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

ABSTRACT: 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-? 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.

SUBMITTER: Oliveira RG 

PROVIDER: S-EPMC6060383 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Oliveira Ramon Guerra de RG   Guerra Fabiana Sélos FS   Mermelstein Cláudia Dos Santos CDS   Fernandes Patrícia Dias PD   Bastos Isadora Tairinne de Sena ITS   Costa Fanny Nascimento FN   Barroso Regina Cely Rodrigues RCR   Ferreira Fabio Furlan FF   Fraga Carlos Alberto Manssour CAM  

Journal of enzyme inhibition and medicinal chemistry 20181201 1

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 IC<sub>50</sub> values of 3.1 and 3.8 µM for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in  ...[more]

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