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Recent Updates on the Synthesis of Bioactive Quinoxaline-Containing Sulfonamides

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Recent Updates on the Synthesis of Bioactive Quinoxaline-Containing Sulfonamides applied sciences 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 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
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