anti-tuberculosis and antifungal activity. Molecules 2002, 7, 641–656. [CrossRef] 46. El-Gazzar, M.; Nafie, N.H.; Nocentini, A.; Ghorab, M.M.; Heiba, H.I. Supuran, C.T.; Carbonic anhydrase inhibition with a series of novel benzenesulfonamide-triazole conjugates. J. Enzyme Inhib. Med. Chem. 2018, 33, 1565–1574. [CrossRef][PubMed] 47. De Lacorte Singulani, J.; Galeane, M.C.; Ramos, M.D.; Gomes, P.C.; Dos Santos, C.T.; de Souza, B.M.; Palma, M.S.; Fusco Almeida, A.M.; Mendes Giannini, M.J.S. Antifungal activity, toxicity and membranolytic action of a mastoparan analogue peptide. Front. Cell. Infect. Microbiol. 2019, 9, 1–11. 48. Shaik, M.B.; Paala, K.; Shaik, T.B.; Chintha, V.; Shafi, S.S.; Naga Raju, C. Synthesis, characterization and antimicrobial activity of boron, silicon and selenium substituted quinoxaline derivatives. Pharma Innov. J. 2019, 8, 627–632. 49. Soliman, D.H. Synthesis, characterization, anti-bacterial and anti-fungal activities of new quinoxaline 1,4-di-N-Oxide derivatives. IJOC 2013, 3, 65–72. [CrossRef] 50. Shekhar, C.A.; Rao, S.P.; Narsaiah, B.; Allanki, A.D.; Sijwali, P.S. Emergence of pyrido quinoxalines as new family of antimalarial agents. Eur. J. Med. Chem. 2014, 77, 280–287. [CrossRef] 51. Rangisetty, J.B.; Gupta, C.N.; Prasad, A.L.; Srinivas, P.; Sridhar, N.; Parimoo, P.; Veeranjaneyulu, A. Synthesis of new arylamino- quinoxalines and their antimalarial activity in mice. J. Pharm. Pharmacol. 2001, 53, 1409–1413. [CrossRef] 52. Bonilla-Ramírez, L.; Galiano, S.; Quiliano, M.; Aldana, I.; Pabón, A. Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of plasmodium induce their effect by the production of reactive oxygen species. Malar. J. 2019, 18, 201. [CrossRef] 53. Guillon, J.; Cohen, A.; Gueddouda, N.M.; Das, R.N.; Moreau, S.; Ronga, L.; Savrimoutou, S.; Basmaciyan, L.; Monnier, A.; Monget, M.; Rubio, S.; Garnerin, T.; Azas, N.; Mergny, J.L.; Mullié, C.; Sonnet, P. Design, synthesis and antimalarial activity of novel bis{N- [(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives. J. Enzyme Inhib. Med. Chem. 2017, 32, 547–563. [CrossRef][PubMed] 54. Guillon, J.; Moreau, S.; Mouray, E.; Sinou, V.; Forfar, I.; Fabre, S.B.; Desplat, V.; Millet, P.; Parzy, D.; Jarry, C.; et al. New ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: Synthesis and in vitro antimalarial activity. Bioorg. Med. Chem. 2008, 16, 9133–9144. [CrossRef] Appl. Sci. 2021, 11, 5702 22 of 24

55. Guillon, J.; Grellier, P.; Labaied, M.; Sonnet, P.; Léger, J.M.; Déprez-Poulain, R.; Forfar-Bares, I.; Dallemagne, P.; Lemaître, N.; Péhourcq, F.; Rochette, J.; Sergheraert, C.; Jarry, C. Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, Bispyrrolo[1,2-a]quinoxalines, Bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and Bispyrrolo[1,2- a]thieno[3,2-e]pyrazines. J. Med. Chem. 2004, 47, 1997–2009. [CrossRef][PubMed] 56. Parhi, A.K.; Zhang, Y.; Saionz, K.W.; Pradhan, P.; Kaul, M.; Trivedi, K.; Pilch, D.S.; LaVoie, E.J. Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines. Bioorg. Med. Chem. Lett. 2013, 234, 4968–4974. [CrossRef][PubMed] 57. Aravind, K.; Ganesh, A.; Ashok, D. Microwave assisted synthesis, characterization and antibacterial activity of quinoxaline derivatives. J. Chem. Pharm. Res. 2013, 5, 48–52. 58. Abbas, H.A.S.; Al-Marhabi, A.R.; Ammar, Y.A. Design, synthesis and biological evaluation of 2, 3-disubstituted and fused quinoxalines as potential anticancer and antimicrobial agents. Acta Pol. Pharm. 2017, 74, 445–458. 59. Bayoumi, A.; Ghiaty, A.H.; Abd El-Gilil, S.M.; Husseiny, E.; Ebrahim, M.A. Exploration of quinoxaline derivatives as antimicrobial and anticancer agents. J. Heterocyclic. Chem. 2019, 4, 1–21. [CrossRef] 60. Al-Marhabi, A.R.; Abbas, H.-A.S.; Ammar, Y.A. Synthesis, characterization and biological evaluation of some quinoxaline derivatives: A promising and potent new class of antitumor and antimicrobial agents. Molecules 2015, 20, 19805–19822. [CrossRef] 61. Afrough, T.; Bakavoli, M.; Eshghi, H.; Beyzaei, H.; Manesh, M.-M. Synthesis, characterization and in vitro antibacterial evaluation of novel 4-(1-(Pyrimidin-4-yl)Ethyl)-12H-Pyrimido[40,50:5,6] [1,4]Thiazino[2,3-b] quinoxaline derivatives. Polycycl. Aromat. Comp. 2019, 1–11. [CrossRef] 62. Vieira, M.; Pinheiro, C.; Fernandes, R.; Noronha, J.P.; Prudencio, C. Antimicrobial activity of quinoxaline 1,4-dioxide with 2- and 3-substituted derivatives. Microbiol. Res. 2014, 169, 287–293. [CrossRef][PubMed] 63. Nicola, O.; O’Neill, A.J. Revisiting unexploited antibiotics in search of new antibacterial drug candidates: The case of MSD-819 (6-chloro-2-quinoxalinecarboxylic acid 1,4-dioxide). J. Antibiot. 2017, 7, 317–319. 64. Settypalli, T.; Chunduri, V.R.; Maddineni, A.K.; Begari, N.; Allagadda, R.; Kotha, P.; Chippada, A.R. Design, synthesis, in silico docking studies and biological evaluation of novel quinoxaline-hydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase inhibitors and antioxidants. New. J. Chem. 2019, 43, 15435–15452. [CrossRef] 65. Umesh, T.P.; Bhautik, T.B.; Dipak, R.K. A green protocol for the synthesis of quinoxaline derivatives catalyzed by polymer supported sulphanilic acid. Arab. J. Chem. 2017, 10, S2902–S2907. 66. Vijay, K.; Karakavalasa, P.; Vasanthi, R. Synthesis, characterization and pharmacological evaluation of some novel quinoxaline derived chalcones. Der. Pharma. Chemica. 2013, 5, 301–307. 67. Elkaeed, E.; Ghiaty, A.; El-Morsy, A.; El-Gamal, K.; Sakr, H. Synthesis and Biological Evaluation of Some quinoxaline-2-one Derivatives as Novel Anticonvulsant Agents. Chem. Sci. Rev. Lett. 2014, 3, 1375–1387. 68. Hui, X.; Desrivot, J.; Bories, C.; Loiseau, P.M.; Franck, X.; Hocquemiller, R.; Figadere, B. Synthesis and antiprotozoal activity of some new synthetic substituted quinoxalines. Bioorg. Med. Chem. Lett. 2006, 16, 815–820. [CrossRef] 69. E-Chavez, J.J.; Merino, V.; Cervantes, M.-L.; Cruz, I.-R.; Guerrero, D.-Q.; Quintanar, A.-G. The use of iontophoresis in the administration of nicotine and new non-nicotine drugs through the skin for smoking cessation. Curr. Drug Discov. Technol. 2009, 6, 171–185. [CrossRef] 70. Rohde, B.H.; McLaughlin, M.A.; Chiou, L.Y. Existence and role of endogenous ocular Melatonin. J. Ocul. Pharmacol. Th. 1985, 1, 235–243. [CrossRef][PubMed] 71. Hugo, W.B.; Stretton, R.G. Action of quinacillin on staphylococcus aureus. Nature 1964, 202, 1217. [CrossRef][PubMed] 72. Carta, F.; Scozzafava, A.; Supuran, C.T. Sulfonamides: A patent review (2008–2012). Expert. Opin. Ther. Pat. 2012, 22, 747–758. [CrossRef] 73. Actor, P.; Chow, A.W.; Dutko, F.; McKinlay, M.A. "Chemotherapeutics", Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2005; p. 8. 74. Supuran, C.T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert. Opin. Drug. Discov. 2017, 12, 61–88. [CrossRef][PubMed] 75. Carta, F.; Supuran, C.T.; Scozzafava, A. Sulfonamides and their isosters as carbonic anhydrase inhibitors. Future Med. Chem. 2014, 6, 1149–1165. [CrossRef][PubMed] 76. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C.T. Anticancer and antiviral sulfonamides. Curr. Med. Chem. 2003, 10, 925–953. [CrossRef][PubMed] 77. Capasso, C.; Supuran, C.T. Sulfa and trimethoprim-like drugs–antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. J. Enzym. Inhib. Med. Chem. 2014, 29, 379–387. [CrossRef][PubMed] 78. Pareek, A.; Rani, P.; Kishore, D. A Short Review On: Sulphonamides. Int. J. Pharma. BioSci. 2013, 4, 812–820. 79. Khan, H.U.N.; Zaib, S.; Sultana, K.; Khan, I.; Soume, B.-M.; Nadeem, H.; Hassan, M.; Iqbal, J. Metal complexes of tosyl sulfonamides: Design, x-ray structure, biological activities and molecular docking studies. RSC. Adv. 2015, 5, 30125–30132. [CrossRef] 80. Hager, T. The Demon under the Microscope: From Battleﬁeld Hospitals to Nazi Labs, One Doctor’s Heroic Search for The World’s First Miracle Drug; Broadway Books: New York, NY, USA, 2006; ISBN 1-4000-8214-5. 81. Al-Mohammed, N.N.; Alias, Y.; Abdullah, Z.; Shakir, R.M.; Taha, E.M.; Hamid, A.A. Synthesis and antibacterial evaluation of some novel imidazole and benzimidazole sulfonamides. Molecules 2013, 18, 11978–11995. [CrossRef] 82. Alsughayer, A.; Elassar, A.A.Z.; Mustafa, S.; Sagheer, F. Synthesis, structure analysis and antibacterial activity of new potent sulfonamide derivatives. J. Biomater. Nanobiotechnol. 2011, 2, 143–148. [CrossRef] Appl. Sci. 2021, 11, 5702 23 of 24

83. Gorantla, V.; Gundlac, R.; Jadavc, S.S.; Anugu, S.R.; Chimakurthy, J.; Nidasanametla, S.K.; Korupolu, R. Molecular hybrid design, synthesis and biological evaluation of nphenyl sulfonamide linked n-acyl hydrazone derivatives functioning as cox-2 inhibitors: New anti-inflammatory, anti-oxidant and anti-bacterial agents. New J. Chem. 2017, 41, 13516–13532. [CrossRef] 84. Abdel-Aziz, A.A.M.; Angeli, A.; El-Azab, A.S.; Hammouda, M.E.A.; El-Sherbeny, M.A.; Supuran, C.T. Synthesis and anti- inflammatory activity of sulfonamides and carboxylates incorporating trimellitimides: Dual cyclooxygenase/carbonic anhydrase inhibitory actions. Bioorg. Chem. 2019, 84, 260–268. [CrossRef][PubMed] 85. Capasso, C.; Supuran, C.T. An overview of the alpha-, beta-and gamma-carbonic anhydrases from Bacteria: Can bacterial carbonic anhydrases shed new light on evolution of bacteria. J. Enzym Inhib. Med. Chem. 2015, 30, 325–332. [CrossRef][PubMed] 86. Isik, K.; Kocak, O.F. Antimicrobial activity screening of some sulfonamide derivatives on some nocardia species and isolates. Microbiol. Res. 2009, 164, 49–58. [CrossRef] 87. Chohan, Z.H.; Rauf, A.; Naseer, M.M.; Somra, M.A.; Supuran, C.T. Antibacterial, antifungal and cytotoxic properties of some sulfonamide-derived chromones. J. Enzyme Inhib. Med. Chem. 2006, 21, 173–177. [CrossRef][PubMed] 88. Chibale, K.; Haupt, H.; Kendrick, H.; Yardley, V.; Saravanamuthu, A.; Fairlamb, A.H.; Croft, S.L. Antiprotozoal and cytotoxicity evaluation of sulfonamide and urea analogues of quinacrine. Bioorg. Med. Chem. Lett. 2001, 11, 2655–2657. [CrossRef] 89. Supuran, C.T.; Casini, A.; Scozzafava, A. Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents. Med. Res. Rev. 2003, 23, 535–558. [CrossRef] 90. Andrews, K.T.; Fisher, G.M.; Sumanadasa, S.D.M.; Adams, T.-S.; Moeker, J.; Lopez, M.; S-Poulsen, A. Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment. Bioorg. Med. Chem. Lett. 2013, 23, 6114–6117. [CrossRef] 91. Puccetti, L.; Fasolis, G.; Vullo, D.; Chohan, Z.H.; Scozzafava, A.; Supuran, C.T. Carbonic Anhydrase Inhibitors. Inhibition of Cytosolic/Tumor-Associated Carbonic Anhy-drase Isozymes I, II, IX, and XII with Schiff Bases Incorpo-rating Chromone and Aromatic Sulfonamide Moieties, and Their Zinc Complexes. Bioorg. Med. Chem. Lett. 2005, 15, 3096–3101. [CrossRef] 92. Supuran, C.T. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites 2017, 7, 48. [CrossRef] 93. Abbate, F.; Winum, J.Y.; Potter, B.V.; Casini, A.; Montero, L.-J.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase. Bioorg. Med. Chem. Lett. 2004, 14, 231–234. [CrossRef] 94. Garaj, V.; Puccetti, L.; Fasolis, G.; Winum, Y.J.; Montero, L.J.; Scozzafava, A.; Vullo, D.; Innocenti, A.; Supuran, C.T. Carbonic Anhydrase Inhibitors: Synthesis and In-hibition of Cytosolic/Tumor-Associated Carbonic Anhydrase Isozymes I, Ii, and Ix with sulfonamides incorporating 1,2,4-Triazine Moieties. Bioorg. Med. Chem. Lett. 2004, 14, 5427–5433. [CrossRef] 95. Supuran, C.T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov. 2008, 7, 168–181. [CrossRef] 96. Neri, D.; Supuran, C.T. Interfering with pH regulation in tumours as a therapeutic strategy. Nat. Rev. Drug Discov. 2011, 10, 767–777. [CrossRef] 97. Masini, E.; Carta, F.; Scozzafava, A.; Supuran, C.T. Antiglaucoma carbonic anhydrase inhibitors: A patent review. Expert Opin. Ther. Pat. 2013, 23, 705–716. [CrossRef][PubMed] 98. Monti, S.M.; Supuran, C.T.; Simone, G.D. Anticancer carbonic anhydrase inhibitors: A patent review (2008–2013). Expert Opin. Ther. Pat. 2013, 23, 737–749. [CrossRef][PubMed] 99. Supuran, C.T. Structure-based drug discovery of carbonic anhydrase inhibitors. J. Enzym Inhib. Med. Chem. 2012, 27, 759–772. [CrossRef][PubMed] 100. Berredjem, H.; Reggami, Y.; Benlaifa, M.; Berredjem, M.; Bouzerna, N. Antidiabetic and hypolipidemic potential of 3, 4- dihydroisoquinolin-2(1H)- sulfonamide in alloxan induced diabetic rats. Int. J. Pharmacol. 2015, 11, 226–235. [CrossRef] 101. Masereel, B.; Thiry, A.; Dogne, J.M.; Supuran, C.T. Anticonvulsant sulfonamides/sulfamates/sulfamides with carbonic anhydrase inhibitory activity: Drug design and mechanism of action. Curr. Pharm. Des. 2008, 14, 661–671. [CrossRef] 102. Scozzafava, A.; Supuran, C.T.; Carta, F. Antiobesity carbonic anhydrase inhibitors: A literature and patent review. Expert Opin. Ther. Pat. 2013, 23, 725–735. [CrossRef] 103. Supuran, C.T. How many carbonic anhydrase inhibition mechanisms exist. J. Enzym Inhib. Med. Chem. 2016, 31, 345–360. [CrossRef] 104. Carta, F.; Supuran, C.T. Diuretics with carbonic anhydrase inhibitory action: A patent and literature review (2005–2013). Expert Opin. Ther. Pat. 2013, 23, 681–691. [CrossRef] 105. Boyd, A.E. Sulfonylurea receptors, ion channels and fruit flies. Diabetes 1988, 37, 847–850. [CrossRef] 106. Carta, F.; Mannelli, L.D.C.; Pinard, M.; Ghelardini, C.; Scozzafava, A.; McKenna, R.; Supuran, C.T. A class of sulfonamide carbonic anhydrase inhibitors with neuropathic pain modulating effects. Bioorg. Med. Chem. 2015, 23, 1828–1840. [CrossRef] 107. Scozzafava, A.; Supuran, C.T. Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxam- ates with mmp inhibitory properties act as efficient inhibitors of ca isozymes i, ii, and iv, and N-hydroxysulfonamides, Inhibit Both These Zinc. Enzymes J. Med. Chem. 2000, 43, 3677–3687. [CrossRef][PubMed] 108. Scozzafava, A.; Supuran, C.T. Protease Inhibitors: Synthesis of potent bacterial collagenase and matrix metalloproteinase inhibitors incorporating n-4-nitrobenzylsulfonylglycine hydroxamate moieties. J. Med. Chem. 2000, 43, 1858–1865. [CrossRef] [PubMed] 109. Ajeet, A.; Mishra, K.; Kumar, A. Recent advances in development of sulfonamide derivatives and their pharmacological effects- A Review. Am. J. Pharmacol. Sci. 2015, 3, 18–24. Appl. Sci. 2021, 11, 5702 24 of 24

110. Gao, H.; Yamasaki, E.F.; Chan, K.K.; Shen, L.L.; Snapka, R.M. Chloroquinoxaline Sulfonamide (NSC 339004) is a Topoisomerase IIα/β Poison. Cancer Res. 2000, 60, 5937–5940. [PubMed] 111. Kornberg, B.E.; Nikam, S.S. Sulfonamide Derivatives of Substituted Quinoxaline 2,3-Diones as Glutamate Receptor Antagonsts. U.S. Patent 6,096,744, 1 August 2000. 112. Gaillard, P.; Quattropani, A.; Pomel, V.; Rueckle, T.; Klicic, J.; Church, D. Pyrazine Derivatives and Use as pi3k Inhibitors. U.S. Patent 8,877,757, 4 November 2014. 113. Allison, B.D.; Hack, M.D.; Rabinowitz, M.H.; Rosen, M.D. Quinoxaline Compounds. U.S. Patent 7,304,051 B2, 4 December 2007. 114. Pascale, G.; Vincent, P.; J-Isabelle, E.; Jerome, D.; Jasna, K.; Cyril, M. Quinoxaline Compounds and Use Thereof. WO 2008/101979 Al, 28 August 2008. 115. Deng, X.; Liang, J.T.; Mani, N.; Pandit, C.R. Preparation of Quinoxaline Compounds. U.S. Patent 2008/0103300 A, 1 May 2008. 116. Bajjalieh, W.; Bannen, L.C.; Brown, S.D.; Mac, M.B.; Marlowe, C.K.; Nuss, J.M.; Tesfai, Z.; Wang, Y.; Xu, W. Phosphatidylinositol, 3-Kinase Inhibitors and Methods of Their Use. U.S. Patent 7,989,622 B2011, 2 August 2011. 117. Aftab, D.T.; Decillis, A. Phosphatidylinositol 3-Kinase Inhibitors and Methods of Their Use. WO 2012/065057 A3, 18 May 2012. 118. Natarajan, A.; Chen, Q.; Bryant, V.C.; Radhakrishnan, P.; Rajule, R.; Chaturvedi, N. Quinoxaline Compounds and Uses Thereof. WO 2012/071414 A2, 31 May 2012. 119. Harper, S.; Summa, V.; Liverton, N.J.; McCauley, J.A. Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors. U.S. Patent 7,973,040 B2, 5 July 2011. 120. Zhu, Y.-L.; Qian, X. Benzenesulfonamide Derivatives of Quinoxaline, Pharmaceutical Compositions Thereof, and Their Use in Methods for Treating Cancer. U.S. Patent 9.295,671 B2, 29 March 2016. 121. Boezio, C.; Boezio, A.; Bregman, H.; Coats, J.R.; Copeland, K.W.; Dimauro, E.F.; Dineen, T.; Gao, H.; La, D.; Marx, I.E.; Nguyen, H.N.; Peterson, E.A.; Weiss, M. Dhydrobenzoxazine and Tetrahydroquinoxaline Sodium Channel Inhibitors. U.S. Patent 9,346,798 B2016, 28 August 2013. 122. Zhu, L.-Y.; Qian, X. Benzene Sulfonamide Derivatives of Quinoxaline, Pharmaceutical Compositions Thereof, and Their Use in Methods for Treating Cancer. U.S. Patent 9,572,808 B2, 21 February 2017. 123. Klein, M.; Emde, U.; Buchstaller, H.P.; Esdar, C.; Poeschke, O. Quinoxaline Derivatives. U.S. Patent 2013/0217670 A1, 22 August 2013. 124. Danig, P.; Dominique, S. Method for Preparing Substituted n-(3-Amino-Quinoxalin-2-yl)-Sulfonamides and Their Intermediates n-(3-Chloro-Quinoxalin-2-yl)Sulfonamides. WO 2012 /052420 Al, 26 April 2012. 125. Boezio, C.; Boezio, A.; Bregman, H.; Chakka, N.; Coats, J.R.; Copeland, K.W.; Dimauro, E.F.; Dineen, T.; Gao, H.; La, D.; Marx, I.E.; Nguyen, H.N.; Peterson, E.A.; Weiss, M. Tetrahydroquinoxaline Dihydrobenzoxazine and Sodium Channel Inhibitors. WO 2013/122897 Al, 22 August 2013. 126. Gigstad, K.M.; Cardin, D.P.; Hirayama, T.; Hirose, M.; Hu, Y.; Kakei, H.; Lee, H.M.; Motoyaji, T.; NII, N.; Shi, Z.; Vyskocil, S.; Watanabe, H. Quinoxaline Compounds and Uses Thereof. U.S. Patent 10,144,742 B2018, 4 December 2018. 127. Husain, A.; Madhesia, D.; Rashid, M.; Ahmad, A.; Khan, S.A. Synthesis and in vivo diuretic activity of some new benzothiazole sulfonamides containing quinoxaline ring system. J. Enzyme Inhib. Med. Chem. 2016, 31, 1682–1689. [CrossRef] 128. Alavi, S.; Mosslemin, M.H.; Mohebat, R.; Massah, A.R. Green synthesis of novel quinoxaline sulfonamides with antibacterial activity. Res. Chem. Intermed. 2017, 43, 4549–4559. [CrossRef] 129. Ingle, R.; Wadher, S. Synthetic development of antimicrobial novel quinoxaline derivatives. Int. J. Pharm. Chem. 2013, 3, 34–38. [CrossRef] 130. Talari, S.; Karunakaram, D.R.G.; Jupudi, S.; Udhayavani, S. Synthesis of 9-bromo-n-substituted- 6h- indolo [2, 3-b] quinoxaline-3- sulfonamide derivatives containing quinoxaline moiety as prospective antimicrobial agents. Int. J. Pharm. 2013, 3, 145–151. 131. Sharaf El-Din, N. Synthesis of some sulfonamide derivatives with potential antibacterial activity. Chem. Heterocycl. Compd. 2000, 36, 523–528. 132. Potey, C.L.; Kosalge, B.S.; Hadke, A.M. Synthesis and Antimicrobial Activity of Quinoxaline Sulfonamide. IJOART 2013, 2, 126–134. 133. Olayiwola, G.; Obafemi, C.A.; Taiwo, F.O. Synthesis and neuropharmacological activity of some quinoxalinone derivatives. Afr. J. Biotechnol. 2007, 6, 777–786. 134. Barea, C.; Pabon, A.; Castillo, D.; Zimic, M.; Quiliano, M.; Galiano, S.; Pérez-Silanes, S.; Monge, A.; Deharo, E.; Aldana, I. New Salicylamide And Sulfonamide Derivatives of Quinoxaline 1,4-Di-N-Oxide with Antileishmanial And Antimalarial Activities. Bioorg Med. Chem Lett. 2011, 21, 4498–4502. [CrossRef][PubMed] 135. Farrag, A.A.; Ammar, A.Y.; El-Sehemi, G.A.; Thabet, H.K.; Hassan, N.A.-A.; Samy, A.H. Synthesis And Pharmacological Screening of Novel Sulfamoylphenyl Carbamoyl Quinoxaline Derivatives As Anti-Inﬂammatory, Analgesic And Antitumour Agents. J. Chem. Res. 2011, 35, 163–166. [CrossRef] 136. Ingle, R.; Marathe, R.; Magar, D.; Patel, H.M.; Surana, S.J. Sulphonamido-quinoxalines: Search for anticancer agent. Eur. J. Med. Chem. 2013, 65, 168–186. [CrossRef] 137. Ingle, G.R.; Marathe, P.R. Sulfonamido Quinoxalines—Search for Anti-Inflammatory Agents. Int. J. Pharm. Res. Allied Sci. 2012, 4, 46–51.