Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B.

ABSTRACT: Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Mtb protein tyrosine phosphatase B (mPTPB) is a virulence factor required for Mtb survival in host macrophages. Consequently, mPTPB represents an exciting target for tuberculosis treatment. Here, we identified N-phenyl oxamic acid as a highly potent and selective monoacid-based phosphotyrosine mimetic for mPTPB inhibition. SAR studies on the initial hit, compound 4 (IC₅₀ = 257 nM), resulted in several highly potent inhibitors with IC₅₀ values lower than 20 nM for mPTPB. Among them, compound 4t showed a K_i of 2.7 nM for mPTPB with over 4500-fold preference over 25 mammalian PTPs. Kinetic, molecular docking, and site-directed muta

SUBMITTER: Ruddraraju KV 

PROVIDER: S-EPMC7688068 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature