Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents

Scripps Florida. Department of Chemistry. Florida, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA / Fundação Oswaldo cruz. Instituto Oswaldo cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA / Seattle University. College of Scinece and Engineering. Seattle, WA, USA.
Scripps Florida. Department of Moleceular Therapeutics. Florida, USA.
Scripps Florida. Department of Moleceular Therapeutics. Florida, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA.
Scripps Florida. Department of Chemistry. Florida, USA.

Abstract

A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.

Keywords in Portuguese

Doença de Chagas
Estrutura de raios-x
Inibidores de CYP51

Keywords

Chagas disease
non-azole CYP51 inhibitors
structure guided drug design
structure activity and property relationships
x-ray structure

Publisher

American Chemical Society

Citation

CHOI, Jun Yong; et al. Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-Chagas agents. J Med Chem., v.56, n.19, :45p, 2013.

DOI

10.1021/jm401067s

ISSN

0022-2623

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/16917

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Copyright

Restricted access

Embargo date

2030-01-01

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