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Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-15 , DOI: 10.1021/acs.jmedchem.0c00371 Mohamed A Seleem 1 , Nathalia Rodrigues de Almeida 2 , Yashpal Singh Chhonker 3 , Daryl J Murry 3 , Zaira da Rosa Guterres 4 , Amanda M Blocker 5 , Shiomi Kuwabara 5 , Derek J Fisher 5 , Emilse S Leal 6 , Manuela R Martinefski 6 , Mariela Bollini 6 , María Eugenia Monge 6 , Scot P Ouellette 7 , Martin Conda-Sheridan 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-15 , DOI: 10.1021/acs.jmedchem.0c00371 Mohamed A Seleem 1 , Nathalia Rodrigues de Almeida 2 , Yashpal Singh Chhonker 3 , Daryl J Murry 3 , Zaira da Rosa Guterres 4 , Amanda M Blocker 5 , Shiomi Kuwabara 5 , Derek J Fisher 5 , Emilse S Leal 6 , Manuela R Martinefski 6 , Mariela Bollini 6 , María Eugenia Monge 6 , Scot P Ouellette 7 , Martin Conda-Sheridan 1
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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.
中文翻译：
基于圆柱形蛋白酶失调分子的合成和抗衣原体活性。
沙眼衣原体是全球最常见的性传播细菌性疾病，也是世界上不孕症和可预防的感染性失明（沙眼）的主要原因。不幸的是，FDA 还没有批准针对衣原体感染的治疗方法。我们最近报道了两种磺酰吡啶可以阻止病原体的生长。在这里，我们通过在芳香区引入取代基来展示磺酰吡啶分子的SAR。生物学评价研究表明，几种类似物可以损害沙眼衣原体的生长而不影响宿主细胞的活力。这些化合物不会杀死其他细菌，表明对衣原体具有选择性。这些化合物对哺乳动物细胞系表现出轻微的毒性。在果蝇测定中发现这些化合物不具有致突变性，并且在血浆和胃液中表现出良好的稳定性。所呈现的结果表明该支架是开发选择性抗衣原体药物的一个有希望的起点。
更新日期：2020-04-24
中文翻译：
基于圆柱形蛋白酶失调分子的合成和抗衣原体活性。
沙眼衣原体是全球最常见的性传播细菌性疾病，也是世界上不孕症和可预防的感染性失明（沙眼）的主要原因。不幸的是，FDA 还没有批准针对衣原体感染的治疗方法。我们最近报道了两种磺酰吡啶可以阻止病原体的生长。在这里，我们通过在芳香区引入取代基来展示磺酰吡啶分子的SAR。生物学评价研究表明，几种类似物可以损害沙眼衣原体的生长而不影响宿主细胞的活力。这些化合物不会杀死其他细菌，表明对衣原体具有选择性。这些化合物对哺乳动物细胞系表现出轻微的毒性。在果蝇测定中发现这些化合物不具有致突变性，并且在血浆和胃液中表现出良好的稳定性。所呈现的结果表明该支架是开发选择性抗衣原体药物的一个有希望的起点。
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