Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans. Issue 9 (15th May 2018)

• Record Type: Journal Article
• Authors: Ishita, Keisuke; Stefanopoulos, Stavros; Khalil, Ahmed; Cheng, Xiaolin; Tjarks, Werner; Rappleye, Chad A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 9(2018)
• Page Start: 2251
• Page End: 2261
• Publication Date: 2018-05-15
• Subjects: Boc tert-butyloxycarbonyl -- 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 -- Histoplasma capsulatum -- Cryptococcus neoformans; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.01.024
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.