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

Ramon Guerra de Oliveira; Fabiana Sélos Guerra; Cláudia Dos Santos Mermelstein; Patrícia Dias Fernandes; Isadora Tairinne de Sena Bastos; Fanny Nascimento Costa; Regina Cely Rodrigues Barroso; Fabio Furlan Ferreira; Carlos Alberto Manssour Fraga

doi:10.1080/14756366.2018.1490732

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

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1181-1193. doi: 10.1080/14756366.2018.1490732.

Affiliations

¹ a Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto de Ciências Biomédicas , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
² b Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
³ c Laboratório de Farmacologia da Dor e da Inflamação, Instituto de Ciências Biomédicas , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
⁴ d Laboratório de Diferenciação Muscular, Instituto de Ciências Biomédicas , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
⁵ e Instituto de Física , Universidade do Estado do Rio de Janeiro , Rio de Janeiro , Brazil.
⁶ f Centro de Ciências Naturais e Humanas (CCNH) , Universidade Federal do ABC (UFABC) , São Paulo , Brazil.

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-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.

Keywords: LASSBio-1524; Molecular hybridization; N-sulphonylhydrazone; ROCK inhibitor; Rho kinase; fasudil.

MeSH terms

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / chemistry
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
Animals
Cell Line, Tumor
Female
Humans
Hydrazones / chemical synthesis
Hydrazones / chemistry*
Hydrazones / pharmacology
Isoquinolines / chemistry*
Models, Molecular
Powder Diffraction
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology*
Spectrum Analysis / methods
rho-Associated Kinases / antagonists & inhibitors*

Substances

Hydrazones
Isoquinolines
N-(4-nitrobenzylidene)-2-naphthohydrazide
Protein Kinase Inhibitors
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
rho-Associated Kinases
isoquinoline
fasudil

Grants and funding

This work was co-funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq, BR, Grant No 305.991/2017–5, 432.001/2016–6, 304.872/2013–0, 307.664/2015–5 and 402.289/2013–7], Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro [FAPERJ, BR, Grant No. E-26/202.918/2015], Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [Grant No. 2015/26233–7] and Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos [INCT-INOFAR, BR, Grant No 465.249/2014]. Thanks are also due to Departamento de Ciência e Tecnologia (DECIT) of Brazilian Ministry of Health for the financial support [Grant No 25000.447435/2017–00].