title: Design, synthesis and pharmacological screening of novel nitric oxide donors containing 1,5-diarylpyrazolin-3-one as nontoxic NSAIDs.
abstract: 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.
authors: AISSMS College of Pharmacy, Near RTO, Pune 411001, Maharashtra, India. drugdesign1@gmail.com
authors: Shashikant V
authors: SV
authors: Bhandari
authors: Sudarshan C
authors: SC
authors: Dangre
authors: Kailash G
authors: KG
authors: Bothara
authors: Ajit A
authors: AA
authors: Patil
authors: Aniket P
authors: AP
authors: Sarkate
authors: Deepak K
authors: DK
authors: Lokwani
authors: Suraj T
authors: ST
authors: Gore
authors: Bhavana J
authors: BJ
authors: Deshmane
authors: Vyankatesh T
authors: VT
authors: Raparti
authors: Chetan V
authors: CV
authors: Khachane
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects*; D011485:Protein Binding; D011720:Pyrazoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D014456:Ulcer / Q000209:etiology; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D014665:Vasodilator Agents; D009569:Nitric Oxide; D051546:Cyclooxygenase 2