title: Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans.
abstract: Invasive fungal disease constitutes a growing health burden and development of novel antifungal drugs with high potency and selectivity against new fungal molecular targets are urgently needed. Previously, an aminothiazole derivative, designated as 41F5, was identified in our laboratories as highly active against Histoplasma yeast (MIC50 0.4-0.8 μM) through phenotypic high-throughput screening of a commercial library of 3600 purine mimicking compounds (Antimicrob. Agents Chemother.2013, 57, 4349). Consequently, 68 analogues of 41F5 were designed and synthesized or obtained from commercial sources and their MIC50s of growth inhibition were evaluated in Histoplasma capsulatum to establish a basic structure-activity-relationship (SAR) for this potentially new class of antifungals. The growth inhibiting potentials of smaller subsets of this library were also evaluated in Cryptococcus neoformans and human hepatocyte HepG2 cells, the latter to obtain selectivity indices (SIs). The results indicate that a thiazole core structure with a naphth-1-ylmethyl group at the 5-position and cyclohexylamide-, cyclohexylmethylamide-, or cyclohexylethylamide substituents at the 2-position caused the highest growth inhibition of Histoplasma yeast with MIC50s of 0.4 μM. For these analogues, SIs of 92 to >100 indicated generally low host toxicity. Substitution at the 3- and 4-position decreased antifungal activity. Similarities and differences were observed between Histoplasma and Cryptococcus SARs. For Cryptococcus, the naphth-1-ylmethyl substituent at the 5-position and smaller cyclopentylamide- or cyclohexylamide groups at the 2-position were important for activity. In contrast, slightly larger cyclohexylmethyl- and cyclohexylethyl substituents markedly decreased activity.
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA; Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khalil
authors.affiliation: Department of Microbiology, The Ohio State University, USA; Department of Microbial Infection and Immunity, The Ohio State University, USA; The Center for Microbial Interface Biology, The Ohio State University, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Edwards
authors.affiliation: Department of Microbiology, The Ohio State University, USA; Department of Microbial Infection and Immunity, The Ohio State University, USA; The Center for Microbial Interface Biology, The Ohio State University, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Rappleye
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA; The Center for Microbial Interface Biology, The Ohio State University, USA. Electronic address: tjarks.1@osu.edu.
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects; D006658:Histoplasma / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D013844:Thiazoles
keywords: Aminothiazoles; Antifungal activity; Cryptococcus neoformans; Histoplasma capsulatum; Structure–activity-relationship