Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata

Narendran G-Dayanandan, Janet L. Paulsen, Kishore Viswanathan, Santosh Keshipeddy, Michael N. Lombardo, Wangda Zhou, Kristen M. Lamb, Adrienne E. Sochia, Jeremy B. Alverson, Nigel D. Priestley, Dennis L. Wright, Amy C. Anderson

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 μg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.

Original languageEnglish
Pages (from-to)2643-2656
Number of pages14
JournalJournal of Medicinal Chemistry
Volume57
Issue number6
DOIs
StatePublished - Mar 27 2014

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