Abstract

We developed a pharmacophore fusion strategy to design dual-action Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) inhibitors. This involved integrating rhodanine-3-acetic acid with the nitroimidazooxazine/oxazole core of antitubercular nitroimidazoles. The resulting compounds showed potent MptpB inhibition and direct antituberculosis activity. Docking studies indicated a conserved binding mode, with the rhodanine moiety in the P1 pocket and the nitroimidazole core in the P2 pocket. Compound 4 was most promising, exhibiting strong MptpB inhibition (IC50: 0.19 μM), good antituberculosis efficacy (MIC: 1.94 μg/mL), and high selectivity over human PTP1B (345-fold). It also demonstrated excellent metabolic stability, good permeability, acceptable bioavailability in mice, low cytotoxicity, and outperformed Rifampicin and Pretomanid in a macrophage infection model. Mechanistic studies showed that it reversed MptpB-mediated suppression of the macrophage MAPK pathway. This work validates the fusion strategy and identifies a promising lead targeting MptpB for further development.