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Discovery of a new isomannide-based peptidomimetic synthetized by Ugi multicomponent reaction as human tissue kallikrein 1 inhibitor |
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| Authors: | Thalita G. Barros Jorge A.N. Santos Bruno E.G. de Souza Ana Carolina R. Sodero Alessandra M.T. de Souza Dayane P. da Silva Carlos Rangel Rodrigues Sergio Pinheiro Luiza R.S. Dias Bárbara Abrahim-Vieira Luciano Puzer Estela M.F. Muri |
| Affiliation: | 1. Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000 Niterói, RJ, Brazil;2. Instituto Federal de Ciência, Tecnologia e Educação do Sul de Minas Gerais, Campus Inconfidentes, MG, Brazil;3. Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil;4. ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil;5. Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil |
| Abstract: | Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50 for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects. |
| Keywords: | Peptidomimetics Ugi reactions Kallikreins Inhibitors Molecular modeling |
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