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

Journal of Enzyme Inhibition and Medicinal Chemistry

Fanny Nascimento Costa¹  Fabio Furlan Ferreira¹  Isadora Tairinne de Sena Bastos²  Regina Cely Rodrigues Barroso²  Carlos Alberto Manssour Fraga³  Ramon Guerra de Oliveira³  Cláudia dos Santos Mermelstein⁴  Patrícia Dias Fernandes⁵  Fabiana Sélos Guerra⁵ 

[1] Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), São Paulo, Brazi;Instituto de Física, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil;Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Laboratório de Diferenciação Muscular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Laboratório de Farmacologia da Dor e da Inflamação, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;

关键词: Molecular hybridization;    N;    Rho kinase;    ROCK inhibitor;    fasudil;    LASSBio-1524;   

DOI  :  10.1080/14756366.2018.1490732

来源: publisher

【 摘 要 】

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-β 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 µM 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.

【 授权许可】

CC BY