Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors

Autor(es)

de Oliveira, Ramon Guerra ^{[1, 2]} ; Guerra, Fabiana Selos ^{[1, 3]} ; Mermelstein, Claudia dos Santos ^[4] ; Fernandes, Patricia Dias ^{[1, 3]} ; de Sena Bastos, Isadora Tairinne ^[5] ; Costa, Fanny Nascimento ^[6] ; Rodrigues Barroso, Regina Cely ^[5] ; Ferreira, Fabio Furlan ^[6] ; Manssour Fraga, Carlos Alberto ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Programa Posgrad Farmacol & Quim Med, Rio De Janeiro - Brazil

^[2] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Lab Avaliacao & Sintese Subst Bioat LASSBio, Rio De Janeiro - Brazil

^[3] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Lab Farmacol Dor & Inflamacao, Rio De Janeiro - Brazil

^[4] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Lab Diferenciacao Muscular, Rio De Janeiro - Brazil

^[5] Univ Estado Rio de Janeiro, Inst Fis, Rio De Janeiro - Brazil

^[6] UFABC, CCNH, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Enzyme Inhibition and Medicinal Chemistry; v. 33, n. 1, p. 1181-1193, JUL 25 2018.
• Citações Web of Science: 1

Resumo

In this study, we synthesized a new congener series of N-sulphonylhydrazones designed as candidate ROCK inhibitors using the molecular hybridization of the clinically approved drug fasudil (1) and the IKK-beta inhibitor LASSBio-1524 (2). Among the synthesized compounds, the N-methylated derivative 11 (LASSBio-2065) showed the best inhibitory profile for both ROCK isoforms, with IC50 values of 3.1 and 3.8 mu M for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in the scratch assay performed in human breast cancer MDA-MB 231 cells and did not display toxicity in MTT and LDH assays. Molecular modelling studies provided insights into the possible binding modes of these N-sulphonylhydrazones, which present a new molecular architecture capable of being optimized and developed as therapeutically useful ROCK inhibitors. (AU)

• Processo FAPESP: 15/26233-7 - Síntese e caracterização estrutural de cocristais para aplicações em protetores solares e antioxidantes de uso tópico
• Beneficiário: Fabio Furlan Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular