Structure-Based Analysis of Semisynthetic Anti-TB Rufomycin Analogues.

ABSTRACT: This study employed structural information from cocrystals of rufomycin 4 (1a) and caseinolytic protein C1 (ClpC1)-NTD-wt to guide design and semisynthesis of rufomycin analogues, evaluate their antituberculosis (TB) biological profiles, and establish structure-activity relationships (SAR). Covering three regions of interest (ROIs, A-C) as modification sites, 14 of the 30 semisynthetic analogues (2-31) showed similar or improved MICs relative to the main natural precursors, rufomycins 4/6 (1a/b). Compounds 5 and 27 exhibited up to 10-fold enhanced potency against Mycobacterium tuberculosis (Mtb) in vitro, with MIC values of 1.9 and 1.4 nM, respectively. Evaluation of ClpC1-binding properties used existing ClpC1-NTD complexes with rufo

SUBMITTER: Zhou B 

PROVIDER: S-EPMC12038834 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature