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

Luana Janaína de Campos, Mohamed A. Seleem, Jiachen Feng, Kelly Mari Pires de Oliveira, João Víctor de Andrade dos Santos, Shivdeep Hayer, Jonathan B. Clayton, Sharvath Kathi, Derek J. Fisher, Scot P. Ouellette, Martin Conda-Sheridan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2116-2142
Number of pages27
JournalJournal of Medicinal Chemistry
Volume66
Issue number3
DOIs
StatePublished - Feb 9 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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