Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents.
J Med Chem
; 66(3): 2116-2142, 2023 02 09.
Article
in En
| MEDLINE
| ID: mdl-36696579
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Hydrolases
/
Chlamydia trachomatis
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2023
Document type:
Article
Affiliation country:
United States