2. Academic Validation
  3. Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents

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

  • J Med Chem. 2023 Feb 9;66(3):2116-2142. doi: 10.1021/acs.jmedchem.2c01894.
Luana Janaína de Campos 1,  Mohamed A Seleem 1,  Jiachen Feng 1,  Kelly Mari Pires de Oliveira 2,  João Víctor de Andrade Dos Santos 3,  Shivdeep Hayer 4,  Jonathan B Clayton 4 5 6 7,  Sharvath Kathi 8,  Derek J Fisher 8,  Scot P Ouellette 9,  Martin Conda-Sheridan 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 2 Faculty of Biological and Environmental Science, Federal University of Grande Dourados, Dourados, MS 79804-970, Brazil.
  • 3 Faculty of Health Sciences, Federal University of Grande Dourados, Dourados, MS 79804-970, Brazil.
  • 4 Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68182, United States.
  • 5 Department of Food Science and Technology, University of Nebraska─Lincoln, Lincoln, Nebraska 68588, United States.
  • 6 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 7 Nebraska Food for Health Center, University of Nebraska─Lincoln, Lincoln, Nebraska 68508, United States.
  • 8 School of Biological Sciences, Southern Illinois University, Carbondale, Illinois 62901, United States.
  • 9 Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
PMID: 36696579 DOI: 10.1021/acs.jmedchem.2c01894
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.

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