Faculty Publications
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Item Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment(Springer Nature, 2024) Naik, S.; Dinesha, P.; Udayakumar, D.In this study, we present a novel series of (E)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((E)-(((Z)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-?-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the M. tuberculosis H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing S. aureus, B. subtilis, S. mutans, E. coli, S. typhi, and K. pneumoniae. Additionally, their antifungal efficacy against A. fumigatus and A. niger also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.Item Noncovalent inhibitors of DprE1 for tuberculosis treatment: design, synthesis, characterization, in vitro and in silico studies of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamides(Taylor and Francis Ltd., 2025) Naik, S.; Dinesha, P.; Udayakumar, U.In 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.