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Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
Affiliation:1. Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil;2. Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil;3. Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil;1. CONICET-Universidad de Buenos Aires, Instituto de la Química y Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, Argentina;2. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Medicinal, Buenos Aires, Argentina;3. Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH-UNSAM), San Martín, Argentina;4. Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Inorgánica, Analítica y Química-Física, Buenos Aires, Argentina;5. CONICET-Universidad de Buenos Aires, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Buenos Aires, Argentina;1. Departament de Química Inorgànica i Orgànica, Universitat Jaume I, Avda. Sos Baynat s/n 12080 Castelló, Spain;2. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany;3. Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland;4. University of Basel, Petersplatz 1, 4003 Basel, Switzerland;5. Department of Biochemistry and Molecular Biology and Research Institute Hospital 12 de Octubre, Faculty of Veterinary Sciences, Complutense University of Madrid, 28040 Madrid, Spain;1. Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil;2. Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, CEP 31270-901 Belo Horizonte, MG, Brazil;3. Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP, 40296-750 Salvador, BA, Brazil;4. Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, CEP, 50670-420 Recife, PE, Brazil;5. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia;1. Universidade de Pernambuco, Laboratório de Prospecção de Moléculas Bioativas, Programa de Pós-Graduação em Ciência e Tecnologia Aplicadas no Semiárido, 56328-903, Petrolina, PE, Brazil;2. Universidade Federal de Pernambuco, Laboratório de Planejamento e Síntese de Fármacos, Departamento de Ciências Farmacêuticas, 50740-520, Recife, PE, Brazil;3. Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, CEP, 50670-420, Recife, PE, Brazil;4. Universidade Federal de Pernambuco, Laboratório de Parasitologia, Centro Acadêmico de Vitória - CEP, 55608-680, Vitória de Santo Antão, PE, Brazil;5. Universidade Federal de Minas Gerais, Departamento de Bioquímica e Imunologia, CEP, 31270-901, Belo Horizonte, MG, Brazil;6. Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz, CEP, 40296-750, Salvador, BA, Brazil;7. Hospital São Rafael, Centro de Biotecnologia e Terapia Celular, CEP, 41253-190, Salvador, BA, Brazil
Abstract:The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.
Keywords:Covalent inhibitor  Cruzain  Cysteine protease  Group efficiency  Lipophilic efficiency  Nonadditivity  Structure-activity relationship
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