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

Journal of Enzyme Inhibition and Medicinal Chemistry

Fabio Furlan Ferreira¹  Fanny Nascimento Costa¹  Cláudia dos Santos Mermelstein²  Fabiana Sélos Guerra²  Patrícia Dias Fernandes²  Carlos Alberto Manssour Fraga²  Ramon Guerra de Oliveira²  Isadora Tairinne de Sena Bastos³  Regina Cely Rodrigues Barroso³ 

[1] Universidade Federal do ABC (UFABC);Universidade Federal do Rio de Janeiro;Universidade do Estado do Rio de Janeiro;

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

DOI  :  10.1080/14756366.2018.1490732

来源: DOAJ

【 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】

Unknown