title: R-Configuration of 4-Aminopyridyl-Based Inhibitors of CYP51 Confers Superior Efficacy Against Trypanosoma cruzi.
abstract: Sterol 14α-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. We report the development of potent and selective d-tryptophan-derived inhibitors of T. cruzi CYP51. Structural information obtained from the cocrystal structure of CYP51 and (R)-2, which is >1000-fold more potent than its enantiomer (S)-1, was used to guide design of additional analogues. The in vitro efficacy data presented here for (R)-2-(R)-8, together with preliminary in vitro pharmacokinetic data suggest that this new CYP51 inhibitor scaffold series has potential to deliver drug candidates for treatment of T. cruzi infections.
authors.affiliation: Department of Chemistry, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ , Rio de Janeiro, RJ 21040-362, Brazil.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Calvet
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States.
authors.forename: Debora F
authors.initials: DF
authors.lastname: Vieira
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States.
authors.forename: Shamila S
authors.initials: SS
authors.lastname: Gunatilleke
authors.affiliation: Department of Molecular Therapeutics, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States.
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Podust
authors.affiliation: Department of Chemistry, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
keywords: CYP51; R-configuration; T. cruzi; inhibitors