Affiliation:
1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India
Abstract
Background:
Inducible nitric Oxide Synthase (iNOS) plays a key role in the progression
of inflammatory diseases by accelerating the production of NO, which makes it an intriguing target
to treat inflammation in complex diseases. Therefore, the search is on to develop molecules as selective
iNOS inhibitors.
Objective:
The present work was aimed to design, synthesize and evaluate benzimidazole-coumarin
coupled molecules as anti-iNOS agents through in silico and pharmacological studies.
Methods:
A critical study of literature reports on iNOS inhibitors led to the selection of a
(un)substituted coumarin nucleus, 2-aminobenzimidazole, and a 4-atom linker as important structural
components for iNOS inhibition. Two series of compounds (7-16 and 17-26) were designed and synthesized
by coupling these components. The compounds were subjected to docking using iNOS
(1QW4) and nNOS (1QW6) as targets. All compounds were evaluated for NO and iNOS inhibitory
activities in vitro. The selected compound was finally evaluated for anti-inflammatory activity in vivo
using the carrageenan-induced rat paw edema model.
Results:
All compounds showed moderate to good inhibition of NO and iNOS in vitro. Compound
12 was the most potent inhibitor of NO and iNOS. Hence, it was evaluated in vivo for toxicity and
anti-inflammatory activity. It was found to be safe in acute toxicity studies, and effective in reducing
the rat paw edema significantly. Its anti-inflammatory behaviour was similar to that of aminoguanidine,
which is a selective iNOS inhibitor.
Conclusion:
The newly synthesized benzimidazole-coumarin hybrids may serve as potential leads
for the development of novel anti-iNOS agents.
Publisher
Bentham Science Publishers Ltd.
Cited by
3 articles.
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