Design, synthesis and pharmacological screening of novel nitric oxide donors containing 1,5-diarylpyrazolin-3-one as nontoxic NSAIDs.

Various substituted 1,5-diarylpyrazol-3-one derivatives were synthesized and screened for analgesic, anti-inflammatory activities, ulcerogenic potential and for their ability to release nitric oxide. Most compounds exhibited significant analgesic and anti-inflammatory activities. It was interesting to note that out of ten compounds, 7j (59.64%) was found to have anti-inflammatory activity greater than the standard drug Indomethacin (57.89%), whereas compound 7b (57.89%) was found to be equipotent to that of standard, Indomethacin. The pharmacological studies suggested that the presence of 4-nitro and 2-methoxy on phenyl ring at C(5) of pyrazole has a significant anti-inflammatory activity and 4-chloro substitution on same phenyl ring was found to have decreased activity. However only a phenyl substituted derivative was found to have most potent activity. Compound 7j containing plane phenyl at C(5) of pyrazole was found to have significant analgesic activity (56.86%) in acetic acid induced writhing model. Compounds 7d and 7i having 4-chloro substituted phenyl ring showed least analgesic activity (10.78%) and (6.86%) respectively. The compounds also showed significantly reduced GI-ulcerogenicity and gastroprotective results in histopathological studies i.e. they were found to be causing no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity, in both in vitro and in vivo models. Molecular docking studies served to be an important tool for the study of binding of compounds with that of a COX-2 enzyme. The results of the docking studies were found to endorse the result of experimental work. Thus, the rationale used to design the NCEs was found to produce the promising results as anticipated. Therefore it can be said that the strategy employed can serve as an important tool in future for the design and development of novel therapeutic agents of various categories too.

Design, synthesis and pharmacological screening of novel antihypertensive agents using hybrid approach.

Eight derivatives of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiographic, antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compound 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacological results suggested that the antiarrhythmic effects of these compounds were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substituted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the phenyl ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized compounds were significantly potent as antiarrhythmic and antihypertensive; this might be due to the presence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of compounds 8a-8h were promising enough to continue further experiments.