SAR studies on 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents

Abstract

Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of one lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (1), targeting Mt SD in our previous study, an extensive SAR study for optimization of the lead compound was performed through systematic modification of the 3 and 6 positions. This study has successfully led to the discovery of two highly potent advanced leads 6d-4, 6c-4 and several other compounds with comparable potencies (6d-4, MIC-H37Rv = 0.5 μg mL⁻¹; MIC-MDRTB = 4.0 μg mL⁻¹; MIC-RDRTB = 0.5 μg mL⁻¹; Mt SD-IC50 = 14.20 μg mL⁻¹; and 6c-4, MIC-H37Rv = 0.5 μg mL⁻¹; MIC-MDRTB = 4.0 μg mL⁻¹; MIC-RDRTB = 1.0 μg mL⁻¹; Mt SD-IC50 = 6.82 μg mL⁻¹). These advanced lead compounds possess a para-halogen phenyl at the 3 position. In vitro Mt SD inhibitory assay indicates that Mt SD is the target for their antitubercular activity. Moreover, the BacT/ALERT 3D liquid culture technology and in vitro Mt SD inhibitory assay were initially applied.