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: 14Selangor December 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 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institutional affiliations. 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),