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

• Published in: Bioorganic & medicinal chemistry 2017-11, Vol.25 (21), p.6071-6085
• Main Authors: Abbhi, Vasudha, Saini, Lovneet, Mishra, Srishti, Sethi, Gautam, Kumar, Alan Prem, Piplani, Poonam
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Benzimidazole derivatives; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Female; Glaucoma; Glaucoma - drug therapy; Glaucoma - metabolism; Humans; Intraocular pressure; Molecular Docking Simulation; Molecular Structure; Oxidative stress; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Rats; Recombinant Proteins - metabolism; RGCs death; Rho kinase inhibitors; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.09.045

[Display omitted] •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. 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 IC50 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.