Novel Synthetic Routes to Prepare Biologically Active Quinoxalines and Their Derivatives: a Synthetic Review 1

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Review molecules Novel Synthetic Routes to Prepare Biologically ActiveReview Quinoxalines and Their Derivatives: A SyntheticNovel Review Synthetic for Routes the Last to Two Prepare Decades Biologically Active Quinoxalines and Their Derivatives: A Synthetic Review for Hena Khatoonthe Last 1,* and TwoEmilia Abdulmalek Decades 1,2,* 1 Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor 1, 1,2, DarulHena Ehsan, Khatoon Malaysia * and Emilia Abdulmalek * 2 Integrated Chemical BioPhysics Research, Faculty of Science, University Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia1 Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, * Correspondence: [email protected] (H.K.); Darul [email protected] Ehsan, Malaysia (E.A.) 2 Integrated Chemical BioPhysics Research, Faculty of Science, University Putra Malaysia, 43400 UPM Serdang, Received: 19 November 2020; Accepted: 14 SelangorDecember Darul 2020; Ehsan, Published: Malaysia 18 December 2020 * Correspondence: [email protected] (H.K.); [email protected] (E.A.) Abstract: Quinoxalines, a class of N-heterocyclic compounds, are important biological agents, and a significant amount of research activityAbstract: hasQuinoxalines, been directed a class towards of N-heterocyclic this class. compounds, They have are several important biological agents, and a prominent pharmacological effectssigniﬁcant like antifungal, amount of researchantibacterial, activity antiviral, has been directed and antimicrobial. towards this class. They have several promi- Quinoxaline derivatives have diversenent therapeutic pharmacological uses effectsand have like antifungal,become the antibacterial, crucial component antiviral, andin antimicrobial. Quinoxaline drugs used to treat cancerous cells,derivatives AIDS, plant have diverseviruses, therapeutic schizophrenia, uses and certifying have become them the a crucial great component in drugs used to future in medicinal chemistry. Due totreat the cancerous current pandemic cells, AIDS, situation plant viruses, caused schizophrenia, by SARS-COVID certifying 19, them it a great future in medicinal has become essential to synthesize drugschemistry. to combat Due to the deadly current pathogens pandemic situation(bacteria, caused fungi, by viruses) SARS-COVID for 19, it has become essential now and near future. Since quinoxalinesto synthesize is an essent drugsial to moiety combat to deadly treat infectious pathogens diseases, (bacteria, numerous fungi, viruses) for now and near future. synthetic routes have been developedSince by quinoxalines researchers, is anwith essential a prime moiety focus to treaton green infectious chemistry diseases, and numerous synthetic routes have cost-effective methods. This reviewbeen paper developed highlights by researchers, the various with asynthetic prime focus routes on green to chemistryprepare and cost-effective methods. quinoxaline and its derivatives, coveringThis review the literat paperure highlights for the last the two various decades. synthetic A total routes of to 31 prepare schemes quinoxaline and its derivatives, have been explained using the greencovering chemistry the literature approach, for thecost-effective last two decades. methods, A total and of 31quinoxaline schemes have been explained using the derivatives’ therapeutic uses. green chemistry approach, cost-effective methods, and quinoxaline derivatives’ therapeutic uses. Keywords: quinoxaline; SAR; biological applications; green chemistry Keywords:Citation: quinoxaline;Khatoon, H.; Abdulmalek, SAR; biological applications; green chemistry E. Novel Synthetic Routes to Prepare Biologically Active Quinoxalines and Their Derivatives: A Synthetic Review 1. Introduction 1. Introductionfor the Last Two Decades. Molecules 2021, 26, 1055. https://doi.org/10.3390/ Quinoxaline is deﬁned as a weakly basic bi-cyclic compound C8H6N2, having fused Quinoxalinemolecules26041055 is defined as a weaklybenzene basic bi-cyclic and pyrazine compound rings. QuinoxalineC8H6N2, having is a fused nitrogen-containing benzene and heterocyclic compound pyrazine rings. Quinoxaline is a nitrogen-containingand is an indispensable heterocyclic structural compound unit for and both is an chemists indispensable and biochemists. The structure is structuralAcademic unit Editor:for both Luigi chemists Agrofoglio and asbiochemi shownsts. in Figure The structure1. is as shown in Figure 1. Received: 19 November 2020 Accepted: 14 December 2020 Published: 18 February 2021

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FigureFigure 1. Structure 1. Structure of Quinoxaline. of Quinoxaline. Copyright: © 2021 by the authors. Li- Pthalazine,censee MDPI, Quinazolines, Basel, Switzerland. This and CinnolenesPthalazine, are similar Quinazolines, to Quinoxaline and Cinnolenes [1], as shown are similarin Figure to Quinoxaline2. [1], as shown in article is an open access article distributed Figure2. under the terms and conditions of the Creative Commons Attribution (CC BY) Molecules 2020, 25, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules license (https://creativecommons.org/ licenses/by/4.0/).

Molecules 2021, 26, 1055. https://dx.doi.org/10.3390/molecules26041055 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 1055 2 of 30

Molecules 2020, 25, x FOR PEER REVIEW 2 of 32

Figure 2. Isomers ofFigure Quinoxaline. 2. Isomers of Quinoxaline.

Quinoxaline is a lowQuinoxaline melting solid is a and low is melting miscible solid in water. and is It miscible is a weak in base water. and It can is a form weak salts base and can form salts with acids. The synthesis of quinoxaline has been extensively studied for with acids. The synthesis of quinoxaline has been extensively studied for the last two decades. A very the last two decades. A very primitive and effective method to derive quinoxaline is the primitive and effective method to derive quinoxaline is the condensation reaction between ortho condensation reaction between ortho phenylenediamine and dicarbonyl compounds [2,3]. phenylenediamineThis and procedure dicarbonyl requires compounds a high [2,3]. temperature, This procedure a strong requires acid a catalyst, high temperature, and long hours a of strong acid catalyst,heating. and long Recently, hours there of heating. has been Recently, a tremendous there increase has been in greena tremendous methodology increase to synthesize in green methodologyquinoxalines to synthesize such quinoxalines as recyclable such catalyst as recyclable [4], one-pot catalyst synthesis [4], one-pot [5], microwave-assistedsynthesis [5], microwave-assistedsynthesis synthesis [6, 7[6,7],], and and reactions reactions in anin an aqueous aqueous medium medium [8]. [8]. A little modificationA little in their modification structure in brings their structuredifferent bringsmoieties, different whichmoieties, has the remarkable which has the re- pharmacological markableeffect of fighting pharmacological different effectdiseases of fighting with little different side diseaseseffects. Several with little quinoxaline side effects. Sev- derivatives have beeneral tested quinoxaline in the last derivatives two decades have and been produced tested in anti-inflammatory the last two decades [9], andantimalarial produced anti- [10], antidepressantsinflammatory [11], antiviral [9], antimalarial[12], antimicrobial [10], antidepressants activity [13] as [11 antifungal], antiviral [and12], antimicrobialantibacterial activ- agents. The antibacteriality [13] asactivity antifungal [13] and comprise antibacterials both agents.gram-positive The antibacterial and gram-negative activity [13] comprisesbacteria, both including mycobacteriumgram-positive species. and Some gram-negative derivatives bacteria, of quinoxaline-1,4-di- including mycobacteriumN-oxide have species. been shown Some deriva- to inhibit M. tuberculosistives of quinoxaline-1,4-di-to a rate of 99 to 100%N-oxide [14]. haveThe antifungal been shown properties to inhibit of M. quinoxalines tuberculosis have to a rate of 99 to 100% [14]. The antifungal properties of quinoxalines have been tested against numer- been tested against numerous fungal species, and researchers have reported 2-sulphonyl ous fungal species, and researchers have reported 2-sulphonyl quinoxalines, 3-[(alkylthio) quinoxalines, 3-[(alkylthio) methyl] quinoxaline-1-oxide derivatives, and also pyrazolo quinoxalines methyl] quinoxaline-1-oxide derivatives, and also pyrazolo quinoxalines as compounds as compounds with high antifungal activity [15]. with high antifungal activity [15]. Quinoxaline is a vitalQuinoxaline component is a in vital anticancer component drugs, in with anticancer promising drugs, results with [15]. promising The pursuit results [15]. for anticancer drugsThe led pursuit to a breakthrough for anticancer in drugs the anticancer led to a breakthrough activity of several in the anticancerquinoxaline-1,4-di- activity ofN- several oxide derivatives.quinoxaline-1,4-di- A new series of 2-alkylcarbonylN-oxide derivatives. and 2-benzoyl-3-trifluoromethyl A new series of 2-alkylcarbonyl quinoxaline-1,4- and 2-benzoyl-3 di-N-oxide have -trifluoromethylbeen reported to quinoxaline-1,4-di- show in vitro tumorN-oxide activity have beenagainst reported three tocell show linein panels vitro tumor comprising of MCF7(breast),activity against NCI-H three 460(lung), cell line SF-268(CNS) panels comprising [14]. of MCF7(breast), NCI-H 460(lung), One of its biologicalSF-268(CNS) properties [14]. (antiviral) has gained immense attention due to the current outbreak of COVID-19One in December of its biological 2019 and properties has spread (antiviral) rapidly across has gained the globe. immense A pandemic attention arises due to the when a new typecurrent of virus outbreak or bacteria of COVID-19 is detected in December in human 2019 beings and hasand spread can transmit rapidly acrossfrom one the globe. individual to another.A pandemic These pathogens arises when are a highly new type contagious, of virus orand bacteria overtime, isdetected mutates, in making human it beings difficult to controland and can create transmit an effective from one drug individual to combat to another. these infections. These pathogens In the year are 2020, highly a contagious,new pandemic situationand arose overtime, after the mutates, outbreak making of the it Ebola difficult virus to controlin the year and 2013 create (December) an effective in drug Guinea to combat these infections. In the year 2020, a new pandemic situation arose after the outbreak of [16,17], called SARS-COVID 19, which originated in Wuhan China [18]. It has spread globally in a the Ebola virus in the year 2013 (December) in Guinea [16,17], called SARS-COVID 19, short duration of time, affecting millions of people. It is very similar to bat coronavirus and is also which originated in Wuhan China [18]. It has spread globally in a short duration of time, believed to have originatedaffecting millionsfrom bats of and people. transmitted It is very to humans similar tofrom bat wet coronavirus animal markets and is in also Wuhan, believed to China[19]. Since havethe quest originated to prepare from bats effective and transmitted coronavirus to humansdrugs is from still wet being animal developed markets and in Wuhan, clinically tested, quinoxalinesChina [19]. Since based the heterocycles quest to prepare stand effectivea fair chance coronavirus to be examined drugs is stillon COVID-19 being developed patients because ofand their clinically impeccable tested, property, quinoxalines an antiviral. based heterocycles stand a fair chance to be examined The biologicalon applications COVID-19 patientsof quinoxaline because derivatives of their impeccable are broad property,and have anaroused antiviral. interest in the scientific community; therefore,The biological this review applications paper ofwill quinoxaline focus on synthesizing derivatives novel are broad quinoxaline and have and aroused its derivatives in interestthe last intwo the decades scientific with community; straightforward therefore, synthetic this review routes paper. It will also focus reviews on synthesizing their potentials to fightnovel infections quinoxaline and has and an itsopen derivatives window in to the be lasttested two on decades infectious with and straightforward non-infectious synthetic diseases. routes. It also reviews their potentials to fight infections and has an open window to be tested on infectious and non-infectious diseases. 2. Synthetic Pathways to Prepare Quinoxalines via Cost-Effective and Green Synthetic Approach

2.1. Using Bentonite Clay K-10 The green organic synthesis approach is gaining much ground for research because it is environment friendly, and limitations like harsh reaction conditions, expensive reagents, and low

2 Molecules 2020, 25, x FOR PEER REVIEW 3 of 32

yield can be eliminated. Clay is a very cheap, heterogeneous green reagent and is readily available. Molecules 2021, 26, 1055 This concept was formulated by A. Hasaninejad et al. [20] to synthesize quinoxaline derivatives3 of 30by using bentonite clay K-10 at room temperature. The reaction is progressed by mixing reactants (1) and (2) with bentonite clay and ethanol in a round bottom flask, as indicated in Scheme 1. After completing the reaction, it is carefully poured on a celite pad and washed with warm ethanol. The 2. Synthetic Pathways to Prepare Quinoxalines via Cost-Effective and Green Synthetic reaction mixtureApproach was concentrated to 5 mL, followed by dilution with 10 mL of water. It was allowed to stand undisturbed2.1. Using Bentonite for 1 h. ClayThe K-10clay was recovered after the formation of pure crystals and used again up to five times. This synthesis agrees with green chemistry protocols, and similar studies on The green organic synthesis approach is gaining much ground for research because it the development of efficient and environmentally friendly methodologies in organic synthesis should is environment friendly, and limitations like harsh reaction conditions, expensive reagents, be established.and low The yield results can were be eliminated. briefed in ClayTable is 1 a and very presented cheap, heterogeneous the best results green in 2.5 reagent g and and 3 g is of clay, with readilya short available.reaction time This of concept 20 min. was formulated by A. Hasaninejad et al. [20] to synthesize quinoxaline derivatives by using bentonite clay K-10 at room temperature. The reaction Tableis 1. progressedThe condensation by mixing of benzene-1,2-diamine reactants (1) and (1 ( 2mmol)) with with bentonite benzyl clay(1 mmol) and in ethanol the presence in a round of variousbottom quantities flask, of asbentonite indicated clay in K-10 Scheme in ethanol1. After (20 completing mL) at room the temperature. reaction, it is carefully poured on a celite padEntry and Grams washed of withClay warm Time ethanol.in Minutes The Isolated reaction Yields% mixture was concentrated to 5 mL, followed1. by dilution0.5 with 10 mL 720 of water. It was allowed 38 to stand undisturbed for 1 h. The clay2. was recovered1 after the formation 120 of pure crystals 43 and used again up to five times. This3. synthesis1.5 agrees with green 90 chemistry protocols, 65 and similar studies on the development4. of efficient and2 environmentally 60 friendly methodologies 93 in organic synthesis should be established.5. The2.5 results were briefed 20 in Table1 and 95 presented the best results in 2.5 g and 3 g of6. clay, with3 a short reaction time 20 of 20 min. 95

SchemeScheme 1. Synthesis 1. Synthesis of 2,3-diphenylquinoxaline of 2,3-diphenylquinoxaline (3) with (3) withreagents reagents and andconditions: conditions: (a) bentonite (a) bentonite clay clay K-10/EtOH/RT/20K-10/EtOH/RT/20 min. min.

DifferentTable solvents 1. The condensation were selected of benzene-1,2-diamine to decide the best solvent (1 mmol) to with synthesize benzyl (1 2,3-diphenylquinoxaline mmol) in the presence of (3), as shownvarious in Table quantities 2. The of bentonitebest yield clay in a K-10 short in ethanoltime was (20 noticed mL) at room in ethanol. temperature.

Entry Grams of Clay Time in Minutes Isolated Yields% Table 2. The effects of different solvents on the reaction of benzene-1,2-diamine with benzil in the presence of bentonite1. clay K-10 at 0.5 room temperature. 720 38 2. 1 120 43 3.Entry 1.5Solvent Time, Min 90 Isolated Yields% 65 4.1 2EtOH 20 60 95 93 5. 2.5 20 95 6.2 3MeOH 30 20 91 95 3 H2O 120 trace

4 CHCl3 30 87 Different solvents were selected to decide the best solvent to synthesize 2,3-diphenyl quinoxaline (3), as5 shownCH in2Cl Table2 2. The30 best yield in a short82 time was noticed in ethanol. Betonite clay6 K-10 overlaysMeCN the way 35 for green chemistry 92 organic synthesis, with exceptionally mild conditions7 THF such as short 30 reaction time, 89 high yield, low cost, and simple experimental and isolation procedures. Betonite clay K-10 overlays the way for green chemistry organic synthesis, with exceptionally mild conditions such as short reaction time, high yield, low cost, and simple experimental and isolation procedures. 3 Molecules 2021, 26, 1055 4 of 30

Table 2. The effects of different solvents on the reaction of benzene-1,2-diamine with benzil in the presence of bentonite clay K-10 at room temperature.

Entry Solvent Time, Min Isolated Yields% 1 EtOH 20 95 2 MeOH 30 91 3 H2O 120 trace 4 CHCl3 30 87 5 CH2Cl2 30 82 6 MeCN 35 92 Molecules 2020, 25, x FOR7 PEER REVIEW THF 30 89 4 of 32

2.2. Using2.2. Phosphate Using Phosphate Based Heterogeneous Based Heterogeneous Catalyst Catalyst(MAP, DAP, (MAP, TSP) DAP, TSP) Since theSince development the development of green of chemistry, green chemistry, enormous enormous research research has been has conducted been conducted to produce to produce clean and environmentally friendly chemical processes [21] to protect human clean and environmentally friendly chemical processes [21] to protect human health and its health and its surroundings. Heterogeneous catalysis has been used extensively in green surroundings. Heterogeneous catalysis has been used extensively in green organic chemistry due to organic chemistry due to its recyclable properties and low energy consumptions. This prop- its recyclable properties and low energy consumptions. This property was utilized by Malek B et al. erty was utilized by Malek B et al. [22] to prepare quinoxaline derivatives by utilizing [22] to phosphate-basedprepare quinoxaline heterogeneous derivatives catalyst by ut fertilizersilizing phosphate-based such as mono-ammonium heterogeneous phosphate catalyst fertilizers(MAP), such di-ammoniumas mono-ammonium phosphate phosphate (DAP), (MAP), or triple-super di-ammonium phosphate phosphate (TSP). In (DAP), order toor test triple- super phosphatethe reliability (TSP). of the In protocolorder to showntest the in reliabi reactionlity Scheme of the2 protocol, various aryl-1,2-diamineshown in reaction (1 mmol)Scheme 2, various (aryl-1,2-diamine4) was condensed (1 with mmol) benzyl (4) was (1 mmol) condensed (5) in EtOHwith benzyl (2 mL) (1 and mmol) phosphate-based (5) in EtOH catalyst(2 mL) and phosphate-basedMAP, DAP, catalyst or TSP MAP, (0.0006 DAP, g). The or resultantTSP (0.0006 product g). The (6) resultant was recrystallized product ( using6) was hot recrystallized ethanol. using hotThe ethanol. catalyst The is retrieved catalyst is from retrieved the reaction from the mixture reaction by simplemixture ﬁltration, by simple washed filtration, with washed hot with hotethanol, ethanol, and and dried dried for for 6 6 h h at at 80 80◦ C.°C.

SchemeScheme 2. Synthetic 2. Synthetic pathway pathway to toprepare prepare 2,3- 2,3-diphenylquinoxalinediphenylquinoxaline derivatives derivatives (6 ()6 )using using phosphate phosphate catalystcatalyst (MAP, (MAP, DAP, DAP, or orTSP). TSP). 2.3. Using Lanthanide Reagent (CAN) 2.3. Using Lanthanide Reagent (CAN) One of the lanthanide reagents, Cerium(IV)ammonium nitrate (CAN), has gained Onemuch of the attention lanthanide in organic reagents, chemistry Cerium(IV) due toammonium its low cost, nitrate miscibility (CAN), in water,has gained and high much attentionreactivity. in organic Using chemistry CAN as due a catalyst to its inlow organic cost, synthesismiscibility is in considered water, and a safe high green reactivity. chemistry Using CAN asapproach a catalyst [ 23in ];organic therefore, synthesis Yao et al.is considered [24] prepared a safe biologically green chemistry important approach quinoxalines [23]; therefore, using Yao et al.a catalytic [24] prepared amount biologically of CAN in important water. The quinoxalines reaction between using a substituted catalytic amount benzil (of7) CAN and in water. Thederivatives reaction ofbetween ortho-phenylenediamine substituted benzil (87) usingand derivatives a catalytic of amount ortho-phenylenediamine of CAN either in (8) using amethyl catalytic cyanide amount or any of proticCAN solvents either producedin methyl quinoxaline cyanide or derivatives any protic (9 ),solvents as presented produced in quinoxalineScheme derivatives3. The product (9), as waspresented achieved in Scheme in 20 min 3. withoutThe product any sidewas products.achieved Quinoxaline’sin 20 min without any sidederivatives products. (Quinoxaline’s9) can be evaluated derivatives for their (9 antimicrobial) can be evaluated properties for thei liker antiviral, antimicrobial antibacterial, properties like antiviral,antifungal, antibacterial, and many antifungal, more. Synthesis and many of more. quinoxalines Synthesis using of quinoxalines lanthanides using as a lanthanides catalyst should be explored as a green chemistry approach. as a catalyst should be explored as a green chemistry approach.

Scheme 3. Synthetic pathway to prepare quinoxaline derivatives (9) using CAN as a catalyst. 4 Molecules 2020, 25, x FOR PEER REVIEW 4 of 32

2.2. Using Phosphate Based Heterogeneous Catalyst (MAP, DAP, TSP) Since the development of green chemistry, enormous research has been conducted to produce clean and environmentally friendly chemical processes [21] to protect human health and its surroundings. Heterogeneous catalysis has been used extensively in green organic chemistry due to its recyclable properties and low energy consumptions. This property was utilized by Malek B et al. [22] to prepare quinoxaline derivatives by utilizing phosphate-based heterogeneous catalyst fertilizers such as mono-ammonium phosphate (MAP), di-ammonium phosphate (DAP), or triple- super phosphate (TSP). In order to test the reliability of the protocol shown in reaction Scheme 2, various aryl-1,2-diamine (1 mmol) (4) was condensed with benzyl (1 mmol) (5) in EtOH (2 mL) and phosphate-based catalyst MAP, DAP, or TSP (0.0006 g). The resultant product (6) was recrystallized using hot ethanol. The catalyst is retrieved from the reaction mixture by simple filtration, washed with hot ethanol, and dried for 6 h at 80 °C.

Scheme 2. Synthetic pathway to prepare 2,3-diphenylquinoxaline derivatives (6) using phosphate catalyst (MAP, DAP, or TSP).

2.3. Using Lanthanide Reagent (CAN) One of the lanthanide reagents, Cerium(IV)ammonium nitrate (CAN), has gained much attention in organic chemistry due to its low cost, miscibility in water, and high reactivity. Using CAN as a catalyst in organic synthesis is considered a safe green chemistry approach [23]; therefore, Yao et al. [24] prepared biologically important quinoxalines using a catalytic amount of CAN in water. The reaction between substituted benzil (7) and derivatives of ortho-phenylenediamine (8) using a catalytic amount of CAN either in methyl cyanide or any protic solvents produced quinoxaline derivatives (9), as presented in Scheme 3. The product was achieved in 20 min without

Molecules 2021, 26,any 1055 side products. Quinoxaline’s derivatives (9) can be evaluated for their antimicrobial properties5 of 30 like antiviral, antibacterial, antifungal, and many more. Synthesis of quinoxalines using lanthanides as a catalyst should be explored as a green chemistry approach.

SchemeScheme 3. Synthetic 3. Synthetic pathway pathway to prepare to preparequinoxaline quinoxaline derivatives derivatives (9) using (9 CAN) using as CANa catalyst. as a catalyst. 2.4. Using Fe as a Catalyst 4 One of the essential examples of the N-heterocyclic compound is pyrrolo[1,2-α]quinoxa Molecules 2020, 25,lines, x FOR PEER which REVIEW are often found in nature, with suitable pharmacological5 of 32 activities. Due to α 2.4. Using Fe asits a Catalyst incredible applications, pyrrolo[1,2- ]quinoxalines has gained immense attention for synthesis via different routes. The synthetic pathways for the preparation of pyrrolo[1,2- One of theα essential examples of the N-heterocyclic compound is pyrrolo[1,2-α]quinoxalines, which are often]quinoxalines found in nature, bywith using suitable Fe pharmacological catalysis with activities. 1-(2-aminophenyl)pyrroles(10) Due to its incredible and cyclic ethers applications, pyrrolo[1,2-has beenα developed]quinoxalines byhas Zheyugained immense et al. [ 25attention]. Synthesis for synthesis of pyrrolo via different quinoxalines was cultivated routes. The syntheticbecause pathways of the low-costfor the preparation and ease of ofpyrrolo[1,2- availabilityα]quinoxalines of reagents. by using Reaction Fe Scheme4 establishes catalysis with the1-(2-aminophenyl)pyrroles(10) synthetic route for bothand cy cyclicclic ethers and has linearbeen developed ethers. by Initially, Zheyu et al. the reaction was focussed [25]. Synthesis of pyrrolo quinoxalines was cultivated because of the low-cost and ease of availability of reagents. Reactionon 1-(2-aminophenyl)pyrrole Scheme 4 establishes the synthetic (10 )route with for THF, both Fecyclic as and a catalyst, linear ethers. and tert-butyl hydroperox- Initially, the reactionide(TBHP), was focussed stirring on 1-(2-aminophenyl)pyrrole at rt for ten hours. The(10) with desired THF, Fe product as a catalyst, [11, 12and] was obtained with a 46% tert-butyl hydroperoxide(TBHP),yield. The percentage stirring at rt was for ten increased hours. The desired to 94% prod byuct the [11,12] addition was obtained of CF 3SO3H as an additive. with a 46% yield.To The conclude, percentage this was reaction increased proceedsto 94% by the by addition the cleavage of CF3SO3 ofH as the an C–Oadditive. bond of cyclic ethers to get To conclude, this reaction proceeds by the cleavage of the C–O bond of cyclic ethers to get C–C and C–C and C-N bonds to synthesize pyrrolo[1,2-α]quinoxalines. C-N bonds to synthesize pyrrolo[1,2-α]quinoxalines.

Scheme 4. Synthetic pathway to prepare pyrrolo[1,2-a]quinoxaline derivatives (11,12) with reagents Scheme 4. Synthetic pathway to prepare pyrrolo[1,2-a]quinoxaline derivatives (11,12) with reagents and and conditions: (a,b) FeCl3(20 mol%)/70% TBHP(3equiv)/CF3SO3H(10 mol%)/t-BuOH(0.5 mL)/RT/10 h/Ar. conditions: (a,b) FeCl3(20 mol%)/70% TBHP(3equiv)/CF3SO3H(10 mol%)/t-BuOH(0.5 mL)/RT/10 h/Ar.

2.5. Using Fluorinated Alcohols (HFIP) The fluorinated2.5. Using alcohols Fluorinated have gained massive Alcohols consideration (HFIP) in organic reactions due to their low nucleophilicity, high Thepolarity, ﬂuorinated strong hydrogen alcohols bond donating have gained ability, and massive the ability consideration to solvate water in organic reactions due [25]. Fluorinatedto alcohols their low can also nucleophilicity, stabilize the helix high conformations polarity, of strongproteins hydrogen[26]. The property bond of donating ability, and the fluorinated alcohol to prepare quinoxaline derivatives has been developed by Khaskar et al. [27]. The reaction wasability progressed to solvate in waterhexafluo [25roisopropanol(HFIP),]. Fluorinated alcohols with canbenzil also (13 stabilize) and the helix conformations orthophenylenediamineof proteins (14) at [ 26room]. temp The for property 1hour to yield of ﬂuorinated 2,3-diphenylquinoxaline alcohol (15 to) with prepare a 95% quinoxaline derivatives yield, as shown in Scheme 5. The condensation of aryl 1,2-diamines with 1,2-dicarbonyl compounds in ethanol or acetic acid is a common approach [28,29], which has problems related to long reaction time, high reaction temperature, low yield, use of toxic organic solvents, and many more. It also has an exemplary green chemistry aspect since the HFIP can quickly recover and be recycled at least five times without any significant activity change. This procedure can be applied in the large scale preparation of quinoxalines.

5 Molecules 2021, 26, 1055 6 of 30

has been developed by Khaskar et al. [27]. The reaction was progressed in hexafluoroiso- propanol(HFIP), with benzil (13) and orthophenylenediamine (14) at room temp for 1hour to yield 2,3-diphenylquinoxaline (15) with a 95% yield, as shown in Scheme5 . The condensation of aryl 1,2-diamines with 1,2-dicarbonyl compounds in ethanol or acetic acid is a common approach [28,29], which has problems related to long reaction time, high reaction temperature, low yield, use of toxic organic solvents, and many more. It also has an exemplary green chemistry aspect since the HFIP can quickly recover and be recycled at least five times without any significant activity change. This procedure can be applied in Molecules 2020, 25, x FORthe PEER large REVIEW scale preparation of quinoxalines. 6 of 32

SchemeScheme 5. Synthetic 5. Synthetic pathway pathway to prepare to prepare 2,3-disubstituted 2,3-disubstituted quinoxalines quinoxalines (15) with (15 HFIP.) with HFIP. 2.6. Using Pyridine as a Catalyst 2.6. Using Pyridine as a Catalyst Quinoxaline derivatives can be synthesized using 1,2-phenylenediamine and two car- Quinoxalinebon derivatives synthones can such be as synthesizedα-dicarbonyls, usingα-halogeno 1,2-phenylenediamine carbonyls, α-hydroxy and two carbonyls, carbonα -azo synthones such carbonyls,as α-dicarbonyls, epoxides, α-halogeno and α, β -dihalides.carbonyls, Quinoxalineα-hydroxy carbonyls, derivatives α can-azo alsocarbonyls, be prepared epoxides, and αvia, β-dihalides. the reaction Quinoxaline of phenacyl halidesderivatives with can phenylene-1,2-diamine, also be prepared via which the isreaction a condensation- of phenacyl halidesoxidation with phenylene-1,2-diamine, reaction in the presence which of a catalystis a condensation-oxidation and/or medium, which reaction formed in the the basis of presence of a catalystthe synthesis and/or medium, of quinoxalines which by formed Narsaiah the etbasis al. [ 30of] the using synthesis pyridine of as quinoxalines a catalyst. As by demon- Narsaiah et al. [30]strated using inpyridine reaction as Scheme a catalyst.6, an As equimolar demonstrated quantity in reaction of 1,2-diaminobenzene Scheme 6, an equimolar derivatives quantity of 1,2-diaminobenzene(16) and phenacyl derivatives bromide (16 (17) )and is reactedphenacyl in bromide THF in the(17) presence is reacted of in pyridine THF in the at room presence of pyridinetemperature. at room temperature. The reaction The was reaction over in 2 was h to over get the in 2 desired h to get product the desired 2-phenyl product quinoxaline 2- 18 phenyl quinoxaline( )(18 in) the in the right right quantity. quantity. The The 10% 10% mole mole of pyridine of pyridine exhibited exhibited optimum optimum results results to prepare 2-phenyl quinoxaline derivatives. Further evaluation of the pharmacological conduct of to prepare 2-phenyl quinoxaline derivatives. Further evaluation of the pharmacological conduct of quinoxalines (18) should be assessed. Since the reaction (Scheme6) can be completed at quinoxalines (18) should be assessed. Since the reaction (Scheme 6) can be completed at room room temperature and is a one-step procedure, more preference can be given to study temperature and biologicalis a one-step properties procedure, like more antifungal, preference antibacterial, can be given antiviral, to study anticancer. biological properties like antifungal, antibacterial, antiviral, anticancer.

Scheme 6. Synthetic pathway to prepare derivative of 2-phenylquinoxaline (18) using pyridine as a catalyst. 6 Molecules 2020, 25, x FOR PEER REVIEW 6 of 32

Scheme 5. Synthetic pathway to prepare 2,3-disubstituted quinoxalines (15) with HFIP.

2.6. Using Pyridine as a Catalyst Quinoxaline derivatives can be synthesized using 1,2-phenylenediamine and two carbon synthones such as α-dicarbonyls, α-halogeno carbonyls, α-hydroxy carbonyls, α-azo carbonyls, epoxides, and α, β-dihalides. Quinoxaline derivatives can also be prepared via the reaction of phenacyl halides with phenylene-1,2-diamine, which is a condensation-oxidation reaction in the presence of a catalyst and/or medium, which formed the basis of the synthesis of quinoxalines by Narsaiah et al. [30] using pyridine as a catalyst. As demonstrated in reaction Scheme 6, an equimolar quantity of 1,2-diaminobenzene derivatives (16) and phenacyl bromide (17) is reacted in THF in the presence of pyridine at room temperature. The reaction was over in 2 h to get the desired product 2- phenyl quinoxaline (18) in the right quantity. The 10% mole of pyridine exhibited optimum results to prepare 2-phenyl quinoxaline derivatives. Further evaluation of the pharmacological conduct of quinoxalines (18) should be assessed. Since the reaction (Scheme 6) can be completed at room Molecules 2021, 26, 1055 7 of 30 temperature and is a one-step procedure, more preference can be given to study biological properties like antifungal, antibacterial, antiviral, anticancer.

SchemeScheme 6. Synthetic 6. Synthetic pathway pathway to prepare to prepare derivative derivative of 2-phenylquinoxaline of 2-phenylquinoxaline (18) using (18) using pyridine pyridine as a as Molecules 2020, 25, x FOR PEER REVIEW 7 of 32 catalyst.a catalyst.

2.7. Using a Solid2.7. Acid Using Catalyst, a Solid AcidTiO2 Catalyst,-Pr-SO3H TiO 2-Pr-SO6 3H The rate of organicThe rate reactions of organic can reactions be accomplished can be accomplished by using catalysts. by using Recyclable catalysts. catalysts Recyclable have catalysts have gained immense focus by organic researchers, such as solid acid catalysts like gained immense focus by organic researchers, such as solid acid catalysts like TiO2-Pr-SO3H, due to TiO2-Pr-SO3H, due to green chemistry synthesis. The properties of TiO2-Pr-SO3H were green chemistry synthesis. The properties of TiO2-Pr-SO3H were used by Atghia and Beigbaghlou used by Atghia and Beigbaghlou [31] to prepare quinoxalines because the reaction can [31] to prepare quinoxalines because the reaction can progress at room temperature with reduced progress at room temperature with reduced reaction times. Many catalysts have been reaction times. Many catalysts have been used in past years to prepare quinoxalines like alumina [32], used in past years to prepare quinoxalines like alumina [32], montmorillonite K-10 [33], montmorillonite K-10 [33], sulphated TiO2 [34], clayzic [35], Zirconium(IV) modified silica gel [36], sulphated TiO2 [34], clayzic [35], Zirconium(IV) modiﬁed silica gel [36], PEG-400 [37], het- PEG-400 [37], heteropolyacid [38], ZrO2/MxOy/MCM-41 [39], cellulose sulfuric acid [40] and Ga(OTf)3 eropolyacid [38], ZrO2/MxOy/MCM-41 [39], cellulose sulfuric acid [40] and Ga(OTf)3 [41]. [41]. Even thoughEven significant, though signiﬁcant, these procedures these procedures have limitations have limitations like long reaction like long times reaction and potential times and hazards in catalystpotential preparations. hazards in catalystThe reaction preparations. Scheme The7 elucidates reaction Schemea simple7 elucidates one-step synthesis a simple one-of quinoxalines.step The synthesisreaction between of quinoxalines. substituted The 1,2- reactionphenylenediamine between substituted (1 mmol) 1,2-phenylenediamine and benzyl (1 mmol) (1 is evaluated undermmol) varied and benzyl solvents (1 mmol)like EtOH, is evaluated THF, MeCN, under EtOAc, varied and solvents toluene, like as EtOH,well as THF,in solvent- MeCN, free conditions.EtOAc, The top and results toluene, were as well attained as in solvent-freein TiO2-Pr-SO conditions.3H (10 mg) The and top EtOH, results with were a 95% attained yield in within 10 min.TiO 2-Pr-SO3H (10 mg) and EtOH, with a 95% yield within 10 min.

SchemeScheme 7. Synthetic 7. Synthetic pathway pathway to prepare to preparequinoxaline quinoxaline derivatives derivatives (21) using (21 catalyst) using catalystTiO2-Pr-SO TiO32H.-Pr-SO 3H. 2.8. Using the Catalytic Amount of Acetic Acid and Aldehydes 2.8. Using the Catalytic Amount of Acetic Acid and Aldehydes Pyrrolo[1,2-a] quinoxalines are a vital class of heterocyclic compounds and are con- Pyrrolo[1,2-a]templated quinoxalines as biological are a heterocycles. vital class of It heterocyclic has gained prominencecompounds becauseand are substitutioncontemplated at as C-4 biological heterocycles.pyrroloquinoxalines It has gained boosts prominence its physiological because properties substitution like at anticancer, C-4 pyrroloquinoxalines antiviral, and an- boosts its physiologicaltiproliferative properties effects. Various like anticancer, synthetic pathwaysantiviral, haveand antiproliferative been developed toeffects. prepare Various pyrrolo- synthetic pathwaysquinoxalines have been [42– developed44] because to it prepare is crucial pyrroloquinoxalines in drug discovery. [42–44] For this because reason, it an is crucial efﬁcient in drug discovery.method For was this established reason, an byefficient Allan me etthod al. [45 was], which established is an acid-catalyzed by Allan et al. reaction[45], which for theis an acid-catalyzedsynthesis reaction of 4-aryl for the substituted synthesis of pyrrolo[1,2-a] 4-aryl substituted quinoxalines pyrrolo[1,2-a] (24). Thisquinoxalines one-pot reaction(24). This in- one-pot reactionvolves involves imine imine formation, formation, followed followed by cyclization by cyclization and air and oxidation. air oxidation. As disclosed As disclosed in reaction in reaction SchemeScheme 8, the8, thereaction reaction progresses progresses by bycyclization cyclization of of1-(2-aminophenyl)pyrroles 1-(2-aminophenyl)pyrroles (22 ( 22) with) with a a substituted aldehydesubstituted (23) aldehyde in acetic acid (23) inand acetic methanol acid and as solvent. methanol The as reaction solvent. is The refluxed reaction for is 8 reﬂuxedh at 60 °C. The established reaction scheme 8 is a classic example of the Pictet-Spengler reaction using catalytic amounts of acetic acid.

Scheme 8. Synthetic pathway to prepare pyrrolo[1,2-a]quinoxalines (24) using a catalytic amount of acetic acid and substituted aldehydes. 7 Molecules 2020, 25, x FOR PEER REVIEW 7 of 32

2.7. Using a Solid Acid Catalyst, TiO2-Pr-SO3H The rate of organic reactions can be accomplished by using catalysts. Recyclable catalysts have gained immense focus by organic researchers, such as solid acid catalysts like TiO2-Pr-SO3H, due to green chemistry synthesis. The properties of TiO2-Pr-SO3H were used by Atghia and Beigbaghlou [31] to prepare quinoxalines because the reaction can progress at room temperature with reduced reaction times. Many catalysts have been used in past years to prepare quinoxalines like alumina [32], montmorillonite K-10 [33], sulphated TiO2 [34], clayzic [35], Zirconium(IV) modified silica gel [36], PEG-400 [37], heteropolyacid [38], ZrO2/MxOy/MCM-41 [39], cellulose sulfuric acid [40] and Ga(OTf)3 [41]. Even though significant, these procedures have limitations like long reaction times and potential hazards in catalyst preparations. The reaction Scheme 7 elucidates a simple one-step synthesis of quinoxalines. The reaction between substituted 1,2-phenylenediamine (1 mmol) and benzyl (1 mmol) is evaluated under varied solvents like EtOH, THF, MeCN, EtOAc, and toluene, as well as in solvent- free conditions. The top results were attained in TiO2-Pr-SO3H (10 mg) and EtOH, with a 95% yield within 10 min.

Scheme 7. Synthetic pathway to prepare quinoxaline derivatives (21) using catalyst TiO2-Pr-SO3H.

2.8. Using the Catalytic Amount of Acetic Acid and Aldehydes Pyrrolo[1,2-a] quinoxalines are a vital class of heterocyclic compounds and are contemplated as biological heterocycles. It has gained prominence because substitution at C-4 pyrroloquinoxalines boosts its physiological properties like anticancer, antiviral, and antiproliferative effects. Various synthetic pathways have been developed to prepare pyrroloquinoxalines [42–44] because it is crucial in drug discovery. For this reason, an efficient method was established by Allan et al. [45], which is an acid-catalyzed reaction for the synthesis of 4-aryl substituted pyrrolo[1,2-a] quinoxalines (24). This Molecules 2021, 26, 1055 8 of 30 one-pot reaction involves imine formation, followed by cyclization and air oxidation. As disclosed in reaction Scheme 8, the reaction progresses by cyclization of 1-(2-aminophenyl)pyrroles (22) with a substituted aldehyde (23) in acetic acid and methanol as solvent. The reaction is refluxed for 8 h at 60 °C. The establishedfor 8 h at reaction 60 ◦C. The scheme established 8 is a reaction classic Schemeexample8 is of a classicthe Pictet-Spengler example of the reaction Pictet-Spengler using catalytic amountsreaction of acetic using acid. catalytic amounts of acetic acid.

Scheme 8.Scheme Synthetic 8. Synthetic pathway pathway to prepare to preparepyrrolo[1,2-a]quinoxalines pyrrolo[1,2-a]quinoxalines (24) using (24 )a usingcatalytic a catalytic amount amount of of acetic acid and substituted aldehydes. Moleculesacetic 2020, 25 acid, x FOR and PEER subs REVIEWtituted aldehydes. 8 of 32 2.9. Using an Excess of Secondary Amines7 in Boiling Benzene 2.9. Using an Excess of Secondary Amines in Boiling Benzene Interferons (IFNs) are glycoproteins made or released by host cells to treat pathogens Interferonssuch (IFNs) as are bacteria, glycoproteins pathogens, made tumoror released cells, by and host especially cells to treat viruses. pathogens Virally such infected as cells pro- bacteria, pathogens,duce tumor and release cells, and proteins especially called viruses. interferons, Virally whichinfected prohibit cells produce the multiplication and release of infected proteins called interferons,cells. Although which available, prohibit the interferon multiplication drugs of have infected side effectscells. Although like low available, potency in long-term interferon drugsusage have side [46 –effects48]. In like the low quest potency to prepare in long-term new usage antiviral [46–48]. drugs, In the Shibinskaya quest to prepare et al. [49] synthe- new antiviral drugs,sized Shibinskaya a series of indoloquinoxalineset al. [49] synthesized (a28 series) having of indoloquinoxalines low toxicity as interferon(28) having inducers and low toxicity as interferon inducers and anti-VSV activity (Vesicular stomatitis virus). The target anti-VSV activity (Vesicular stomatitis virus). The target compound (28) was synthesized by compound (28) was synthesized by following Scheme 9. 1-(2-Bromoethyl)-indole-2,3-dione (26) was following Scheme9. 1-(2-Bromoethyl)-indole-2,3-dione ( 26) was made via isatin alkylation made via isatin alkylation of (25) with an excess of dibromoethane in DMF at room temperature in of (25) with an excess of dibromoethane in DMF at room temperature in the presence of the presence of K2CO3. Further condensation of (26) with 1,2-diaminobenzene in boiling acetic acid K CO . Further condensation of (26) with 1,2-diaminobenzene in boiling acetic acid forms forms 6-bromoethyl-6H-indolo-[2,3-b]quinoxaline2 3 (27). The final compound (28) was achieved by 6-bromoethyl-6H-indolo-[2,3-b]quinoxaline (27). The ﬁnal compound (28) was achieved by aminodebromination of (27) by an excess of secondary amines in boiling benzene. 27 All the synthesizedaminodebromination indoloquinoxalines of ( exhibited) by an excessinterferons of secondary inducing activities. amines in boiling benzene.

SchemeScheme 9. Synthetic 9. Synthetic pathway pathway to to prepare prepare Indoloquinoxalines Indoloquinoxalines (28 (28). ).

2.10. Using 6-chloro-7-fluoro-1,2-All the synthesizedDiaminobenzene indoloquinoxalines with Diketones exhibited interferons inducing activities. AIDS, which is Acquired immune deficiency syndrome, is caused by an immune deficiency virus called HIV. HIV weakens the immune system and makes the body susceptible to various infections [50]. Even though various anti-HIV drugs are available, they become resistant over time, which is the foremost hurdle in the treatment process. To overcome the virus-resistance, the utilization of integrase inhibitors with the anti-HIV drug has shown certifying results. To date, three drugs Raltegravir, Elvitegravir, and Dolutegravir, are available as intergrase inhibitors. Resistant to Raltegravir and Elvitegravir has been reported with no side effects [51]; therefore, the development of an anti-HIV drug is essential. In the pursuit to prepare the anti-HIV agents, Patel et al. [52] applied two ligands-based drug approaches: pharmacophore forming and 3D QSAR. The results were merged to prepare quinoxalines and their derivatives and were scrutinized for antiviral properties. A new sequence of 6-chloro-7-fluoro quinoxaline derivatives was formed, as indicated in Scheme 10. The first step entails the protection of the amino group of 3-chloro-4-fluoro benzamine (29) via acetylation reaction to give an intermediate N-(3-chloro-4-fluorophenyl)acetamide (30) with 89% yield. Further, the nitration reaction is carried out to yield another intermediate N-(2-nitro-4- fluoro-5-chlorophenyl)acetamide (31) with a 90% yield. The reduction of the nitro group to an amino 8 Molecules 2021, 26, 1055 9 of 30

2.10. Using 6-chloro-7-fluoro-1,2-Diaminobenzene with Diketones AIDS, which is Acquired immune deficiency syndrome, is caused by an immune deficiency virus called HIV. HIV weakens the immune system and makes the body susceptible to various infections [50]. Even though various anti-HIV drugs are available, they become resistant over time, which is the foremost hurdle in the treatment process. To overcome the virus-resistance, the utilization of integrase inhibitors with the anti-HIV drug has shown certifying results. To date, three drugs Raltegravir, Elvitegravir, and Dolutegravir, are available as intergrase inhibitors. Resistant to Raltegravir and Elvitegravir has been reported with no side effects [51]; therefore, the development of an anti-HIV drug is essential. In the pursuit to prepare the anti-HIV agents, Patel et al. [52] applied two ligands-based drug approaches: pharmacophore forming and 3D QSAR. The results were merged to prepare quinoxalines and their derivatives and were scrutinized for antiviral properties. A new sequence of 6-chloro-7-fluoro quinoxaline derivatives was formed, as indicated in Scheme 10. The first step entails the protection of the amino group of 3-chloro- 4-fluoro benzamine (29) via acetylation reaction to give an intermediate N-(3-chloro-4- fluorophenyl)acetamide (30) with 89% yield. Further, the nitration reaction is carried out to yield another intermediate N-(2-nitro-4-fluoro-5-chlorophenyl)acetamide (31) with a Molecules 2020, 25, x90% FOR yield.PEER REVIEW The reduction of the nitro group to an amino group ensued in the9 of forma- 32 tion of 1,2-diamino-4-chloro-4-fluorobenzene (33). The product was recrystallized with group ensued dichloromethanein the formation withof 1,2-diamino-4-chloro-4-fluorobenzene a 90% yield. The diamino group is engaged (33). The in ringproduct closure was with recrystallized withvarious dichloromethane diketones (34) with to generate a 90% yiel 6-chloro-7-fluorod. The diamino quinoxalines group is engaged (35), and in finalring purificationclosure with various diketonesis achieved (34) via to columngenerate chromatography. 6-chloro-7-fluoro The quinoxalines synthesized (35 compounds), and final (purification35) were assessed is achieved via columnfor their chromatograp anti-HIV activityhy. The and synthesized bulky substitutions compounds at ( C-2,35) were C-3 exhibited assessed for the their best anti-HIVanti- HIV activity andagents bulky compared substitutions to less at bulkyC-2, C-3 substitutions. exhibited the Furthermore, best anti-HIV the agents fluoro groupcompared at C-2, to C-3less also bulky substitutions.recorded Furthermore, as good anti-HIV the fluoro agents. group at C-2, C-3 also recorded as good anti-HIV agents.

Scheme 10. SchemeSynthesis 10. ofSynthesis 6-chloro-7-fluoroquinoxaline of 6-chloro-7-ﬂuoroquinoxaline derivatives derivatives (35) with reagents (35) with and reagents conditions: and conditions: (a) HOAc/Ac(a)2O, HOAc/Ac (b) 70%2 O,HNO (b)3 70%/concentrated HNO3/concentrated H2SO4 (c) concentrated H2SO4 (c) concentrated H2SO4, (d H) Zn/Hydrazinium2SO4,(d) Zn/Hydrazinium monoformate;monoformate; (e) (i) C2H5OH, (e)( i()Cii) 2CHH53OH,OH, ((iiiii)) CH HOAc:CH3OH, (iii3)OH HOAc:CH (3:2)/NaOAc,3OH (3:2)/NaOAc, (iv) HOAc/NaOAc. (iv) HOAc/NaOAc.

3. Synthetic Pathways to Prepare Biologically Active Quinoxaline Derivatives

3.1. Synthesis of Quinoxalin-2-Mercaptoacetyl Urea as Antiviral Agents A pandemic situation in western Africa infected almost 28,000 individuals in 2014–2015 (WHO: Ebola situation report 2015). Even though vaccines are existing, it adversely affects some patients; therefore, it becomes requisite to formulate new antiviral drugs and vaccines. A series of quinoxaline- 2-mercaptoacetyl urea analogs was devised by Loughran et al. [53] and tested for their antiviral properties on Marburg, Ebola VP40 VLP budding assays in HEK293T cells. The reaction Scheme 11 depicts the formulation of the target compound (38) by alkylation of quinoxaline thiols (36) with α-chloroacetamidoureas (37). The alkylating agents (37) were attained via the reaction of commercially available anilines or heteroaromatic amines (R-NH-Ar) with commercially available chloroacetyl isocyanate. The synthesized product quinoxalin-2-mercaptoacetyl urea showed improved potency as an RNA viral egress inhibitors and inhibited live virus egress (VSVM40).

9 Molecules 2021, 26, 1055 10 of 30

3. Synthetic Pathways to Prepare Biologically Active Quinoxaline Derivatives 3.1. Synthesis of Quinoxalin-2-Mercaptoacetyl Urea as Antiviral Agents A pandemic situation in western Africa infected almost 28,000 individuals in 2014–2015 (WHO: Ebola situation report 2015). Even though vaccines are existing, it adversely affects some patients; therefore, it becomes requisite to formulate new antiviral drugs and vaccines. A series of quinoxaline-2-mercaptoacetyl urea analogs was devised by Loughran et al. [53] and tested for their antiviral properties on Marburg, Ebola VP40 VLP budding assays in HEK293T cells. The reaction Scheme 11 depicts the formulation of the target compound (38) by alkylation of quinoxaline thiols (36) with α-chloroacetamidoureas (37). The alkylating agents (37) were attained via the reaction of commercially available anilines or heteroaromatic amines Molecules 2020, 25, x(R-NH-Ar) FOR PEER REVIEW with commercially available chloroacetyl isocyanate. 10 of 32

SchemeScheme 11. 11. SyntheticSynthetic pathway pathway to toprepare prepare quin quinoxalin-2-mercaptoacetyloxalin-2-mercaptoacetyl urea urea (38 (38). ). The synthesized product quinoxalin-2-mercaptoacetyl urea showed improved potency 3.2. Synthesis of Quinoxaline Nucleosides as Anti-HIV Agents as an RNA viral egress inhibitors and inhibited live virus egress (VSVM40). Quinoxalines have various pharmacological applications such as anti-inflammatory, antidepressant-tranquillizing,3.2. Synthesis of antitumor, Quinoxaline and Nucleosides anti-hepatitis as Anti-HIV B virus Agents (HBV) activity. The biological significance of quinoxalineQuinoxalines derivatives have prompted various pharmacological Ali et al. [54] to synthesize applications some such homo as anti-inﬂammatory, unsaturated acylnucleosidesantidepressant-tranquillizing, quinoxaline derivatives. antitumor, and anti-hepatitis B virus (HBV) activity. The bio- Numerous logicalacylonuclosides signiﬁcance analogs of quinoxaline have chemotherapeutic derivatives prompted antiviral Ali activities, et al. [54] toand synthesize structure- some activity relationshipshomo unsaturated in acylnucleosides acylnucleosides play quinoxaline a crucial derivatives. role in their antiviral target Numerous acylonuclosides analogs have chemotherapeutic antiviral activities, and stru enzymes(phosphorylation) [55]. cture-activity relationships in acylnucleosides play a crucial role in their antiviral target Scheme 12 illustrates the layout of a new series of acyclic quinoxaline nucleosides. The enzymes(phosphorylation) [55]. quinoxaline base (39) with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (40) in the Scheme 12 illustrates the layout of a new series of acyclic quinoxaline nucleosides. presence of NaH/DMFThe quinoxaline gives (41 base) which (39) withon further (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate acid hydrolysis yields 1-(2,3-dihydroxy propyl)- 6,7-dimethyl-quinoxaline-2-one(40) in the presence (42 of). The NaH/DMF target product gives (41 ()42 which) showed on further inhibition acid hydrolysisof HIV-1 with yields an 1-(2,3- EC50 value of 0.15dihydroxy ± 0.1 µg/mL propyl)-6,7-dimethyl-quinoxaline-2-one and a therapeutic index of (SI) 73. (42). The target product (42) showed inhibition of HIV-1 with an EC50 value of 0.15 ± 0.1 µg/mL and a therapeutic index of (SI) 73.

10 Molecules 2021, 26, 1055 11 of 30

Molecules 2020, 25, x FOR PEER REVIEW 11 of 32

SchemeScheme 12.12. SyntheticSynthetic pathwaypathway toto prepareprepare acyclicacyclic quinoxalinequinoxaline nucleosidesnucleosides ((4141,42,42).). 3.3. Synthesis of Penta-1,4-dien-3-one Oxime Containing a Quinoxaline Nucleus as 3.3. Synthesis Antiviralof Penta-1,4-dien-3 Agents -one Oxime Containing a Quinoxaline Nucleus as Antiviral Agents A well-knownA plant well-known virus is known plant virus as the is Tobacco known mosaic as the Tobaccovirus (TMV), mosaic which virus is known (TMV), to which infect is nine plant species,known toincluding infect nine tobacco, plant species, tomato, including pepper, tobacco,and cucumbers tomato, pepper, [56]. Controlling and cucumbers plant [56 ]. diseases, onceControlling infected, is planta severe diseases, problem once faced infected, by agriculture is a severe industries. problem Traditional faced by antimicrobial agriculture in- agents and plantdustries. virucides Traditional have caused antimicrobial resistance agents in plant and pathogens; plant virucides therefore, have causeda synthesis resistance of safe in agricultural chemicalsplant pathogens; is always therefore, in demand. a synthesis The of agricultural safe agricultural chemicals chemicals derived is always from in natural demand. products are Theenvironmentally agricultural chemicals friendly and derived have fromuniq naturalue bioactivities. products Xia are et environmentally al. [57] synthesized friendly a series of penta-1,4-dien-3-oneand have unique bioactivities.oxime comprising Xia et al.a [quinoxaline57] synthesized moiety, a series equivalent of penta-1,4-dien-3-one to curcumin oxime comprising a quinoxaline moiety, equivalent to curcumin isolated from plant Cur- isolated from plant Curcuma Longa L. The synthesized compounds displayed antibacterial and cuma Longa L. The synthesized compounds displayed antibacterial and antiviral activities, antiviral activities, with distinct activity against TMV. As revealed in Scheme 13, 2-chloroquinoxaline with distinct activity against TMV. As revealed in Scheme 13, 2-chloroquinoxaline (43) (43) and penta-1,4-dien-3-one oxime ether (44) were stirred for 30 min and refluxed for 4 h at 80 °C to and penta-1,4-dien-3-one oxime ether (44) were stirred for 30 min and refluxed for 4 h get the targetat compound 80 ◦C to get (45 the). The target product compound is recrystallized (45). The productwith acetonitrile is recrystallized and dichloromethane. with acetonitrile Some compoundsand dichloromethane. demonstrated significant, Some compounds beneficial, demonstrated protective, and significant, inactivation beneficial, activity protective, against TMV, with a and50% inactivationeffective concentration activity against (EC50) TMV, of 287.1, with a157.6, 50% effectiveand 133.0 concentration mg mL−1, respectively. (EC50) of The 287.1, findings were157.6, superior and133.0 to or mg equal mL− to1, respectively.those of ningnanmycin The findings (356.3, were superior 233.7, and to or 121.6 equal mg to thosemL−1, of respectively).ningnanmycin (356.3, 233.7, and 121.6 mg mL−1, respectively).

11 Molecules 2021, 26, 1055 12 of 30

Molecules 2020, 25, x FOR PEER REVIEW 12 of 32

Scheme 13. SchemeSynthetic pathway 13. Synthetic to prepare pathway penta-1,4-dien-3-one to prepare oxime penta-1,4-dien-3-one (45) with quinoxaline moiety. oxime (45) with quinoxaline moiety.

3.4. Synthesis of Methyl-2-[3-(3-phenylquinoxalin-2-ylsulfanyl)propanamidoalkanoates3.4. Synthesis of Methyl-2-[3-(3-phenylquinoxalin-2-ylsulfanyl)propanamidoalkanoates and N-Alkyl-3-((3- and phenyl quinoxalin-2ylsulfanyl)propanamides as Antitumor Agents N-Alkyl-3-((3-phenyl quinoxalin-2ylsulfanyl)propanamides as Antitumor Agents Quinoxalines have immense anticancer properties and experimented with in many research projects. Compounds Quinoxalineswith quinoxaline havenucleus immense have found anticancer ground in many properties anticancer and agents. experimented with in many Quinoxaline derivativesresearch validate projects. the right Compounds anticancer action withthrough quinoxaline separate mechanisms, nucleus involving have found ground in many tyrosine kinase inhibition,anticancer C-MET agents. kinase Quinoxalineinhibition, induction derivatives of apoptosis, validate tubulin polymerization the right anticancer action through inhibition, and selectiveseparate induction mechanisms, of tumors hypoxia involving [58]. tyrosine kinase inhibition, C-MET kinase inhibition, in- Rayes et al. [58] synthesized new sets of quinoxaline moieties coupled with amino acids, or N- alkylamines are ductionshown in Schemes of apoptosis, 14 and 15 tubulin to evaluate polymerization their antitumor activities. inhibition, Synthesis and of selective(47) induction of tumors is accomplishedhypoxia by reacting [58 phenylquinoxalines-2(1]. H)-thione (46) and triethylamine, with acrylic acid derivatives underRayes reflux for et al.4–6 [h.58 The] synthesized attained compound new (47 sets) was of treated quinoxaline with hydrazine moieties coupled with amino hydrate in ethylacids, alcohol oraffordedN-alkylamines (48) with 88% yield, are shownas depicted in in Schemes Scheme 15. 14The and reaction 15 wasto evaluate their antitumor further progressed with NaNO2 and HCl in an ice bath for 15 min. The azide derivative (49) is extracted with ethylactivities. acetate. Furthermore, Synthesis ( of49) (reaction47) is accomplishedwith amino acid methyl by reacting ester hydrochlorides phenylquinoxalines-2(1 H)-thione in the presence (of46 triethylamine) and triethylamine, yielded (50). Likewise, with acrylic the azide acid derivative derivatives was also under reacted reﬂuxwith for 4–6 h. The attained alkyl amines to procurecompound (51). (47) was treated with hydrazine hydrate in ethyl alcohol afforded (48) with The synthesized compounds (50,51) manifested unique anticancer properties with IC50′S in the 88% yield, as depicted in Scheme 15. The reaction was further progressed with NaNO2 low molar range. The most active compound exhibited IC50′S of 1.9 and 2.3 µg/mL on the HCT-116 and HCl in an ice bath for 15 min. The azide derivative (49) is extracted with ethyl acetate. and the MCF-7 cell lines, respectively, compared to reference drug doxorubicin (IC50 3.23 µg/mL). Therefore, it is indispensableFurthermore, to expand (49) this reaction area of study, with to amino prepare acidquinoxaline methyl derivatives ester hydrochlorides via the in the presence thiation of novelof 3-phenylquinoxalin-2(1 triethylamine yieldedH)-one to ( 50get). potent Likewise, anticancer the drugs. azide derivative was also reacted with alkyl Molecules amines2020, 25, x to FOR procure PEER REVIEW (51). 13 of 32

SchemeScheme 14. 14.SyntheticSynthetic pathway pathway to prepare to prepare S-alkyl S-alkylationation of ofphenyl phenyl quinoxaline-2(1 quinoxaline-2(1HH)-thione)-thione (47 (47) with) with ◦ reagentsreagents and and conditions: conditions: (a) (triethylamine/ethanol/reflux/78a) triethylamine/ethanol/reﬂux/78 °C/CHC/CH2=CHCOOC2=CHCOOC2H5. 2H5.

n R Abrv NR1R2

0 H Gly NH(CH2)2CH3

1 H β Alanine NH(CH2)13CH3

0 CH2COOCH3 L-Asp NH(CH2)3CH3

0 CH2CH2COOCH3 L-Glu NHCH2CH=CH2

0 CH(CH3)2 L-Val

0 CH2CH(CH3)2 L-leu

0 CH2CH2SCH3 L-Meth

Scheme 15. Synthetic pathways to prepare methyl-2-[3-(3-phenylquinoxalin-2- ylsulfanyl)propanamidoalkanoates (50) and N-alkyl-3-((phenylquinoxalin-2-yl

sulfanyl)propanamides (51) with reagents and conditions: (a) NH2NH2/C2H5OH/78 °C/reflux/4 h, (b)

13 Molecules 2020, 25, x FOR PEER REVIEW 13 of 32

Molecules 2021, 26, 1055 13 of 30 Scheme 14. Synthetic pathway to prepare S-alkylation of phenyl quinoxaline-2(1H)-thione (47) with

reagents and conditions: (a) triethylamine/ethanol/reflux/78 °C/CH2=CHCOOC2H5.

n R Abrv NR1R2

0 H Gly NH(CH2)2CH3

1 H β Alanine NH(CH2)13CH3

0 CH2COOCH3 L-Asp NH(CH2)3CH3

0 CH2CH2COOCH3 L-Glu NHCH2CH=CH2

0 CH(CH3)2 L-Val

0 CH2CH(CH3)2 L-leu

0 CH2CH2SCH3 L-Meth

Scheme 15.Scheme Synthetic 15. Synthetic pathways pathways toto prepare prepare methyl-2-[3-(3-phenylquinoxalin-2-ylsulfanyl)propanami methyl-2-[3-(3-phenylquinoxalin-2- ylsulfanyl)propanamidoalkanoatesdoalkanoates (50) and N-alkyl-3-((phenylquinoxalin-2-yl(50) and N-alkyl-3-((phenylquinoxalin-2-yl sulfanyl)propanamides (51) with reagents ◦ sulfanyl)propanamidesand conditions: (51) with (a) reagents NH2NH 2and/C 2conditions:H5OH/78 (aC/reﬂux/4) NH2NH2/C h,2H (b5)OH/78 NaNO °C/reflux/42/HCl/H2 O/reﬂux/15h, (b) min, (c) NH (CH )nCHRCOOCH /HCl/triethylamine/ethyl acetate/25 ◦C/24 h, (d)NHR1R2/ethyl 2 2 3 13 acetate/25 ◦C/24 h.

The synthesized compounds (50,51) manifested unique anticancer properties with IC500S in the low molar range. The most active compound exhibited IC500S of 1.9 and 2.3 µg/mL on the HCT-116 and the MCF-7 cell lines, respectively, compared to reference drug doxorubicin (IC50 3.23 µg/mL). Therefore, it is indispensable to expand this area of study, to prepare quinoxaline derivatives via the thiation of novel 3-phenylquinoxalin- 2(1H)-one to get potent anticancer drugs. Molecules 2020, 25, x FOR PEER REVIEW 14 of 32 Molecules 2021, 26, 1055 14 of 30

NaNO2/HCl/H2O/reflux/15 min, (c) NH2(CH2)nCHRCOOCH3.HCl/triethylamine/ethyl acetate/25 °C/24 h, (d)NHR1R2/ethyl acetate/25 °C/24 h. 3.5. Synthesis of Quinoxaline Derivatives as Anticancer Agents 3.5. Synthesis of Quinoxaline Derivatives as Anticancer Agents Cancer is still a cause of significant deaths globally and is contemplated as a signif- Cancer isicant still health a cause problem. of significant Quinoxalines deaths globally are an essentialand is contemplated base for anticancer as a significant drugs and health have problem. Quinoxalinesproved to possessare an essential selective base adenosine for anticancer triphosphate drugs and (ATP) have inhibitors proved into manypossess kinases selective [59 ]. adenosine triphosphateThe antitumor (ATP) activity inhibitors of kinase in many inhibitors kinases comprising [59]. The diaryl antitumor urea has activity earned of immense kinase inhibitors comprisingattention diaryl because urea of has its earned binding immense mode. Owingattention to because its beneficial of its binding anticancer mode. properties, Owing to its beneficialAbouzid anticancer et al. properties, [60] synthesized Abouzid an et array al. [60] of quinoxaline-basedsynthesized an array compounds of quinoxaline-based with amide, compounds withurea, amide, thiourea, urea, and thiourea, sulfonamide and sulfonam moieties.ide Quinoxalines moieties. Quinoxalines is derived is from derived the reaction from the of o-phenylenediamine and α-keto-carboxylic acids [61]. The chloroquinoxalines (52) were reaction of o-phenylenediamine and α-keto-carboxylic acids [61]. The chloroquinoxalines (52) were further refluxed with m-aminobenzoic acid in n-butanol, the solution was left to cool, further refluxed with m-aminobenzoic acid in n-butanol, the solution was left to cool, and the surplus and the surplus of m-aminobenzoic acid was removed, dissolving in 5% NaOH and pre- of m-aminobenzoic acid was removed, dissolving in 5% NaOH and precipitated by dropwise cipitated by dropwise addition of concentrated HCl. The intermediate (53) was activated addition of concentratedas acid chloride HCl. derivatives The intermediate (54) by refluxing(53) was activated with an excess as acid of chloride thionyl chloridederivatives [62 ](54 and) by refluxingthen with followed an excess by of treatment thionyl withchloride the appropriate[62] and then amount followed of aromaticby treatment amines with (aniline, the appropriate p-chloroaniline,amount of aromatic p-methoxyaniline) amines in(an dichloromethane,iline, p-chloroaniline, yielding thep-methoxyaniline) final product (55 )[63in ], dichloromethane,as indicated yielding in the Scheme final product16. (55) [63], as indicated in Scheme 16.

Scheme 16.Scheme Synthetic 16. Synthetic pathway pathway for preparing for preparing (55) with (55 reagents) with reagents and conditions: and conditions: (a) m-aminobenzoic (a) m-aminobenzoic acid/Bu-OH/concacid/Bu-OH/conc HCl/reflux/5 HCl/reflux/5 h, (b) thionyl h, (b) thionylchloride/dry chloride/dry benzene/reflux/5 benzene/reflux/5 h, (c) aromatic h, (c) aromatic amines/TEA/dryamines/TEA/dry DCM/reflux/5 DCM/reflux/5 h. h.

In another route,In another (Scheme route, 17) (Scheme 2,3-dichloroquin 17) 2,3-dichloroquinoxalineoxaline was refluxed was with reﬂuxed p-phenylenediamine with p-phenylene to get an amidediamine intermediate to get an (56 amide). The amide intermediate derivative (56 ).on The further amide treatment derivative with on phenyl further isocyanate, treatment with phenyl isocyanate, phenyl isothiocyanate in dry toluene resulted in thiourea and urea phenyl isothiocyanate in dry toluene resulted in thiourea and urea quinoxaline derivatives (57,58) quinoxaline derivatives (57,58)[64]. [64].

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SchemeScheme 17. Synthetic 17. Synthetic pathway pathway for the for preparation the preparation of ( of57 ()57 and) and (58 ()58 with) with reagents reagents and and conditions, conditions, (a (a) ) p- p-phenylenediamine/phenylenediamine/n-butanol/110°,n-butanol/110 (b◦),( benzeneb) benzene sulphonyl sulphonyl chlori chlorides/drydes/dry pyridine/2 pyridine/2 h, (c h,) (phenylc) phenyl isocyanatesisocyanates or isothiocyanate or isothiocyanates/drys/dry toluene/reflux/5 toluene/reﬂux/5 h. h.

The preparedThe preparedquinoxaline quinoxaline scaffolds scaffoldswere screened were screenedfor their cytotoxicity for their cytotoxicity against three against tumor three cell lines. Sometumor of the cell prepared lines. Some quinoxaline of the prepared derivatives quinoxaline (58) had activity derivatives against (58 human) had activity colon carcinoma against (HCT 116)human cell lines colon (IC50 carcinoma = 2.5 µM). (HCT Therefore, 116) cell it lines is an (IC50 exemplar = 2.5 µ compoundM). Therefore, for itfurther is an exemplarstudies for the optimizationcompound and for development further studies of anticancer for the optimization drugs. and development of anticancer drugs. 3.6. Synthesis of 4-(2-Methyl quinoxaline-3-yloxy)benzaldehyde and 3.6. SynthesisN-((4-(2-methylquinoxaline-3-yloxy)phenyl)methylene)-4-Substituted of 4-(2-Methyl quinoxaline-3-yloxy)benzaldehyde and N-((4-(2-methylquinoxaline-3- Benzenamine as yloxy)phenyl)methylene)-4-SubstAntibacterial/Antifungalituted Agents Benzenamine as Antibacterial/Antifungal Agents An aim toAn synthesize aim to synthesize new Schiff new bases Schiff contai basesning containing quinoxaline quinoxaline moieties moieties using 2-chloro-3- using 2- chloro-3-methylquinoxaline as a reactant was created by Singh et al. [65]. The C2 chlo- methylquinoxaline as a reactant was created by Singh et al. [65]. The C2 chlorine is replaced by an rine is replaced by an ether linkage affixed to a benzene ring having a free aldehyde ether linkage affixed to a benzene ring having a free aldehyde or amine group. The reaction Scheme or amine group. The reaction Scheme 18, expounds the synthetic pathway to prepare 18, expounds the synthetic pathway to prepare 4-(2-methyl quinoxaline-3-yloxy)benzaldehyde (60) 4-(2-methyl quinoxaline-3-yloxy)benzaldehyde (60) and N-((4-(2-methylquinoxaline-3- and N-((4-(2-methylquinoxaline-3-yloxy)phenyl)methylene)-4-substitutedyloxy)phenyl)methylene)-4-substituted benzenamine (63) using 2-chloro-3-methyl benzenamine (63 quinox-) using 2- chloro-3-methylaline(59 quinoxaline(). A mixture59 of). ( 59A) mixture and 4-hydroxy of (59) benzaldehydeand 4-hydroxy was benzaldehyde refluxed in acetonitrilewas refluxed for in acetonitrile30 for h to 30 afford h to afford (60) as (60 an) intermediate.as an intermediate. The intermediate The intermediate (60) on (60 treating) on treating with assorted with assorted sub- substitutedstituted amines amines yielded yielded (62). In (62 another). In another pathway, pathway, the nucleus the nucleus (59) is ( 59treated) is treated with 4-amino with 4-amino phenol and refluxedphenol for 30 and h in refluxed acetonitrile for 30 to hget in a acetonitrile second intermediate to get a second (62). The intermediate final quinoxaline (62). The derivative final (63) is generatedquinoxaline by the derivative reaction (of63 )(62 is) generated with substituted by the reaction aromatic of al (62dehydes.) with substituted All compounds aromatic were purified usingaldehydes. ethanol, All with compounds a 60–70% were yields. purified using ethanol, with a 60–70% yields. All synthesized compounds were checked for their antimicrobial activities. Most of the newly formed Schiff bases [17,19] were screened for antibacterial and antifungal properties with promising

15 Molecules 2020, 25, x FOR PEER REVIEW 16 of 32 Molecules 2021, 26, 1055 16 of 30 results. Therefore, it keeps an open window to synthesize more novel quinoxalines and study for their anti-infectious properties.

Scheme 18.Scheme Synthetic 18. Synthetic pathway pathway to prepare to prepare the Schiff the bases Schiff ( bases61) and (61 )(63 and) with (63) withreagents reagents and and conditions, conditions, (a) 4- (a) 4-Hydroxybenzaldehyde/anhydrousHydroxybenzaldehyde/anhydrous K K2CO2CO3/acetonitrile/reflux,3/acetonitrile/reflux, ( (bb)) substitutedsubstituted amines/ethanol/reflux. amines/ethanol/ (c) reflux. 4-aminophenol/anhydrous(c) 4-aminophenol/anhydrous K2CO3/acetonitrile/reflux, K2CO3/acetonitrile/reflux, (d) substituted benzaldehyde/ethanol/reflux.(d) substituted benzaldehyde/ethanol/reflux. All synthesized compounds were checked for their antimicrobial activities. Most of the newly formed Schiff bases [17,19] were screened for antibacterial and antifungal properties 3.7. Synthesis of 2-(5-Arylthiazolo[2,3-c][1,2,4]triazol-3-yl)quinoxaline Derivatives as TP Enzyme Inhibitor with promising results. Therefore, it keeps an open window to synthesize more novel Over thequinoxalines last years, several and study derivatives for their of anti-infectious the six-membered properties. ring with two nitrogen atoms have been synthesized and were reported to show inhibition for Thymidine phosphorylase(TP) [66], which is one of the classes3.7. Synthesis of enzymes of 2-(5-Arylthiazolo[2,3-c][1,2,4]triazol-3-yl)quinoxaline involved in catabolism for both prokaryotic and Derivatives eukaryotic as organisms TP Enzyme Inhibitor [67–69]. The low-cost synthesis and large-scale preparations of 2-(5-arylthiazolo [2,3-c] [1,2,4] triazol- Over the last years, several derivatives of the six-membered ring with two nitrogen 3-yl)quinoxalines were synthesized by Almandil et al. [70]. The quinoxaline-2-carbohydrazide (64) is atoms have been synthesized and were reported to show inhibition for Thymidine phos- treated with potassium thiocyanate(KSCN) in the presence of an acid, followed by basic solution phorylase(TP) [66], which is one of the classes of enzymes involved in catabolism for both treatment to develop (65), as set in reaction Scheme 19. Furthermore, the formed intermediate (65) prokaryotic and eukaryotic organisms [67–69]. The low-cost synthesis and large-scale was reacted preparationswith several ofsubstituted 2-(5-arylthiazolo phenacyl [2,3-c] bromide [1,2,4] to triazol-3-yl)quinoxalines afford the crude compound were synthesized (66). The product wasby washed Almandil with et al.water [70]. and The quinoxaline-2-carbohydrazidepurified using hot methanol (with64) is a treated 75–80% with yield. potassium The synthesized quinoxalinethiocyanate(KSCN) derivatives in the(66) presence were screened of an acid,for inhibitory followed potential by basic against solution TP treatment enzymes. to develop (65), as set in reaction Scheme 19. Furthermore, the formed intermediate (65) was reacted with several substituted16 phenacyl bromide to afford the crude compound Molecules 2021, 26, 1055 17 of 30

Molecules 2020, 25(66, x ).FOR The PEER product REVIEW was washed with water and puriﬁed using hot methanol with a17 75–80% of 32 yield. The synthesized quinoxaline derivatives (66) were screened for inhibitory potential They displayedagainst a range TP of enzymes. inhibition They with displayed IC50 between a range 3.50 of inhibition± 0.20 to 56.40 with ± IC50 1.20 betweenµM as compared 3.50 ± 0.20 to to ± µ ± µ standard 7-Deazaxanthine56.40 1.20 withM as IC50 compared = 38.68 to ± standard1.12 µM. 7-Deazaxanthine with IC50 = 38.68 1.12 M.

Scheme 19.Scheme Synthetic 19. pathwaySynthetic to pathway prepare to2-(5-arylthiazo prepare 2-(5-arylthiazolo[2,3-c][1,2,4]triazol-3-yl)quinoxalinelo[2,3-c][1,2,4]triazol-3-yl)quinoxaline (66) derivatives.(66 ) derivatives.

3.8. Synthesis 3.8.of Spiro[thiadozoline-quinoxa Synthesis of Spiro[thiadozoline-quinoxaline]line] Derivatives as DerivativesAntibacterial as Agents Antibacterial Agents 1,3-dipolar cycloaddition is a subject of intense research owing to their great synthetic 1,3-dipolarvalue. cycloaddition It is a synthesis is a subject of five-membered of intense re heterocyclicsearch owing compounds to their great with synthetic significant value. physio- It is a synthesislogical of five-membered properties. Synthesis heterocyclic of spiro[thiadiazoline-quinoxaline] compounds with significant physiological derivatives was properties. developed Synthesis of spiro[thiadiazoline-quinoxaline]by Mokhtar et al. [71] by 1,3-dipolar derivatives cycloaddition was developed of 3-methylquinoxaline-2-thione by Mokhtar et al. [71] by 1,3- and dipolar cycloadditiontheir N-alkylated of 3-methylquinoxaline-2-thione derivatives. As presented inand reaction their Scheme N-alkylated 20, thionation derivatives. of N-alkyl As presented inquinoxaline reaction Scheme (67) with 20, phosphorous thionation of pentasulphide(P N-alkyl quinoxaline4S10) in refluxing(67) with pyridine phosphorous formed pentasulphide(Pvarieties4S10) in of refluxing alkyl quinoxaline pyridine derivativesformed varieties (68). On of furtheralkyl quinoxaline investigation, derivatives 1,3-dipolar (68 cycload-). On further investigation,dition was 1,3-dipolar performed cycloaddition on 1-ethyl-3-methyl was performed quinoxaline-2-thione on 1-ethyl-3-methyl (69) with quinoxaline-2- an equimolar thione (69) withquantity an equimolar of diphenyl quantity hydrazonoyl of diphenyl (70 ).hydrazonoyl The reaction (70 mixture). The reaction is refluxed mixture in dry is tetrahydro-refluxed 71 in dry tetrahydrofuran(THF)furan(THF) in the in presence the presence of triethylamine of triethylamine (Et3N). One(Et3N). cycloadduct One cycloadduct ( ) was obtained(71) was on obtained on aa dipolarophillic dipolarophillic group group C=S. C=S. Diphenyl Diphenyl nitrile nitrile imine imine ylide(DPNI) ylide(DPNI) is isgenerated generated in insitu situ from from diphenyl hydrazonoyl chloride. diphenyl hydrazonoyl chloride. The newly derived spiro[thiadiazoline-quinoxaline] exhibited antibacterial activities. As reported, the ethyl group’s presence enhanced the properties by 64 µg/mL against streptococcus fascines to 128 µg/mL against S.aureus. Further studies on spiro[thiadiazoline-quinoxaline] should be examined on other pathogens.

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Scheme Scheme20. Synthetic 20. pathwaySynthetic to prepare pathway Spiro[thiadozoline-quinoxaline]derivatives to prepare Spiro[thiadozoline-quinoxaline]derivatives (71). (71). 3.9. Synthesis of Bistetrazoloquinoxalines as Antiallergic Agents The newly derived spiro[thiadiazoline-quinoxaline] exhibited antibacterial activities. Tetrazoles are a class of heterocyclic compounds comprising the five-membered ring with four µ nitrogen atoms andAs one reported, carbon atom the. The ethyl fusion group’s of tetrazoles presence with quinoxalines enhanced displays the properties remarkable by 64 g/mL against strep- biological activities;tococcus for example, fascines 4-chlorotetrazolo to 128 µ-(1,5-a)g/mL quinoxalines against S.aureus. obstruct mast Further cell-mediated studies on spiro[thiadiazoline- allergic reactionsSchemequinoxaline] [72]. 20.The Synthetic synthesis should ofpathway bistetrazolo-[1,5-a; be examined to prepare 5 on′, Spiro[thiadozoline-quinoxaline]derivatives1′-c]-quinoxalines other pathogens. was designed by (71). Prasanna. et al. [73] using one-pot three-component synthesis. Scheme 21, displays the reaction of 2,3-diketoquinoxalines3.9. Synthesis (72) with POCl of Bistetrazoloquinoxalines3(Phosphorous oxychloride) and as sodium Antiallergic azide, resulting Agents in the 3.9.formation Synthesis of bistetrazoloquinoxalines of Bistetrazoloqui noxalines(73). The reaction as Antiallergic mixture was Agents refluxed for 2–3 h, cooled, poured in crushed ice, andTetrazoles recrystallized are by a classrectified of spirit. heterocyclic The starting compounds material (73) is comprisingsynthesized the five-membered ring by condensationTetrazoles withof o-phenylenediamine are four a class nitrogen of heterocyclic with atoms oxalic and acid compounds onein 4N carbonHCl, applying atom.comprising Philip’s The procedure fusion the five-membered of [74]. tetrazoles with ring quinoxalines with four nitrogenTherefore, good atoms displaysyields, and short one remarkable reaction carbon times, atom biologicaland. The ease fusionof preparations activities; of tetrazoles certify for example, an with ideal quinoxalinesreaction 4-chlorotetrazolo-(1,5-a) to displays remarkable quinox- prepare bistertazoloquinoxalines. biological activities;alines obstruct for example, mast cell-mediated4-chlorotetrazolo allergic-(1,5-a) reactions quinoxalines [72]. Theobstruct synthesis mast ofcell-mediated bistetrazolo- allergic reactions[1,5-a; [72]. 50, 1The0-c]-quinoxalines synthesis of bistetrazolo-[1,5-a; was designed by Prasanna. 5′, 1′-c]-quinoxalines et al. [73] using was one-potdesigned three- by Prasanna. et componental. [73] using synthesis. one-pot Schemethree-component 21, displays synthesis. the reaction Scheme of 2,3-diketoquinoxalines 21, displays the reaction (72) with of 2,3-diketoquinoxalinesPOCl3(Phosphorous (72) with POCl oxychloride)3(Phosphorous and sodium oxychloride) azide, and resulting sodium in azide, the formation resulting of in biste- the formation oftrazoloquinoxalines bistetrazoloquinoxalines (73). The(73). reaction The reaction mixture mixture was refluxed was refluxed for 2–3 h,for cooled, 2–3 h, poured cooled, in poured in crushedcrushed ice, ice, and and recrystallized recrystallized by by rectified rectified spirit. spirit. The The starting starting material material (73 (73) is) is synthesized synthesized by condensationby condensation of o-phenylenediamine of o-phenylenediamine with oxalic acid with in 4N oxalic HCl, acidapplying in 4N Philip’s HCl, applying procedure Philip’s [74]. Therefore, goodprocedure yields, [74short]. Therefore, reaction times, good and yields, ease short of preparations reaction times, certify and an ease ideal of preparationsreaction to prepare bistertazoloquinoxalines.certify an ideal reaction to prepare bistertazoloquinoxalines.

Scheme 21. Synthetic pathway to prepare bistetrazoloquinoxalines (73) via one-pot synthesis. 18

SchemeScheme 21. Synthetic 21. Synthetic pathway pathway to prepare to prepare bistetrazoloquinoxalines bistetrazoloquinoxalines (73) via (73 )one-pot via one-pot synthesis. synthesis. 18 Molecules 2020, 25, x FOR PEER REVIEW 19 of 32

3.10. Synthesis of 4-{4-[2-(4-(2-Substituted quinoxaline-3-yl)piperazin-1-yl)ethyl] phenyl} Thiazoles Antipsychotic Agents Molecules 2021, 26, 1055 19 of 30 Schizophrenia is a lifelong psychotic disorder that affects a small percentage of people and is considered a significant problem to existing health diseases worldwide [75]. The development of antipsychotic3.10. drugs Synthesis was offirst 4-{4-[2-(4-(2-Substituted introduced in the 1950s quinoxaline-3-yl)piperazin-1-yl)ethyl] to manage schizophrenia, which phenyl} was the first breakthroughThiazoles in this Antipsychotic field [76]. In Agents a novel quest to prepare antipsychotic drugs with minimum side effects, ChandraSchizophrenia Sekhar synthesized is a lifelong a series psychotic of 4-{4-[2-(4-(2-substituted disorder that affects quinoxaline-3-yl)piperazin- a small percentage of peo- 1-yl)ethyl]ple phenyl and thiazoles is considered (81), a novel significant atypical problem antipsychotics to existing [77]. health The reaction diseases Scheme worldwide 22 exhibits [75]. the formationThe development of 2-Chloro-3-(piperazin-2-yl)quinoxaline of antipsychotic drugs was first ( introduced76) and 2-methoxy-3-(piperazin-2- in the 1950s to manage yl)quinoxalineschizophrenia, (78), which which is one wasof the the prime first compon breakthroughents to inprepare this field antipsychotic [76]. In a drug. novel quest to The chloroprepare compound antipsychotic (74) on drugs reacting with with minimum piperazine side (75 effects,) in the Chandra presence Sekhar of anhydrous synthesized Na2CO a 3 yielded (76series). Furthermore, of 4-{4-[2-(4-(2-substituted 2-chloro-3-methoxy quinoxaline-3-yl)piperazin-1-yl)ethyl] quinoxaline (77) was attained phenylon stirring thiazoles with methanol (81),in the a novelpresence atypical of phase antipsychotics transfer cata [77lyst]. The triethyl-benzyl reaction Scheme ammonium 22 exhibits chloride(TEBAC) the formation of at room temperature,2-Chloro-3-(piperazin-2-yl)quinoxaline which on further reaction with (76 piperazine) and 2-methoxy-3-(piperazin-2-yl)quinoxaline in acetonitrile yielded 2-methoxy-3- (piperazin-2-yl)(78), which quinoxaline is one of (78 the). prime components to prepare antipsychotic drug.

SchemeScheme 22. Synthetic 22. Synthetic pathway pathway to prepare to prepare piperazinyl piperazinyl quinoxalines quinoxalines (76,78). (76,78).

In the last Thestep, chloro the prepared compound piperazinyl (74) on quinoxalines reacting with (79 piperazine) and chloroethyl (75) in phenyl the presence thiazoles of an-(80) in equimolarhydrous quantity Na 2inCO the3 yieldedpresence (76 of). Na Furthermore,2CO3 and a catalytic 2-chloro-3-methoxy amount of KI quinoxaline in DMF, afforded4-{4- (77) was [2-(4-(2-subsitutedquinoxalin-3-yl)piperazin-1-yl)ethyl]attained on stirring with methanol in the presence phenyl} of phase thiazoles transfer (81 catalyst) as the final triethyl-benzyl product, as shown in ammoniumScheme 23. chloride(TEBAC) The synthesized at compounds room temperature, (81) were which evaluated on further for reaction their antipsychotic with piperazine in acetonitrile yielded 2-methoxy-3-(piperazin-2-yl) quinoxaline (78). activities in animals as models. Some of the synthesized quinoxalines (81) were more active than In the last step, the prepared piperazinyl quinoxalines (79) and chloroethyl phenyl standard drug Risperidone, hence satisfying all criteria to be classified as an antipsychotic drug thiazoles (80) in equimolar quantity in the presence of Na CO and a catalytic amount of according to Meltzer’s classification [78]. Further studies of this synthesized2 3 drug (81) are crucial for KI in DMF, afforded4-{4-[2-(4-(2-subsitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} a breakthroughthiazoles in schizophrenia (81) as the final and product, other asmental shown disorders in Scheme in 23patients.. The synthesized compounds (81) were evaluated for their antipsychotic activities in animals as models. Some of the synthesized quinoxalines (81) were more active than standard drug Risperidone, hence satisfying all criteria to be classified as an antipsychotic drug according to Meltzer’s classification [78]. Further studies of this synthesized drug (81) are crucial for a breakthrough in schizophrenia and other mental disorders in patients.

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Scheme 23. SyntheticScheme pathway 23. Synthetic to prepare pathway 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1- to prepare 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1- yl)ethyl] phenyl} thiazoles (81). yl)ethyl] phenyl} thiazoles (81).

3.11. Synthesis of Quinoxaline-2,3(1H,4H)-Dithione Derivatives as Antimicrobial Agents Scheme 23. 3.11.Synthetic Synthesis pathway of to Quinoxaline-2,3(1H,4H)-Dithione prepare 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1- Derivatives as Antimicrobial Agents The synthesis of quinoxaline-2,3-(1H,4H)-dithione was summarized by Baashen 2018. [79], yl)ethyl] phenyl} thiazolesThe synthesis(81). of quinoxaline-2,3-(1H,4H)-dithione was summarized by Baashen which is a key method to prepare quinoxaline dithione derivatives in heterocyclic chemistry. 2018. [79], which is a key method to prepare quinoxaline dithione derivatives in heterocyclic Quinoxaline-2,3(13.11. Synthesis ofH Quinoxalin,4H)-dithionee-2,3(1H,4H)-Dithione (59) can be synthesized Derivati byves using as Antimicrobial a wide range Agents of thionating agents such as phosphorouschemistry. pentasulfide, Quinoxaline-2,3(1 thiourea, and sodiumH,4 Hhydrogen)-dithione sulfide (59 )[80,81] can beas synthesizedillustrated in by using a wide range SchemeThe 24. synthesis The thionationof thionatingof quinoxaline-2,3-(1H,4H)-dith of quinoxaline-2,3(1H,4H)-dione agents such asione phosphorous was ( 82summarized) with pentasulfide, a crystalline by Baashen zwitterionic thiourea, 2018. [79], and sodium hydrogen which is a key method to prepare quinoxaline dithione derivatives in heterocyclic chemistry. dipyridine-diphosphorussulfide pentasulfi [80,81]de as complex illustrated in refluxing in Scheme pyridine 24. for The 1 h thionation produces quinoxaline- of quinoxaline-2,3(1H,4H)-dione 2,3(1Quinoxaline-2,3(1H,4H)-dithioneH (84,4H) )-dithionewith 83% yield.(59) can The be reaction synthesized of 2,3-dichloroquinoxaline by using a wide range (of83 thionating) with thiourea agents such as phosphorous(82) withpentasulfide, a crystalline thiourea, zwitterionic and sodium hydrogen dipyridine-diphosphorus sulfide [80,81] as illustrated pentasulfide in complex in re- affords (84) in moderatefluxing to good pyridine yields. The for best 1 h yield produces (86%) of quinoxaline-2,3(1 quinoxaline-2,3(1H,4HH)-dithione,4H)-dithione was (84) with 83% yield. synthesizedScheme 24. by The treatment thionation of (83 of) with quinoxaline-2,3(1H,4H)-dione sodium hydrogen sulfide(NaSH) (82) with in ethanol a crystalline under refluxzwitterionic for 5 h followeddipyridine-diphosphorus by neutraThelization reaction pentasulfi with acid. ofde 2,3-dichloroquinoxaline complex in refluxing pyridine (83 for) 1 with h produces thiourea quinoxaline- affords (84) in moderate to 2,3(1H,4H)-dithionegood (84) yields. with 83% The yield. best The yield reaction (86%) of 2,3-dichloroquinoxaline of quinoxaline-2,3(1 (83H) ,4withH)-dithione thiourea was synthesized by affords (84) in moderatetreatment to good of yields. (83) with The best sodium yield (86%) hydrogen of quinoxaline-2,3(1 sulfide(NaSH)H,4H)-dithione in ethanol was under reflux for 5 h synthesized by treatmentfollowed of by(83) neutralizationwith sodium hydrogen with sulfide(NaSH) acid. in ethanol under reflux for 5 h followed by neutralization with acid.

Scheme 24. Synthetic pathway to prepare quinoxaline-2,3(1H,4H)-dithione (84), using thionating reagents.

20 Scheme 24. SyntheticScheme pathway 24. Synthetic to prepare pathway quinoxaline-2,3(1 to prepareH,4H quinoxaline-2,3(1)-dithione (84), usingH thionating,4H)-dithione (84), using thionating reagents. reagents. 20 The synthesized quinoxaline dithiones were further modiﬁed to provide different quinoxaline based heterocyclic compounds. The synthesized compounds should be investigated for their antimicrobial properties like antiviral, antibacterial, antifungal. The depicted Scheme 25 exempliﬁes the synthesis of quinoxaline dithione derivatives. Molecules 2020, 25, x FOR PEER REVIEW 21 of 32

The synthesized quinoxaline dithiones were further modified to provide different quinoxaline Molecules 2021based, 26, 1055 heterocyclic compounds. The synthesized compounds should be investigated for their 21 of 30 antimicrobial properties like antiviral, antibacterial, antifungal. The depicted Scheme 25 exemplifies the synthesis of quinoxaline dithione derivatives.

Scheme 25. SyntheticScheme pathway 25. Synthetic to prepare pathway derivatives to prepare of quinoxaline-2,3-dithiones derivatives of quinoxaline-2,3-dithiones (85,86,87), using (85 ,86,87), using different reagents,different (a) alkynonitriles/dioxane/KOH/heated reagents, (a) alkynonitriles/dioxane/KOH/heated at temp 20–25 °C/1 at temp h, ( 20–25b) 3-phenyl-2-◦C/1 h, (b) 3-phenyl-2- propynonitrile/dioxane/KOH/heatedpropynonitrile/dioxane/KOH/heated at temp 20–25 °C/5 at temp h, ( 20–25c) acetylene/dioxane/KOH/heated◦C/5 h, (c) acetylene/dioxane/KOH/heated at at ◦ temp 200–250 °C/1temp h. 200–250 C/1 h. 3.12. Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline and 3.12. Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline as Anti- bis([1,2,4]triazolo)[4,3-a:30,40-c]quinoxaline as Anti-Tumor Agents Tumor Agents A new series of [1,2,4]triazolo[4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:30,40- A new series ofc]quinoxaline [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been and bis([1,2,4]triazolo)[4,3-a:3 synthesized by Ibrahim′ et,4′-c]quinoxaline al. [82]. Furthermore, derivatives have beenthey synthesize were biologicallyd by Ibrahim evaluated et foral. their[82]. cytotoxicFurthermore, activities they against were threebiologically tumor cell lines evaluated for their (HePG-2,cytotoxic activities Hep-2, and against Caco-2). three Further tumor studiescell lines were (HePG-2, planned Hep-2, to evaluate and Caco-2). their topoiso- Further studies weremerase planned 11(Topo to evaluate 11) inhibitions their topoisomerase and DNA intercalating 11(Topo 11) afﬁnities inhibitions as prospective and DNA antiprolif- intercalating affinitieserative as prospective activities. antiproliferative As shown in reaction activities. Scheme As shown26, the in target reaction compounds Scheme 26,91, the92, 93 have target compounds 91been, 92, prepared93 have been by stirring prepared 2, 3-dichloroquinoxalineby stirring 2, 3-dichloroquinoxaline with hydrazine with hydrate hydrazine to afford 89, hydrate to afford which89, which on subsequent on subsequent heating heating with triethylorthoformate with triethylorthoformate gives 4-chloro gives [1,2,4]triazolo[4,3-4-chloro a]quinoxaline (90). The intermediate 90 afforded three different quinoxaline derivatives [1,2,4]triazolo[4,3-a]quinoxaline (90). The intermediate 90 afforded three different quinoxaline on treatment with hydrazine hydrate to get 4-hydrazinyl-[1,2,4] triazolo[4,3-a]quinoxaline derivatives on treatment with hydrazine hydrate to get 4-hydrazinyl-[1,2,4] triazolo[4,3- (91), with alkyl amines to get (92) and aliphatic alcohols to produce (93). a]quinoxaline (91), with alkyl amines to get (92) and aliphatic alcohols to produce (93). In another synthetic route, as demonstrated in Scheme 27, the synthesized compound (91) on treatment with an alcoholic solution of CS2 and KOH produced bis [1,2,4] triazolo[4, 3-a: 30, 40-c]quinoxaline-3-thiol (95). The Potassium salt (96) on treatment with ethyl-4- bromobutyrate in dry DMF afforded (97).

21 Molecules 2021, 26, 1055 22 of 30

Molecules 2020, 25, x FOR PEER REVIEW 22 of 32

Scheme 26.Scheme Synthetic 26. pathwaySynthetic to prepare pathway [1,2,4]triazolo[4,3-a]quinoxaline to prepare [1,2,4]triazolo[4,3-a]quinoxaline (91,92,93) with reagents (91,92,93) with reagents and conditions (a) NH2NH2.H2O/ethanol/room temperature, (b) triethyl orthoformate/reflux/4 h, (c)

NH2NH2.Hand2O/ethanol/reflux/4 conditions ( h,a) (d NH) alkylamines/TEA/reflux/42NH2.H2O/ethanol/room h, (e) aliphatic temperature, alcohols/TEA/reflux/4 (b) triethyl orthoformate/reflux/4 h, h. (c) NH2NH2.H2O/ethanol/reflux/4 h, (d) alkylamines/TEA/reflux/4 h, (e) aliphatic alcohols/TEA/reflux/4 h. In another synthetic route, as demonstrated in Scheme 27, the synthesized compound (91) on Molecules 2020, 25, x FOR PEER REVIEW 23 of 32 treatment with an alcoholic solution of CS2 and KOH produced bis [1,2,4] triazolo[4, 3-a: 3′, 4′- c]quinoxaline-3-thiol (95). The Potassium salt (96) on treatment with ethyl-4-bromobutyrate in dry DMF afforded (97). Compounds 91 and 95 demonstrated the highest activities against the observed cell lines (tumor cells) with IC50 values ranging from 0.29 to 0.90 µM comparable to doxorubicin (IC50 ranging from 0.51 to 0.73 µM).

Scheme Scheme27. Synthetic 27. pathwaySynthetic to prepare pathway deriva totive prepare of bis([1,2,4]triazolo)[4,3-a:3 derivative of bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline 0,40-c]quinoxaline (97) with reagents and conditions; (a) absolute ethanol/KOH/CS2/reflux/6 h, (b) absolute (97) with reagents and conditions; (a) absolute ethanol/KOH/CS /reﬂux/6 h, (b) absolute ethanol/KOH/heating/10 min, (c) ethyl-4-bromobutyrate/dry DMF/KI/heating in w.b./3 h. 2 ethanol/KOH/heating/10 min, (c) ethyl-4-bromobutyrate/dry DMF/KI/heating in w.b./3 h. 3.13. Synthesis of Thiadiazino and Thiazolo Quinoxaline Derivatives as Antibacterial/Antifungal Agents Compounds 91 and 95 demonstrated the highest activities against the observed cell Quinoxalines are pharmacologically useful agents like Dazoquinast(antiallergic), U8044(antidepressant,lines (tumor anxiolytic), cells) with LU IC5073,068(anticonvulsant values ranging fromglycine/NMDA), 0.29 to 0.90 andµM extant comparable in to doxorubicin antibiotics, such(IC50 as Echinomycin, ranging from which 0.51 is known to 0.73 toµ inhibitM). the growth of gram-positive bacteria [83]. Fused quinoxalines have been reported to have antimicrobial activities; therefore, Ammar. et al. [84] synthesized new quinoxaline derivatives incorporating aromatic thiadiazine or thiazole moieties fused to 6-(morpholine-4-sulfonyl)-1,4-dihydroquinoxaline to acquire improved antimicrobial agents. As depicted in the reaction Scheme 28, 6-Morpholinosulfonyl-2,3-dichloroquinoxaline (98) was synthesized in good yields by chlorinating 6-morpholinosulfonylquinoxalindione (97) utilizing phosphorus oxychloride. The intermediate (98) were further subjected to different synthetic routes to devise potent quinoxaline derivatives. On treatment with 1,4-binucleophiles (thiocarbohydrazide (i) and pyazole-1-carbothiohydrazide (ii)), and 2,3-dichloroquinoxaline derivative (98) produced a single product which was formulated as 3-hydrazinyl-7-(morpholinosulfonyl)-1H-[1,3,4]thiadiazino[5, 6-b]quinoxaline(99) and 3-methyl-1- (7-(morpholinosulfonyl)-1H-[1,3,4]thiadiazino[5, 6-b]quinoxalin-3-yl)-1H-pyrazol-3-ol(100). In a similar manner, 2, 3-dichloro derivatives (98) was treated with 4-amino-5-methyl-4H-1,2,4- triazole-3-thiol (iii) in refluxing ethanol provided a single product, 2,3-methyl-9-morpholinosulfonyl-5H-[1,2,4]triazolo [2, 3, 3, 4] [1, 3, 4]thiadiazino[5, 6-b]quinoxaline (101). The synthesized compounds 98, 99, 100, 101 exhibited bacterial and fungal activity with results comparable to that of Norfloxacin. The synthesized compounds had significant MICs value (1.95– 31.25) µg/mL, comparable to that of Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL).

23 Molecules 2021, 26, 1055 23 of 30

3.13. Synthesis of Thiadiazino and Thiazolo Quinoxaline Derivatives as Antibacterial/Antifungal Agents Quinoxalines are pharmacologically useful agents like Dazoquinast(antiallergic), U8044(antidepressant, anxiolytic), LU 73,068(anticonvulsant glycine/NMDA), and extant in antibiotics, such as Echinomycin, which is known to inhibit the growth of gram-positive bacteria [83]. Fused quinoxalines have been reported to have antimicrobial activities; therefore, Ammar. et al. [84] synthesized new quinoxaline derivatives incorporating aromatic thiadiazine or thiazole moieties fused to 6-(morpholine-4-sulfonyl)-1,4-dihydroquinoxaline to acquire improved antimicrobial agents. As depicted in the reaction Scheme 28, 6- Morpholinosulfonyl-2,3-dichloroquinoxaline (98) was synthesized in good yields by chlorinating 6-morpholinosulfonylquinoxalindione (97) utilizing phosphorus oxychloride. The intermediate (98) were further subjected to different synthetic routes to devise potent quinoxaline derivatives. Molecules 2020, 25, x FOR PEER REVIEW 24 of 32

SchemeScheme 28. Synthetic 28. pathwaysSynthetic to prepare pathways derivatives to prepareof 6-(morpholine-4-sulfonyl)-1,4- derivatives of 6-(morpholine-4-sulfonyl)-1,4-

dihydroquinoxaline (97,98,99,100,101) with reagents and conditions: (a) POCl3, (b) dihydroquinoxaline (97,98,99,100,101) with reagents and conditions: (a) POCl3,(b) thiocarbo- thiocarbohydrazide (i) acetonitrile/reflux/8 h, (c) 5-hydroxy-3-methyl-1H-pyrazole-1- hydrazide (i) acetonitrile/reflux/8 h, (c) 5-hydroxy-3-methyl-1H-pyrazole-1-carbothiohydrazide carbothiohydrazide (ii)/acetonitrile/reflux/8 h, (d) 4- amino-5-methyl-4H-1,2,4-triazole-3-thiol (iii) in acetonitrile(ii)/acetonitrile/reflux/8 containing DMF/reflux/5 h. h, (d) 4- amino-5-methyl-4H-1,2,4-triazole-3-thiol (iii) in acetonitrile containing DMF/reflux/5 h. 3.14. Synthesis of 6-[(het)arylthiomethyl]quinoxaline Derivatives as Antiviral Agents EnterovirusesOn (EVs) treatment are viral withpathogens 1,4-binucleophiles belonging to a (thiocarbohydrazideclass of Picornaviridae family. (i) and pyazole-1-carbothio Coxsackievirushydrazide A and B, poliovirus, (ii)), and echoviruses 2,3-dichloroquinoxaline are Enteroviruses that causes derivative infection (in98 man) produced after a single product absorption andwhich replication was in formulated a gastrointestinal as 3-hydrazinyl-7-(morpholinosulfonyl)-1H-[tract [85]. The infection is typically asymptomatic but 1,3,4]thiadiazino[5, extends to secondary organs, leading to severe diseases [86,87]. The US food and drug administration have not assigned6-b]quinoxaline(99) any specific antiviral andagent 3-methyl-1-(7-(morpholinosulfonyl)-1H-[for Enteroviruses; therefore, Sanna. et al. [88] prepared 1,3,4]thiadiazino[5, 6- quinoxalineb]quinoxalin-3-yl)-1H-pyrazol-3-ol(100). derivatives and evaluated them for their antiviral activity against representatives of ssRNA, dsRNA, and dsDNA viruses. As shown in Scheme 29, 6-(bromomethyl)-2, 3-dimethoxyquinoxaline (102) and benzenethiol derivatives or pyridine-2-thiol (103) were stirred in dry DMF, in Cs2CO3 at 70 °C for 2.5 h. After

24 Molecules 2021, 26, 1055 24 of 30

In a similar manner, 2, 3-dichloro derivatives (98) was treated with 4-amino-5-methyl- 4H-1,2,4-triazole-3-thiol (iii) in refluxing ethanol provided a single product, 2,3-methyl-9- morpholinosulfonyl-5H-[1,2,4]triazolo [2, 3, 3, 4] [1, 3, 4]thiadiazino[5, 6-b]quinoxaline (101). The synthesized compounds 98, 99, 100, 101 exhibited bacterial and fungal activity with results comparable to that of Norfloxacin. The synthesized compounds had significant MICs value (1.95–31.25) µg/mL, comparable to that of Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL).

3.14. Synthesis of 6-[(het)arylthiomethyl]quinoxaline Derivatives as Antiviral Agents Enteroviruses (EVs) are viral pathogens belonging to a class of Picornaviridae family. Coxsackievirus A and B, poliovirus, echoviruses are Enteroviruses that causes infection in man after absorption and replication in a gastrointestinal tract [85]. The infection is typically asymptomatic but extends to secondary organs, leading to severe diseases [86,87]. The US food and drug administration have not assigned any speciﬁc antiviral agent for Enteroviruses; therefore, Sanna. et al. [88] prepared quinoxaline derivatives and evaluated them for their antiviral activity against representatives of ssRNA, dsRNA, and ds- DNA viruses. As shown in Scheme 29, 6-(bromomethyl)-2, 3-dimethoxyquinoxaline (102) and ben- ◦ Molecules 2020, 25,zenethiol x FOR PEER derivatives REVIEW or pyridine-2-thiol (103) were stirred in dry DMF, in Cs2CO325at of 7032 C for 2.5 h. After cooling and dilution with water, light-colored powders were attained and

cooling and dilutionpuriﬁed with by EtOH/Hwater, light-colored2O. The derivatives powders of 6-[(het)arylthiomethyl]quinoxalineswere attained and purified by EtOH/H (1042)O. were The derivativesformed, of 6-[(het)arylthiomethyl]quinoxalines showing potent antiviral activity (104 against) were coxsackievirusformed, showing B5, potent with EC50antiviral in the µ activity againstsub-micromolar coxsackievirus B5, range with (0.3–0.06 EC50 in M).the sub-micromolar range (0.3–0.06 µM).

Scheme 29.Scheme Synthetic 29. pathwaySynthetic to pathway prepare to6-[(het)ary prepare 6-[(het)arylthiomethyl]quinoxalineslthiomethyl]quinoxalines derivatives derivatives (104) with (104 ) with ◦ reagents andreagents conditions: and conditions: (a) dry DMF/Cs (a) dry2CO DMF/Cs3/70 °C/2.52CO h.3/70 C/2.5 h.

3.15. Synthesis of Quinoxaline-2-carboxylate 1,4-dioxide Derivatives as Antimycobacterium Tuberculosis Agents Over the last two decades, many mono, di-N-oxides, 2-oxo derivatives of quinoxalines have been prepared and tested for their antimicrobial activities; for example, quinoxalin-2-ones have antifungal properties [89], and quinoxalin-1-oxides have antibacterial properties [90]. In the pursuit to obtain potent antimicrobial compounds, Jaso et al. [91] synthesized new 6(7)- substituted quinoxaline-2-carboxylate-1,4-dioxide derivatives and examined for their antituberculosis activity. Tuberculosis is an infection of Mycobacterium tuberculosis and is considered a leading cause of death in infectious diseases, especially in developing countries. The development of new antitubercular compounds to improve the current chemotherapeutic antituberculosis treatments is necessary and beneficial. As displayed in Scheme 30, the starting compound (105) (benzofuroxane, 5-substituted or 5,6- disubstituted benzofuroxane) was added to β-keto ester; the mixture was allowed to stand at 0 °C. Triethylamine was added dropwise and stirred in darkness for 1–3 days. The obtained crude solid or brown oil was precipitated and washed with diethyl ether and purified using ethanol. Quinoxaline- 2-carboxylate 1,4-dioxide derivatives (106, 107, 108, 109) were obtained and evaluated for in vitro antituberculosis activity, with EC90/MIC values ranging between 0.01 and 2.30.

25 Molecules 2021, 26, 1055 25 of 30

3.15. Synthesis of Quinoxaline-2-carboxylate 1,4-dioxide Derivatives as Antimycobacterium Tuberculosis Agents Over the last two decades, many mono, di-N-oxides, 2-oxo derivatives of quinoxalines have been prepared and tested for their antimicrobial activities; for example, quinoxalin-2-ones have antifungal properties [89], and quinoxalin-1-oxides have antibacterial properties [90]. In the pursuit to obtain potent antimicrobial compounds, Jaso et al. [91] synthesized new 6(7)-substituted quinoxaline-2-carboxylate-1,4-dioxide derivatives and examined for their antituberculosis activity. Tuberculosis is an infection of Mycobacterium tuberculosis and is considered a leading cause of death in infectious diseases, especially in developing countries. The development of new antitubercular compounds to improve the current chemotherapeutic antituberculosis treatments is necessary and beneﬁcial. As displayed in Scheme 30, the starting compound (105) (benzofuroxane, 5-substituted or 5,6-disubstituted benzofuroxane) was added to β-keto ester; the mixture was allowed to stand at 0 ◦C. Triethylamine was added dropwise and stirred in darkness for 1–3 days. The obtained crude solid or brown oil was precipitated and washed with diethyl ether and puriﬁed using ethanol. Quinoxaline-2-carboxylate 1,4-dioxide derivatives (106, 107, 108, 109) were obtained and evaluated for in vitro antituberculosis activity, with EC90/MIC

Molecules 2020, 25values, x FORranging PEER REVIEW between 0.01 and 2.30. 26 of 32

Scheme 30.Scheme Synthetic 30. Synthetic pathways pathways to prepare to preparequinoxalin quinoxaline-2-carboxylate-1,4-dioxidee-2-carboxylate-1,4-dioxide derivatives derivatives (106, (106, 107, 108, 107109,) 108with, 109 reagents) with reagentsand conditions: and conditions: (a, b, c, d ()a β, b-keto, c, d ester/triethylene) β-keto ester/triethylene amine/diethyl amine/diethyl ether. ether.

3.16. Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline Derivatives as Antiviral/Antimicrobial Agents The triazoles have a great significance as antimicrobial agents and quinoxalines have known to possess immense biological activity against infections; therefore, a series of antiviral and antimicrobial agents containing triazoles fused with quinoxalines, [1,2,4] triazolo [4, 3-a]quinoxalines and their isosteres, pyrimido-quinoxaline, were synthesized by Henen. et al. [92]. The thioamide group is introduced to increase the bioactivity of [1,2,4] triazolo[4, 3- a]quinoxaline as an antiviral agent. Furthermore, [1,3,4] oxadiazole and [1,2,4]-triazole subunits enhances the antimicrobial activity, hence were incorporated in [1,2,4]-triazolo [4, 3-a]quinoxaline ring. The synthetic pathway affording (111) was accomplished via reaction of 4-chloro-8-methyl- [1,2,4]-triazolo[4, 3-a] quinoxaline-1-amine(110) with mercapto oxadiazole or mercapto triazole in the presence of anhydrous K2CO3 (Scheme 31). The reaction mixture was stirred overnight and poured into ice-cold water and recrystallized using DMF/water. Similarly, in another route, the starting reactant (110), when treated with an appropriate amount of 3-(substituted benzylidene amino)-5- mercapto-1H-1,2,4-triazoles formed (113), and were purified using DMF/water. The antiviral compound (112) was synthesized by a mixture of 4-chloro-8-methyl [1, 2, 4] triazolo [4, 3-a] quinoxaline-1-amine (110) and appropriate isothiocyanate derivatives in EtOH, refluxed for 6 h. The newly synthesized compound (112) was tested for its antiviral properties on African monkey kidney cells against the Herpes simplex virus. The tested compounds displayed a reduction in plaque(plaque-reduction assay was used) by 25% at 20 mg/mL.

26 Molecules 2021, 26, 1055 26 of 30

3.16. Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline Derivatives as Antiviral/Antimicrobial Agents The triazoles have a great significance as antimicrobial agents and quinoxalines have known to possess immense biological activity against infections; therefore, a series of antiviral and antimicrobial agents containing triazoles fused with quinoxalines, [1,2,4] triazolo [4, 3-a]quinoxalines and their isosteres, pyrimido-quinoxaline, were synthesized by Henen. et al. [92]. The thioamide group is introduced to increase the bioactivity of [1,2,4] triazolo[4, 3-a]quinoxaline as an antiviral agent. Furthermore, [1,3,4] oxadiazole and [1,2,4]-triazole subunits enhances the antimicrobial activity, hence were incorporated in [1,2,4]-triazolo [4, 3-a]quinoxaline ring. The synthetic pathway affording (111) was accomplished via reaction of 4-chloro- 8-methyl-[1,2,4]-triazolo[4, 3-a] quinoxaline-1-amine(110) with mercapto oxadiazole or mercapto triazole in the presence of anhydrous K2CO3 (Scheme 31). The reaction mixture was stirred overnight and poured into ice-cold water and recrystallized using DMF/water. Similarly, in another route, the starting reactant (110), when treated with an appropriate amount of 3-(substituted benzylidene amino)-5-mercapto-1H-1,2,4-triazoles formed (113), and were purified using DMF/water. The antiviral compound (112) was synthesized by a mixture of 4-chloro-8-methyl [1, 2, 4] triazolo [4, 3-a] quinoxaline-1-amine (110) and appropriate isothiocyanate derivatives in EtOH, refluxed for 6 h. Molecules 2020, 25, x FOR PEER REVIEW 27 of 32

SchemeScheme 31. Synthetic 31. Synthetic pathways pathwaysto prepare toderivatives prepare of derivatives 4-chloro-8-methyl-[1,2,4]-triazolo[4,3-a] of 4-chloro-8-methyl-[1,2,4]-triazolo[4,3-a] quinoxaline-1-aminequinoxaline-1-amine (111, 112, 113 (111). , 112, 113). 4. Conclusions Quinoxalines are an essential class of nitrogen-containing heterocycles with a wide range of physiological effects. Quinoxalines have gained much interest in medicinal chemistry, owing to their well-known biological activity to fight infectious and non-infectious diseases; therefore, simple synthetic routes using the green methodology, cost-effective methods, and some biologically significant pathways have been summarized in this review paper. The current epidemic situation in the world has prompted researchers to synthesize effective drugs to fight COVID-19. Ongoing trials are under-way to synthesize drugs and vaccines. Since quinoxalines have a wide range of applications to fight infectious diseases, it should be well studied and tested for their antiviral properties.

Funding: This research paper was made under the funding of University Putra Malaysia.

Conflicts of Interest: The authors declared no conflict of interest. 27 Molecules 2021, 26, 1055 27 of 30

The newly synthesized compound (112) was tested for its antiviral properties on African monkey kidney cells against the Herpes simplex virus. The tested compounds displayed a reduction in plaque(plaque-reduction assay was used) by 25% at 20 mg/mL.

4. Conclusions Quinoxalines are an essential class of nitrogen-containing heterocycles with a wide range of physiological effects. Quinoxalines have gained much interest in medicinal chemistry, owing to their well-known biological activity to fight infectious and non-infectious diseases; therefore, simple synthetic routes using the green methodology, cost-effective methods, and some biologically significant pathways have been summarized in this review paper. The current epidemic situation in the world has prompted researchers to synthesize effective drugs to fight COVID-19. Ongoing trials are under-way to synthesize drugs and vaccines. Since quinoxalines have a wide range of applications to fight infectious diseases, it should be well studied and tested for their antiviral properties.

Author Contributions: Conceptualization: H.K.; methodology: H.K.; writing: H.K.; initial draft analysis: E.A.; review: E.A.; editing: E.A.; supervision: E.A. All authors have read and agreed to the published version of the manuscript. Funding: This research paper was made under the funding of University Putra Malaysia. Conﬂicts of Interest: The authors declared no conﬂict of interest.

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