Synthesis, characterization, in vitro antimycobacterial and cytotoxicity evaluation, DFT calculations, molecular docking and ADME studies of new isomeric benzimidazole-1,2,3-triazole-quinoline hybrid mixtures.

Autor: Nyoni NTP; School of Chemistry and Physics, College of Agriculture, Engineering and Science, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa., Ncube NB; School of Chemistry and Physics, College of Agriculture, Engineering and Science, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa., Kubheka MX; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, School of Laboratory Medicine and Medical Sciences, College of Heath Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa., Mkhwanazi NP; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, School of Laboratory Medicine and Medical Sciences, College of Heath Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa., Senzani S; School of Laboratory Medicine and Medical Science, College of Heath Health Sciences, University of KwaZulu Natal, Medical School Campus, Durban 4001, South Africa., Singh T; School of Chemistry and Physics, College of Agriculture, Engineering and Science, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa., Tukulula M; School of Chemistry and Physics, College of Agriculture, Engineering and Science, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa. Electronic address: TukululaM@ukzn.ac.za.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Dec; Vol. 141, pp. 106904. Date of Electronic Publication: 2023 Oct 09.
DOI: 10.1016/j.bioorg.2023.106904
Abstrakt: New benzimidazole-1,2,3-triazole-quinoline hybrids and their intermediates, differing in substitutions at the C-2 and/or C6 positions of the benzimidazole ring, were successfully synthesized in 55---80 % yields, with the C6-substituted ones forming as inseparable tautomeric mixtures. The synthesized compounds were fully characterised by FT-IR, 1D- and 2D-NMR, and HRMS. In-depth NMR analysis and DFT molecular calculations showed that the tautomeric mixtures formed in a ratio of almost 1:1 ratio (cis and trans), except for 5 g, where the ratio is 1:2. In vitro antimycobacterial activity evaluation against the H37Rv strain of Mycobacterial tuberculosis was undertaken on all synthesized compounds, and a selected number were further screened for their cytotoxicity on TZM-bl cell lines. Hybrid compounds showed excellent MIC 90 activities ranging from 1.07 to 8.66 μM and were all more efficacious than the first-line reference drug, ethambutol (MIC 90  = 9.54 μM). In particular, hybrid compounds 5b (MIC 90  = 1.54 μM, CC 50  = 58.89 μM and % cell viability = 14.07), 5d (MIC 90  = 2.08 μM, CC 50  = 0.27 μM, and % cell viability = 149.50 %) and 5 g (MIC 90  = 1.49 μM, CC 50  = 4.62 μM and % cell viability = 44.03) were the most promising. Significantly, 5b and 5 g were over six times more efficacious than ethambutol but exhibited cytotoxicity towards TZM-bl cell-lines compared to 5d, which was over four times more active than ethambutol. The physical combination (mimicking combination therapy) of individual pharmacophoric components making up 5 g were less active, indicating the synergistic effect of hybridization. In addition, more than 60 % of all the synthesized hybrids showed better activity than their respective pharmacophoric components. In silico ADME studies of the hybrids revealed favourable physico-chemical properties, while molecular modeling studies suggested binding interactions with Val 61, Gly 62, Glu 65, Ala 66, and Phe 69 amino acid in a reported similar manner to bedaquiline, an approved quinoline-based anti-TB drug.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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