Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in .

This article reports the rational medicinal chemistry of a natural product, agrimophol (), as a new disruptor of intrabacterial pH (pH) homeostasis in (). Through the systematic investigation of the structure-activity relationship of , scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative was achieved. Compound showed 100-fold increased potency in the ability to reduce pH to pH 6.0 and similarly improved mycobactericidal activity compared with against both -BCG and . Compound possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar p value to natural . This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pH, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.