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

Mohamed A. Seleem, Nathalia Rodrigues De Almeida, Yashpal Singh Chhonker, Daryl J. Murry, Zaira Da Rosa Guterres, Amanda M. Blocker, Shiomi Kuwabara, Derek J. Fisher, Emilse S. Leal, Manuela R. Martinefski, Mariela Bollini, María Eugenia Monge, Scot P. Ouellette, Martin Conda-Sheridan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4370-4387
Number of pages18
JournalJournal of Medicinal Chemistry
Volume63
Issue number8
DOIs
StatePublished - Apr 23 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Seleem, M. A., Rodrigues De Almeida, N., Chhonker, Y. S., Murry, D. J., Guterres, Z. D. R., Blocker, A. M., Kuwabara, S., Fisher, D. J., Leal, E. S., Martinefski, M. R., Bollini, M., Monge, M. E., Ouellette, S. P., & Conda-Sheridan, M. (2020). Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases. Journal of Medicinal Chemistry, 63(8), 4370-4387. https://doi.org/10.1021/acs.jmedchem.0c00371