Design and synthesis of benzimidazole-based Rho kinase inhibitors for the treatment of glaucoma

Vasudha Abbhi; Lovneet Saini; Srishti MishraGautam SethiAlan Prem KumarPoonam Piplani

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Design and synthesis of benzimidazole-based Rho kinase inhibitors for the treatment of glaucoma

机译：Design and synthesis of benzimidazole-based Rho kinase inhibitors for the treatment of glaucoma

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Graphical abstract Display Omitted Highlights ? A series of benzimidazole derivatives has been synthesized and characterized as ROCK inhibitors. ? The IOP lowering effect of the compounds has been determined in the treated and the contralateral eye. ? Free radical scavenging activity of the compounds has been carried out. ? Rho kinase inhibitory activity and in silico studies have been done. ? Compound 9j was found to be most active and can be explored for treatment of glaucoma. Abstract Rho kinase inhibitors (ROCK II) play a key role in glaucoma management attributed to their IOP lowering ability and neuroprotective effects. In the present study, a series of novel benzimidazole derivatives ( 9a – m ) has been synthesized and evaluated for their IOP lowering, Rho kinase inhibitory and antioxidant properties. The synthesized compounds were found to be lipophilic and showed a significant IOP lowering effect both in the treated and the contralateral eye comparable to the reference standard fasudil. The nitrophenyl piperazine substituted compound 9j exhibited significant IOP lowering (51.56%) and an inhibition of 57.25 and 77.92% towards ROCK II enzyme at a concentration of 0.5 and 1?mM respectively. It possessed a considerable free radical scavenging activity exhibiting an IC 50 value of 95.49?μg/mL in DPPH assay. The molecular docking studies of compound 9j indicated the binding of the compound at the active site of recombinant human ROCK II which makes it a promising antiglaucoma agent.

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《Bioorganic and medicinal chemistry》 |2017年第21期|6071-6085|共15页
作者
Vasudha Abbhi; Lovneet Saini; Srishti MishraGautam SethiAlan Prem KumarPoonam Piplani;
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作者单位

University Institute of Pharmaceutical Sciences, UGC-Center of Advanced Study (UGC-CAS), Panjab;

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore;

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原文格式 PDF
正文语种英语
中图分类药学;
关键词
Glaucoma; Intraocular pressure; Oxidative stress; RGCs death; Rho kinase inhibitors; Benzimidazole derivatives;

Design and synthesis of benzimidazole-based Rho kinase inhibitors for the treatment of glaucoma

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