Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases

J Med Chem. 2020 Apr 23;63(8):4370-4387. doi: 10.1021/acs.jmedchem.0c00371. Epub 2020 Apr 15.

Abstract

Chlamydia trachomatis is the most common sexually transmitted bacterial disease globally and the leading cause of infertility and preventable infectious blindness (trachoma) in the world. Unfortunately, there is no FDA-approved treatment specific for chlamydial infections. We recently reported two sulfonylpyridines that halt the growth of the pathogen. Herein, we present a SAR of the sulfonylpyridine molecule by introducing substituents on the aromatic regions. Biological evaluation studies showed that several analogues can impair the growth of C. trachomatis without affecting host cell viability. The compounds did not kill other bacteria, indicating selectivity for Chlamydia. The compounds presented mild toxicity toward mammalian cell lines. The compounds were found to be nonmutagenic in a Drosophila melanogaster assay and exhibited a promising stability in both plasma and gastric fluid. The presented results indicate this scaffold is a promising starting point for the development of selective antichlamydial drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Chlamydia trachomatis / drug effects*
  • Chlamydia trachomatis / physiology
  • Chlorobenzenes / chemical synthesis
  • Chlorobenzenes / pharmacology
  • Dose-Response Relationship, Drug
  • Drosophila melanogaster
  • HeLa Cells
  • Humans
  • Mice
  • Peptide Hydrolases / metabolism*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology

Substances

  • Chlorobenzenes
  • Protease Inhibitors
  • Pyridines
  • Peptide Hydrolases
  • chlorobenzene