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Synthesis and pharmacological evaluation of novel isoquinoline
N-sulphonylhydrazones designed as ROCK inhibitors
#MMPMID30044647
Oliveira RG
; Guerra FS
; Mermelstein CDS
; Fernandes PD
; Bastos ITS
; Costa FN
; Barroso RCR
; Ferreira FF
; Fraga CAM
J Enzyme Inhib Med Chem
2018[Dec]; 33
(1
): 1181-1193
PMID30044647
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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 IC(50) 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.
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