Abstract
Therapeutically potential prodrugs of piroxicam were synthesized by effective masking of enolic hydroxyl group through generation of ester congeners. The reaction facilitated using N,N′-dicyclohexylcarbodiimide coupled with acetic acid, benzoic acid, p-toluic acid, m-toluic acid, and cinnamic acid. Synthesized prodrugs were characterized for confirmation of the said structures. The modification of piroxicam showed better anti-inflammatory activity as evoked by all prodrugs. Interestingly, compound 3e, cinnamic acid ester prodrug, depicted 75 percent inhibition of rat paw edema as compared to 56 percent for parent piroxicam at 6 h of study. The present work proves the applicability not only with increased anti-inflammatory activity, but also with marked attenuation in ulcerogenicity. Novel prodrug 3e, cinnamic acid derivative, was found to be the least ulcerogenic having ulcer index of 0.67 as compared to parent drug piroxicam with 2.67.
Highlights
The gastrointestinal side effects such as dyspepsia and frank ulceration constitute the most frequent of every adverse reaction that are caused by nonsteroidal anti-inflammatory drugs (NSAIDs) [1]
The highest flying factor in the development of GI ulceration induced by NSAIDs is the inhibition of prostaglandin synthesis, as endogenous prostaglandins are known to have cytoprotective action on gastric mucosa [4]
The designing of prodrugs has given the success to overcome the undesirable properties associated with the parent drug, piroxicam
Summary
The gastrointestinal side effects such as dyspepsia and frank ulceration constitute the most frequent of every adverse reaction that are caused by nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. 1,2-benzothiazine-3-carboxamide4-hydroxy-2-methyl-N-(2-pyridyl)-1,1-dioxide, is effectively employed to treat rheumatoid arthritis, osteoarthritis, and musculoskeletal inflammation [2]. It is susceptible to produce gastric ulcerations associated with gastrointestinal (GI) bleeding and hemorrhages as prominent side effects [3]. The highest flying factor in the development of GI ulceration induced by NSAIDs is the inhibition of prostaglandin synthesis, as endogenous prostaglandins are known to have cytoprotective action on gastric mucosa [4]. NSAIDs generate GI lesions by two different mechanisms: direct contact effect and generalized systemic effect which may occur after absorption following intravenous dosing [5]
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