Design and Synthesis of Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors

The molecular chaperone
Hsp90, essential in all eukaryotes, plays
a multifaceted role in promoting survival, virulence, and drug resistance
across diverse pathogenic fungal species. The chaperone is also critically
important, however, to the pathogen’s human host, preventing
the use of known clinical Hsp90 inhibitors in antifungal applications
due to concomitant host toxicity issues. With the goal of developing
Hsp90 inhibitors with acceptable therapeutic indices for the treatment
of invasive fungal infections, we initiated a program to design and
synthesize potent inhibitors with selective activity against fungal
Hsp90 isoforms over their human counterparts. Building on our previously
reported derivatization of resorcylate natural products to produce
fungal-selective compounds, we have developed a series of synthetic
aminopyrazole-substituted resorcylate amides with broad, potent, and
fungal-selective Hsp90 inhibitory activity. Herein we describe the
synthesis of this series, as well as biochemical structure–activity
relationships driving selectivity for the Hsp90 isoforms expressed
by Cryptococcus neoformans and Candida albicans, two pathogenic fungi of major clinical importance.