7-Hydroxy-(E)-3-phenylmethylene-chroman-4-one analogues as efflux pump inhibitors against Mycobacterium smegmatis mc2 155

• Bonducellin modulated MIC of ethidium bromide by 8 fold at 62.5 mg/L.
• 7-Hydroxy-(E)-3-phenylmethylene-chroman-4-one is a basic skeleton of bonducellin.
• A series of 7-hydroxy-(E)-3-phenylmethylene-chroman-4-one analogue was synthesized.
• Compounds (1, 7–11, 13–15, 17 and 19) modulated MIC of EtBr by ≥4 fold.
• Compounds 8, 13 and 17 were found to be most potent EPI in Mycobacterium smegmatis mc2 155.

Efflux pump (EP) induces resistance in mycobacteria and hence could be explored as a new target for the discovery of anti-TB agents. In search for efflux pump inhibitors from natural products, bonducellin, a homoisoflavonoid was isolated from Caesalpinia digyna roots and evaluated for modulation and EP inhibitory activity. Bonducellin showed modulation in the MIC of EtBr by eight fold at a concentration of 62.5 mg/L and also showed significant EP inhibitory activity. A synthetic scheme was designed to prepare analogues of 7-hydroxy-(E)-3-phenylmethylene-chroman-4-one by modification at the phenylmethylene-ring and the synthesized compounds were evaluated in accumulation and efflux assays. Analogues 1, 7–11, 13–15, 17 and 19 were found to be good modulators and decreased the MIC of EtBr by ≥4 fold at sub-inhibitory concentration. The compounds 8, 13 and 17 were the most potent inhibitors of ethidium bromide efflux in Mycobacterium smegmatis mc2 155.

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