Design, synthesis, in vitro and in silico evaluation of novel substituted 1,2,4-triazole analogues as dual human VEGFR-2 and TB-InhA inhibitors

• Published in: Bioorganic chemistry 2023-12, Vol.141, p.106883-106883, Article 106883
• Main Authors: Zawal, Amira G., Abdel-Aziz, Marwa M., Elbatreek, Mahmoud H., El-Shanawani, Abdalla A., Abdel-Aziz, Lobna M., Elbaramawi, Samar S.
• Format: Article
• Language: English
• Subjects: 1,2,4-triazole compounds; Benzothiazole; Benzoxazole; Docking; VEGFR
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106883

[Display omitted] •6a-l and 11a-e were synthesized and assessed against human VEGFR-2 and TB-InhA.•6a, 6c, 6e, 6f, 6h, 6l, 16a, 11d and 11e were assessed for cytotoxic activity.•6e and 11a increased apoptosis and induced cell cycle arrest.•6h, 6i, 6l and 11c showed excellent Mtb InhA inhibition activity.•Docking study revealed high binding affinities toward targeted enzymes. Cancer is a leading cause of death globally and has been associated with Mycobacterium tuberculosis (Mtb). The angiogenesis-related VEGFR-2 is a common target between cancer and Mtb. Here, we aimed to synthesize and validate potent dual human VEGFR-2 inhibitors as anticancer and anti-mycobacterial agents. Two series of 1,2,4-triazole-based compounds (6a-l and 11a-e) were designed and synthesized through a molecular hybridization approach. Activities of all synthesized compounds were evaluated against human VEGFR-2 in addition to drug-sensitive, multidrug-resistant and extensive-drug resistant Mtb. Compounds 6a, 6c, 6e, 6f, 6h, 6l, 11a, 11d and 11e showed promising inhibitory effect on VEGFR-2 (IC50 = 0.15 – 0.39 µM), anti-proliferative activities against cancerous cells and low cytotoxicity against normal cells. The most potent compounds (6e and 11a) increased apoptosis percentage. Additionally, compounds 6h, 6i, 6l and 11c showed the highest activities against all Mtb strains, and thus were evaluated against enoyl-acyl carrier protein reductase (InhA) which is essential for Mtb cell wall synthesis. Interestingly, the compounds showed excellent InhA inhibition activities with IC50 range of 1.3 – 4.7 µM. Docking study revealed high binding affinities toward targeted enzymes; human VEGFR-2 and Mtb InhA. In conclusion, 1,2,4-triazole analogues are suggested as potent anticancer and antimycobacterial agents via inhibition of human VEGFR-2 and Mtb InhA.