Hybrid triazoles: Design and synthesis as potential dual inhibitor of growth and efflux inhibition in tuberculosis

• Identification of novel tractable molecule is discussed.
• Analoging of newer chemotype and novel mechanism is conferred.
• A report discussing antimycobacterial activity with efflux inhibition.
• PDST145 was identified as hit.

Efflux inhibition is proven bacterial machinery responsible for removal of bacterial wastage including antibiotics. Recently, efflux inhibitors (EI) have been tested with encouraging results as an adjuvant therapy for treatment of tuberculosis (TB). Although, EI have emerged as innovative approach of treatment for multi drug resistant (MDR) & extensively drug resistant tuberculosis (XDR-TB), toxicity profile limits their wider use. To address this issue, we have attempted synthesizing hybrid molecules those results by combining known EI and triazole. This synthesis was aimed to arrive at structure that possesses pharmacophore from known EI. Synthesized molecules were evaluated as growth inhibitors (GI) and Efflux inhibitor of TB initially against Mycobacterium smegmatis mc2155. Pharmacologically active compounds were then tested for their cytotoxicity to further narrow down search. Most active compounds 144, 145, 154 and 163 were then tested for their GEI action against Mycobacterium tuberculosis (Mtb). Synthesized compounds were also tested for their synergistic action with first line and second line anti-TB drugs and ethidium bromide (EtBr). We arrived at compound 135 as most potent dual inhibitor of tuberculosis.

A substituted triazoles has been identified and then modified to yield PDST145, a potent antitubercular agent.Figure optionsDownload as PowerPoint slide