title: Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity.
abstract: Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated. The two most active compounds (6, 14) both in the parasite amastigotes and in the enzyme contain the nitro group in para position of the aromatic ring. The permeability screening in Caco-2 cell and cytotoxicity assay in human cells were performed for those most active compounds and both showed to be less cytotoxic than the reference drug, benznidazole. Compound 6 was the most promising, since besides activity it showed good permeability and selectivity index, higher than the reference drug. Thereby the compound 6 was considered as a possible candidate for additional studies.
authors.affiliation: LAPEN - Laboratório de Planejamento e Síntese de Quimioterápicos Potencialmente Ativos contra Doenças Negligenciadas, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 São Paulo, SP, Brazil.
authors.forename: Ricardo Augusto
authors.initials: RA
authors.lastname: Massarico Serafim
authors.affiliation: LPFCC - Laboratório de Permeabilidade de Fármacos em Culturas Celulares, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, São Paulo, SP, Brazil.
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Gonçalves
authors.affiliation: Universidade de São Paulo, Departamento de Análises Clínicas e Toxicológicas, São Paulo, SP, Brazil.
authors.forename: Felipe Pereira
authors.initials: FP
authors.lastname: de Souza
authors.affiliation: Universidade de São Paulo, Departamento de Análises Clínicas e Toxicológicas, São Paulo, SP, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: de Melo Loureiro
authors.affiliation: LPFCC - Laboratório de Permeabilidade de Fármacos em Culturas Celulares, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, São Paulo, SP, Brazil.
authors.forename: Silvia
authors.initials: S
authors.lastname: Storpirtis
authors.affiliation: LQMC - Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Universidade de São Paulo (USP), Instituto de Física de São Carlos, São Carlos, SP, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Krogh
authors.affiliation: LQMC - Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Universidade de São Paulo (USP), Instituto de Física de São Carlos, São Carlos, SP, Brazil.
authors.forename: Adriano Defini
authors.initials: AD
authors.lastname: Andricopulo
authors.affiliation: LQOS - Laboratório de Química Orgânica Sintética, Universidade Estadual de Campinas (UNICAMP), Instituto de Química, Campinas, SP, Brazil.
authors.forename: Luiz Carlos
authors.initials: LC
authors.lastname: Dias
authors.affiliation: LAPEN - Laboratório de Planejamento e Síntese de Quimioterápicos Potencialmente Ativos contra Doenças Negligenciadas, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 São Paulo, SP, Brazil. Electronic address: elizabeth.igne@gmail.com.
authors.forename: Elizabeth Igne
authors.initials: EI
authors.lastname: Ferreira
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000970:Antineoplastic Agents; D006835:Hydrazones; D010069:Oxadiazoles; D014344:Trypanocidal Agents
keywords: Anti-Trypanosoma cruzi compounds; Bioisosters; Furoxan derivatives; Molecular hybrids; N-acylhydrazone derivatives; Nitric oxide donor groups