Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans |
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Authors: | Keisuke Ishita Stavros Stefanopoulos Ahmed Khalil Xiaolin Cheng Werner Tjarks Chad A. Rappleye |
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Affiliation: | 1. Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, United States;2. Department of Microbiology, The Ohio State University, Columbus, OH, United States;3. Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States |
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Abstract: | The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthalenylmethyl)-2-thiazolyl]cyclohexanecarboxamide (41F5), a fungistatic agent previously identified through phenotypic screening (Antimicrob Agents Chemother. 2013;57:4349). Modifications to improve potency and water-solubility of 41F5 focused primarily on the 5-naphthalenyl group, the thiazole core, and the methylene linker between these two structural elements. In general, compounds with lipophilic [5+6] bicyclic ring systems, such as the 7-benzothiophenyl- and 4-indanyl groups, at the 5-position were 2–3 times more active against both fungal species as compared to 41F5. Also, introduction of a carbonyl group at the methylene linker of 41F5 resulted in a 2–3-fold increase in potency. These highly active compounds also showed generally low toxicities against murine P388D1 macrophages resulting in selectivity indices ranging from 63 to >200. Compounds that were highly active against fluconazole-sensitive C. neoformans strains had almost identical activity against fluconazole-resistant variants of this fungus indicating that 14α-demethylase is not their molecular target. Highly active compounds also retained activity against H. capsulatum phagocytosed into P388D1 macrophages. |
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Keywords: | Boc DMAP 4-dimethylaminopyridine DCM dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HIV human immunodeficiency virus HOBt hydroxybenzotriazole HR-ESI high resolution–electrospray ionization LDA lithium diisopropyl amide MIC minimal inhibitory concentration rxn reaction SAR structure-activity-relationship SD standard deviation SM supplementary material SI selectivity index TFA trifluoroacetic acid THF tetrahydrofuran Aminothiazoles Antifungal activity Structure-activity-relationship Corresponding author at: 484 West 12th Avenue, Columbus, OH 43210, USA. |
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