Design, synthesis, and evaluation of anti-inflammatory, analgesic, ulcerogenicity, and nitric oxide releasing studies of novel indomethacin analogs as non-ulcerogenic derivatives

Abstract

Most non-steroidal anti-inflammatory drugs (NSAIDs) suffer from the deadlier gastrointestinal (GI) toxicities. The free -COOH group is responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main objective was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. The results of synthesis and pharmacological screening of a series of hybrid molecules having general formula 2-(5-(5-(substituted phenyl)-2-oxo-ethylthio)-1,3,4-oxadiazole-2-yl)-2-phenyl-1H-indol-1-yl)-2-oxoethyl nitrate are described. These compounds were tested in vivo for their anti-inflammatory, analgesic, and ulcerogenic properties, and subjected to histopathological studies. Compound 7c, 2-(5-(5-(3-hydroxyphenyl)-2-oxo-ethylthio)-1,3,4-oxadiazole-2-yl)-2-phenyl-1H-indol-1-yl)-2-oxoethyl nitrate, was the most potent in this series. The compounds that showed significantly reduced GI ulcerogenicity also showed promising results in histopathological studies, and they were found to cause no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity in an in vitro method. In conclusion, the designed hybrid molecules were found to be significantly promising.

Keywords:

• Hybrid drugs
• indomethacin
• 1,3,4-oxadiazole
• nitric oxide donor
• ulcerogenicity

Acknowledgements

The authors are thankful to the Principal, AISSMS College of Pharmacy, Pune, for providing laboratory facilities. The authors are also thankful to Professor N. S. Vyawahare, Head, Department of Pharmacology, for his continuous support and guidance throughout the project. The authors also wish to thank the Shimadzu Analytical Center and Department of Chemistry, University of Pune, for providing facilities for spectral studies of compounds. The authors are also thankful to Satav’s Pathology Laboratory, Pune, for providing facilities for histopathological studies.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content of this paper.