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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors

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Avelar, Leandro A. A. [1] ; Camilo, Cristian D. [1] ; de Albuquerque, Sergio [2] ; Fernandes, William B. [1, 3] ; Goncalez, Cristiana [2] ; Kenny, Peter W. [1] ; Leitao, Andrei [1] ; McKerrow, James H. [3] ; Montanari, Carlos A. [1] ; Menaca Orozco, Erika V. [1] ; Ribeiro, Jean F. R. [1] ; Rocha, Josmar R. [1] ; Rosini, Fabiana [1] ; Saidel, Marta E. [1]
Total Authors: 14
[1] Univ Sao Paulo, Inst Quim Sao Carlos, Grp Quim Med IQSC USP, Sao Carlos, SP - Brazil
[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14049 Ribeirao Preto, SP - Brazil
[3] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 - USA
Total Affiliations: 3
Document type: Journal article
Source: PLoS Neglected Tropical Diseases; v. 9, n. 7 JUL 2015.
Web of Science Citations: 12

A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A K-i value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 mu M was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds. (AU)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support type: Research Projects - Thematic Grants