Noncovalent inhibitors of DprE1 for tuberculosis treatment: design, synthesis, characterization, <i>in vitro</i> and <i>in silico</i> studies of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamides

In this study, we present a novel series of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamide derivatives, which exert their inhibitory effect on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) <i>via</i> 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 <i>Mycobacterium tuberculosis</i> 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 <i>in silico</i> 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.