Non-Steroidal Ani-Inflammatory Drugs (NSAIDs) are widely used in the treatment of inflammation, pain and fever through blockade of the arachidonic acid pathway. Its long term intake is concomitant with gastrointestinal toxicity due to their non-selective inhibition of COX isozymes. Replacing the gastrotoxic carboxylic gp with other less acidic heterocyclic bioisosteres such as oxadiazoles and triazoles, is a potential strategy in the treatment of inflammation. Another strategy is to develop NSAIDs/NO hybrids that release NO which has gastro-protective properties. Herein, we employed the two strategies to design two novel series of NSAIDs, quinolone-1,2,4-triazoles and 1,3,4-oxadiazoles. A nitric oxide donating oxime was added through two spacers; phenacyl bromide and P-aminoacetophenone. A paw-edema thickness assay showed that all the synthesized compounds have promising anti-inflammatory activity, with 1,3,4-oxadiazole derivatives exhibiting higher activity than 1,2,4-triazoles. Hybrids with a para-aminoacetophenone spacer showed superior anti-inflammatory activity compared to those possessing a phenacyl bromide spacer. An in-vitro COX inhibitory assay was employed to calculate the IC50 of each compound. 1,2,4-triazoles showed inhibition of the COX-1, with IC50’s ranging from 0.48 to 28 µM while 1,3,4-Oxadiazoles showed potent inhibition of both COXs with IC50 range of (0.9–17) and (2.30–5.00) µM on COX-1 and 2 respectively. The 1,3,4-Oxadiazoles were non-selective toward both COXs with a selectivity index (SI) range of (0.17–3.00), while the 1,2,4-triazoles were selective for COX-1 with a SI of (0.0005–0.3). Kinetic studies suggest a non-competitive mode of inhibition for both series on both COXs and Ki was estimated for each series. Finally, all compounds exhibited a safe GI profile with Ulcer indices of (0–6.88). In conclusion, the two strategies successfully produced NSAIDs with enhanced anti-inflammatory activity and minimized gastrointestinal side effects.

Design, synthesis and biological evaluation of novel NSAIDs with improved gastrointestinal safety profile

255th National Meeting (2018)

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