Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds

Autor(es)

Lameiro, Rafael da Fonseca ^[1] ; Shamim, Anwar ^[1] ; Rosini, Fabiana ^[1] ; Cendron, Rodrigo ^[1] ; Jatai Batista, Pedro Henrique ^[1] ; Montanari, Carlos Alberto ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sao Carlos Inst Chem, Grp Quim Med & Biol IQSC USP, Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Future Medicinal Chemistry; v. 13, n. 1, p. 25-44, JAN 2021.
• Citações Web of Science: 0

Resumo

Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials \& methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy. (AU)

• Processo FAPESP: 18/03279-0 - Atividade anti-Trypanosoma cruzi de agentes não-peptídicos como inibidores da cisteíno protease cruzaína
• Beneficiário: Rafael da Fonseca Lameiro
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 18/03985-1 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Anwar Shamim
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: Auxílio à Pesquisa - Temático