Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents

Chlamydia trachomatis (CT)
causes
the most prevalent sexually transmitted bacterial disease in the United
States. The lack of drug selectivity is one of the main challenges
of the current antichlamydial pharmacotherapy. The metabolic needs
of CT are controlled, among others, by cylindrical proteases and their
chaperones (e.g., ClpX). It has been shown that dihydrothiazepines
can disrupt CT-ClpXP. Based on this precedent, we synthesized a dihydrothiazepine
library and characterized its antichlamydial activity using a modified
semi-high-throughput screening assay. Then, we demonstrated their
ability to inhibit ClpX ATPase activity in vitro,
supporting ClpX as a target. Further, our lead compound displayed
a promising selectivity profile against CT, acceptable cytotoxicity,
no mutagenic potential, and good in vitro stability.
A two-dimensional quantitative structure–activity relationship
(2D QSAR) model was generated as a support tool in the identification
of more potent antichlamydial molecules. This study suggests dihydrothiazepines
are a promising starting point for the development of new and selective
antichlamydial drugs.