Compounds Derived from 5‐Fluoropyridine and Benzo[b]thiophene: Killing Mycobacterium tuberculosis and Reducing its Virulence

Abstract

AbstractThe rise of drug‐resistant Mycobacterium tuberculosis (Mtb) has extended the duration of tuberculosis (TB) treatment and reduced the likelihood of cure. One strategy to combat this issue is the development of inhibitors targeting the virulence factors of bacterial pathogens. Mtb’ catalase (KatG) is crucial for its detoxification mechanisms and also serves as a significant virulence factor for the bacterium. In this study, twelve derivatives synthesized from 5‐fluoropyridine and benzo[b]thiophene demonstrated antimycobacterial efficacy with minimum inhibitory concentrations (MICs) varying between 0.5 and 32 μg/mL. Compound 2, 1‐(benzo[b]thiophen‐2‐ylmethylene) thiosemicarbazide, emerged as the most potent candidate. It effectively inhibited Mtb KatG, enhanced the production of reactive oxygen species (ROS) in Mtb, and achieved Mtb killing within 96 hours at a concentration of 2 μg/mL (4×MIC). Molecular docking simulations revealed that compound 2 binds tightly to the active site of Mtb‐KatG with a docking score of 114, indicating that it may serve as a potent inhibitor of Mtb‐KatG. The rabbit skin tuberculosis model was employed to assess the virulence of Mtb. Animal study results indicated that the granulomas induced by Mtb after treatment with compound 2 were reduced in size, exhibited a lower bacterial load, and the bacteria were no longer aggregated, in contrast to those caused by untreated Mtb. Hence, compound 2 can be regarded as a molecule capable of neutralizing the virulence factors of Mtb. This research offers insights into the design of anti‐Mtb molecules with novel mechanisms of action.