Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51

University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.
Scripps Florida. Department of Chemistry. Florida, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultra-Estrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.
University of California - San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.
University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.
University of California - San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.
Scripps Florida. Department of Molecular Therapeutics. Florida, USA.
University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.
Scripps Florida. Department of Chemistry. Florida, USA
University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.

Abstract

Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure−activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal Nphenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95−2.48 Å). The 5-chlorosubstituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.

Keywords

Chagas Disease
Trypanosoma cruzi

DeCS

Doença de Chagas
Trypanosoma cruzi

Publisher

American Chemical Society

Citation

VIEIRA, Debora F. et al. Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51. J. Med. Chem. v.57, n.23, p.10162−10175, 2014.

DOI

10.1021/jm501568b

ISSN

0022-2623

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/10768

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