Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment
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Date
2024
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Springer Nature
Abstract
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.
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4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 2 trifluoromethyl benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 4 bromo benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 4 chloro benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 4 fluoro benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 4 methoxy benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 4 methyl benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl 4 trifluoromethyl benzenesulfonate, 4 e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl benzenesulfonate derivative, 4e z amino pyrazin 2 yl methylene hydrazineylidene methyl phenyl benzene sulfonate, chemical compound, ciprofloxacin, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 2 trifluoromethyl benzenesulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 4 bromobenzene sulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 4 chlorobenzene sulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 4 fluorobenzene sulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 4 methoxybenzene sulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 4 methylbenzene sulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl 4 trifluoromethyl benzenesulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl benzenesulfonate, e 4 2 pyrazine 2 carbonyl hydrazineylidene methyl phenyl benzenesulfonate derivative, pyrazinamide, pyrazine 2 carbohydrazide, streptomycin, unclassified drug, z pyrazine 2 carbohydrazonamide, alcohol dehydrogenase, bacterial protein, benzenesulfonic acid, benzenesulfonic acid derivative, DprE1 protein, Mycobacterium tuberculosis, pyrazine derivative, tuberculostatic agent, animal cell, antibacterial activity, antifungal activity, antimicrobial activity, antineoplastic activity, Article, Aspergillus fumigatus, Aspergillus niger, Bacillus subtilis, carbon nuclear magnetic resonance, cell viability, controlled study, cytotoxicity, density functional theory, drug analysis, drug design, Escherichia coli, growth inhibition, Klebsiella pneumoniae, minimum inhibitory concentration, MTT assay, Mycobacterium tuberculosis, nonhuman, proton nuclear magnetic resonance, Staphylococcus aureus, structure activity relation, tuberculosis, Vero cell line, zone of inhibition, chemistry, drug effect, drug therapy, enzymology, microbial sensitivity test, molecular docking, Alcohol Oxidoreductases, Antitubercular Agents, Bacterial Proteins, Benzenesulfonates, Drug Design, Microbial Sensitivity Tests, Molecular Docking Simulation, Pyrazines, Structure-Activity Relationship, Tuberculosis
Citation
Molecular Diversity, 2024, 28, 6, pp. 4221-4239