Synthesis and antimycobacterial activity of disubstituted benzyltriazoles
The increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB), serves as a strong incentive for the discovery and development of new agents for the treatment of this plight. In search for such drugs, we investigated a series of benzyltriazole derivatives. We herein report the design, synthesis and biological activity of disubstituted benzyltriazoles against the human virulent H37Rv strain of Mtb as well as the toxicity on human embryonic kidney (HEK-293) cells. The derivative 21 featuring trifluoromethyl substituent in para position on the phenyl ring and n-butyl chain in position 4 on the triazole ring was the most active with MIC90 and MIC99 values of 1.73 and 3.2 µM, respectively, in the albumin-free medium. It also displays high selectivity towards bacteria growth inhibition (SI > 58), thus stands as a better hit for further investigation, including lead optimization, DMPK parameters determination and assessment of its activity in animal models.
KeywordsTuberculosis TB Drug discovery Benzyltriazole Click chemistry
This work was funded by a South African National Research Foundation Grant to DDN’Da (UID 76443). The South African Medical Research Council is gratefully acknowledged for financial support of the antimycobacterial screening assays (SHIP-MRC grant to DFW). The authors thank Dr D. Otto for NMR analysis and Dr JHL Jordaan for MS analysis. Isoniazid was generously donated by Aspen Pharmacare (Port Elizabeth, South Africa).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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