Naik, S.Dinesha, P.Udayakumar, U.2026-02-032025Journal of Biomolecular Structure and Dynamics, 2025, 43, 12, pp. 6351-63657391102https://doi.org/10.1080/07391102.2024.2427368https://idr.nitk.ac.in/handle/123456789/20518In this study, we present a novel series of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamide derivatives, which exert their inhibitory effect on decaprenylphosphoryl-?-D-ribose 2’-epimerase (DprE1) via the establishment of non-covalent interactions with the pivotal Cys387 residue located within the enzyme’s active site. These compounds underwent scrutiny for their efficacy in combatting the Mycobacterium tuberculosis H37Rv strain, and compounds T8 and T13 exhibited promising antitubercular activity, boasting a minimal inhibitory concentration (MIC) of 7.99 and 8.27 µM respectively. Additionally, three compounds, T2, T3 and T12, showcased substantial antibacterial activity whereas compounds T12 and T13 exhibited pronounced antifungal efficacy. Remarkably, all active compounds demonstrated negligible cytotoxicity, and none posed harm to normal cells. To attain a more profound comprehension of the attributes of these compounds, we conducted in silico investigations to evaluate their Absorption, Distribution, Metabolism and Excretion properties. Additionally, molecular docking analyses were executed to elucidate their interactions with the DprE1 enzyme. Finally, Density Functional Theory studies were leveraged to explore the electronic characteristics of these compounds, thereby providing insights into their potential utility in the realm of pharmaceuticals. © 2024 Informa UK Limited, trading as Taylor & Francis Group.1 4 dihydroquina zolinylpyrazine 2 carboxamide3 amino 2 pyrazin 2 yl 1 2 4 triazolo 5 1 b quinazolin 9 3h onechemical compoundciprofloxacindpre1enzymefluconazolen 2 2 chloro 6 methoxyquinolin 3 yl 4 oxo 1 4 dihydro quinazolin 3 2h yl pyrazine 2 carboxamiden 2 3 4 dihydroxyphenyl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 2 4 bromophenyl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 2 4 cyanophenyl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 2 4 fluorophenyl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 2 4 hydroxyphenyl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 2 4 nitrophenyl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 2 5 bromo 2 hydroxyphenyl 4 oxo 1 4 dihydroquina zolin 3 2h yl pyrazine 2 carboxamiden 2 isoquinolin 4 yl 4 oxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 4 oxo 2 2 trifluoromethyl phenyl 1 4 dihydroquinazo lin 3 2h yl pyrazine 2 carboxamiden 4 oxo 2 o tolyl 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 4 oxo 2 phenyl 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 4 oxo 2 thiophen 2 yl 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamiden 4 oxo 2 thioxo 1 4 dihydroquinazolin 3 2h yl pyrazine 2 carboxamidenoncovalent inhibitorprotein inhibitorstreptomycintuberculostatic agentunclassified drugalcohol dehydrogenasebacterial proteinDprE1 protein, Mycobacterium tuberculosisenzyme inhibitorpyrazine derivativeabsorptionArticleBacillus subtiliscarbon nuclear magnetic resonancecomputer modelcytotoxicitydesigndistribution parameterselectrophilicityEscherichia coliexcretionin vitro studyKlebsiella pneumoniaemetabolismmicroorganismminimum inhibitory concentrationmolecular dockingMycobacterium tuberculosisnonhumanoptical densitypharmaceutical careproton nuclear magnetic resonanceStaphylococcus aureussynthesisthin layer chromatographytuberculosischemistrydrug designdrug effectdrug therapyenzyme active siteenzymologyhumanmicrobial sensitivity teststructure activity relationAlcohol OxidoreductasesAntitubercular AgentsBacterial ProteinsCatalytic DomainDrug DesignEnzyme InhibitorsHumansMicrobial Sensitivity TestsMolecular Docking SimulationPyrazinesStructure-Activity RelationshipTuberculosis