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Synthesis of new piperazinyl-pyrrolo[1,2- a ]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction

hal.structure.identifierRégulations Naturelles et Artificielles [ARNA]
dc.contributor.authorGUILLON, Jean
hal.structure.identifierJawaharlal Nehru University [JNU]
dc.contributor.authorNIM, Shweta
hal.structure.identifierRégulations Naturelles et Artificielles [ARNA]
dc.contributor.authorMOREAU, Stéphane
hal.structure.identifierRégulations Naturelles et Artificielles [ARNA]
dc.contributor.authorRONGA, Luisa
hal.structure.identifierRégulations Naturelles et Artificielles [ARNA]
dc.contributor.authorSAVRIMOUTOU, Solène
hal.structure.identifierRégulations Naturelles et Artificielles [ARNA]
dc.contributor.authorTHIVET, Elisabeth
hal.structure.identifierInstitut de Chimie de la Matière Condensée de Bordeaux [ICMCB]
dc.contributor.authorMARCHIVIE, Mathieu
hal.structure.identifierInstitut de biologie et chimie des protéines [Lyon] [IBCP]
dc.contributor.authorDI PIETRO, Attilio
hal.structure.identifierAmity Institute of Integrative Sciences and Health
dc.contributor.authorPRASAD, Rajendra
hal.structure.identifierMolécules bioactives et chimie médicinale [B2MC]
dc.contributor.authorLE BORGNE, Marc
dc.date.issued2020-01-15
dc.description.abstractEnTwo series of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives were prepared via a Buchwald–Hartwig cross-coupling reaction and then evaluated for their ability to inhibit the drug efflux activity of CaCdr1p and CaMdr1p transporters of Candida albicans overexpressed in a Saccharomyces cerevisiae strain. In the initial screening of twenty-nine piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives, twenty-three compounds behaved as dual inhibitors of CaCdr1p and CaMdr1p. Only four compounds showed exclusive inhibition of CaCdr1p or CaMdr1p. Further biological investigations were developed and for example, their antifungal potential was evaluated by measuring the growth of control yeast cells (AD1-8u−) and efflux pump-overexpressing cells (AD-CDR1 and AD-MDR1) after exposition to variable concentrations of the tested compounds. The MIC80 values of nineteen compounds ranging from 100 to 901 μM for AD-CDR1 demonstrated that relative resistance index (RI) values were between 8 and 274. In comparison, only seven compounds had RI values superior to 4 in cells overexpressing Mdr1p. These results indicated substrate behavior for nineteen compounds for CaCdr1p and seven compounds for CaMdr1p, as these compounds were transported via MDR transporter overexpressing cells and not by the AD1-8u− cells. Finally, in a combination assay with fluconazole, two compounds (1d and 1f) have shown a synergistic effect (fractional inhibitory concentration index (FICI) values ≤ 0.5) at micromolar concentrations in the AD-MDR1 yeast strain overexpressing CaMdr1p-protein, indicating an excellent potency toward chemosensitization.
dc.language.isoen
dc.publisherRoyal Society of Chemistry
dc.title.enSynthesis of new piperazinyl-pyrrolo[1,2- a ]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction
dc.typeArticle de revue
dc.identifier.doi10.1039/C9RA09348F
dc.subject.halSciences du Vivant [q-bio]/Sciences pharmaceutiques/Pharmacologie
dc.subject.halSciences du Vivant [q-bio]/Sciences pharmaceutiques/Médicaments
dc.subject.halChimie/Chimie thérapeutique
bordeaux.journalRSC Advances
bordeaux.page2915-2931
bordeaux.volume10
bordeaux.issue5
bordeaux.peerReviewedoui
hal.identifierhal-02449065
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-02449065v1
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