Linking azoles to isoniazid via hydrazone bridge: Synthesis, crystal structure determination, antitubercular evaluation and computational studies
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Tarih
2022
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Elsevier
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
The current emergence of drug-resistant and multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains has complicated and hampered attempts to eliminate or considerably reduce the global prevalence of the often life-threatening disease tuberculosis (TB). Hence, the development of novel antitubercular agents is crucial to combat this challenge. Here, we applied the molecular hybridization approach to link isoniazid (INH), the frontline antitubercular drug, to various azole rings (pyrazole, imidazole, and triazole) through hydrazone functionality. The designed compounds were synthesized and characterized by using spectral techniques including IR, H-1 NMR, C-13 NMR and HRMS. Additionally, single crystal X-ray analysis was employed to resolve the proposed chemical structure of INH-T. All compounds were then extensively screened for their antitubercular activities against Mtb H37Rv, drug-resistant and MDR Mtb strains, as well as against a clinical Mtb isolate with no mutation. Notably, INH-azole hybrids presented outstanding antimycobacterial activity with negligible cytotoxicity. Computational methods based on density functional theory calculations and molecular dynamics simulations were applied to identify the characteristic reactive centers of the title compounds, predict stability towards autoxidation, understand their interactions with water molecules and predict the temperature dependence of density. Finally, molecular docking studies revealed that new INH-azole hybrids are likely to exert their antimycobacterial activity via direct inhibition of the Mtb InhA enzyme. (C) 2022 Elsevier B.V. All rights reserved.
Açıklama
Anahtar Kelimeler
Tuberculosis, Molecular hybridization, X-ray analysis, DFT, Molecular dynamics, Interactions with water
Kaynak
Journal of Molecular Liquids
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
354
