Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

Publication date: Available online 2 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Keisuke Ishita, Stavros Stefanopoulos, Ahmed Khalil, Xiaolin Cheng, Werner Tjarks, Chad Rappleye
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] bicyclics 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 compard 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.

Graphical abstract

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