Background: In recent decades, several viruses have jumped from animals to humans, triggering sizable outbreaks. The current unprecedent outbreak SARS-COV-2 is prompting a search for new cost-effective therapies to combat this deadly pathogen. Suitably functionalized polysubstituted quinoxalines show very interesting biological properties (antiviral, anticancer, and antileishmanial), ensuring them a bright future in medicinal chemistry. Objectives: Focusing on the promising development of new quinoxaline derivatives as antiviral drugs, this review forms part of our program on the anti-infectious activity of quinoxaline derivatives. Methods: Study compiles and discusses recently published studies concerning the therapeutic potential of the antiviral activity of quinoxaline derivatives, covering the literature between 2010 and 2020. Results: A final total of 20 studies included in this review. Conclusions: This review points to a growing interest in the development of compounds bearing a quinoxaline moiety for antiviral treatment. This promising moiety with different molecular targets warrants further investigation, which may well yield even more encouraging results regarding this scaffold.

Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promises for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between January 2018 and January 2023.

Background. The past decades have seen numerous efforts to develop new antitubercular agents. Currently, the available regimens are lengthy, only partially effective, and associated with high rates of adverse events. The challenge is therefore to develop new agents with faster and more efficient action. The versatile quinoxaline ring possesses a broad spectrum of pharmacological activities, ensuring considerable attention to it in the field of medicinal chemistry. Objectives. In continuation of our program on the pharmacological activity of quinoxaline derivatives, this review focuses on potential antimycobacterial activity of recent quinoxaline derivatives and discusses their structure—activity relationship for designing new analogs with improved activity. Methods. The review compiles recent studies published between January 2011 and April 2021. Results. The final total of 23 studies were examined. Conclusions. Data from studies of quinoxaline and quinoxaline 1,4-di-N-oxide derivatives highlight that specific derivatives show encouraging perspectives in the treatment of Mycobacterium tuberculosis and the recent growing interest for these scaffolds. These interesting results warrant further investigation, which may allow identification of novel antitubercular candidates based on this scaffold.

The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC₅₀ = 2.49 ± 1.33 μM and IC₅₀ = 3.96 ± 2.03 μM for compound 11a and IC₅₀ = 5.3 ± 2.12 μM and IC₅₀ = 7.12 ± 1.59 μM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties.

Le noyau quinoxaline est un hétérocycle azoté prometteur en chimie thérapeutique de par ses nombreuses applications biologiques. Certaines molécules porteuses de ce noyau dans leur structure disposent déjà d’une autorisation de mise sur le mar- ché, tandis que d’autres sont actuellement en cours d’évaluation à différentes phases d’essais cliniques. Parmi ces quinoxalines, deux d’entres elles, XK469 et CQS, ont été développées et évaluées en essais cliniques de phase II pour leurs propriétés anti cancéreuses liées à un mécanisme d’action ciblant les topoisomérases. En se basant sur les structures de ces deux composés, ainsi que sur les précédents travaux menés au sein de notre laboratoire, l’objectif de ce travail de thèse a été de synthétiser de nouvelles quinoxalines à potentialité anti proliférative et d’évaluer leurs propriétés biologiques et pharmacologiques. La première partie de ce travail rapporte la synthèse de deux séries de quinoxalines porteuses d’un cycle époxyde substitué par différents groupements. Les composés obtenus l’ont été sous la forme d’un mélange de diastéroisomères cis/trans. La première série présentant un atome de chlore en position 2 du noyau quinoxaline a été obtenue selon la méthodologie TDAE, un donneur d’électrons organique utilisé depuis de nombreuses années dans notre laboratoire. La seconde série a été obtenue grâce à une réaction de couplage de Sonogashira réalisée sur les composés de la première série, permettant de greffer un motif alcyne à la place du chlore en position 2. Les propriétés anti prolifératives de ces deux séries de composés ont été évaluées sur deux lignées cellulaires de neuroblastome, SK-N-SH et IMR-32. Les résultats de cette évaluation ont permis l’identification d’un composé hit dont l’optimisation a été menée dans la deuxième partie de ce travail. Cette optimisation se focalise sur la variation de la substitution chlorée du noyau quinoxaline par analogie structurale avec les composés de référence XK469 et CQS. Ainsi, un nombre réduit de molécules a été synthétisé avant d’être évalué contre des lignées cellulaires à l’origine de tumeurs intracrâniennes de l’enfant et de l’adulte, de médulloblastome (HD-MB03 et ONS-76) et de glioblastome (U87-MG et U251-MG). Dans cette deuxième partie, l’évaluation biologique des composés a reposé sur des tests de viabilité cellulaire sur cultures cellulaires en monocouche, mais aussi sur un modèle de sphéroïdes développé au CRCM mimant une tumeur solide, se rapprochant d’un modèle clinique. Enfin, le mécanisme d’action de ces composés a également été étudié, étayant l’hypothèse posée au début de ce travail de thèse d’une action anti topoisomérase