Novel sulindac derivatives: synthesis, characterisation, evaluation of antioxidant, analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibition activity

Abstract

A new series of N 0-(substituted phenyl)-2-(1-(4-(methylsulfinyl) benzylidene)À5-fluoro-2-methyl-1H-inden-3yl) acetohydrazide derivatives (1-25) were prepared in good yields in an efficient manner. All the compounds were fully characterised by the elemental analysis and spectral data. Synthesised compounds were evaluated for antioxidant activity by DPPH method. Compounds 7 (R ¼ 3-methoxyphenyl), 3 (R ¼ 4dimethylaminophenyl) and 23 (R ¼ 2,4,5-trimethoxy phenyl) substitutions were found to be having highly potent antioxidant activity. Compound 3, with para dimethylaminophenyl substitution was found to be having highest antioxidant activity. It was further evaluated in vivo for various analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibitory activity in different animal models. Lead compound 3 was found to be significant anti-inflammatory and analgesic agent. It was also evaluated for ulcerogenic activity and demonstrated significant ulcerogenic reduction activity in ethanol and indomethacin model. The LD 50 of compound 3 was found to be 131 mg/kg. The animals treated with compound 3 prior to cisplatin treatment resulted in a significant reduction in COX-2 protein expression when compared to cisplatin-treated group. Sulindac derivative with para dimethylaminophenyl substitution was found to be the most potent antioxidant, anti-inflammatory and analgesic agent as well as with significant gastric sparing activity as compared to standard drug sulindac. Compound 3 significantly downregulated liver tissue COX-2 gene expression.

Determination of Pleiotropic Effect of Warfarin in VKORC1 and CYP2C9 Genotypes in Patients With Heart Valve Replacement

“…The CB-Docked uses Vina for protein-ligand docking (14). The best docking pose was selected based on the Vina score (19). The MD simulations were performed to check the binding of warfarin with the wild-type and mutant CYP2C9 dynamically.…”

Medicinal Chemistry of Indane and Its Analogues: A Mini Review

“…The in vivo anti‐inflammatory and analgesic investigations by tail flicking method, hot plate method, acetic acid‐induced writhing, yeast induced hyperthermia, and carrageenan induced paw edema confirmed the anti‐inflammatory potency of the test acetohydrazide derivatives of Sulindac, with compound 50 b (Figure 10) being the most potent inhibitor of the symptoms of inflammation. The acute toxicity analysis on test compounds displayed a lower ulcerogenic index in the gastric tissues of the animal models, which prompted the reticence of COX‐2 protein expression in liver tissues of animal models [45] …”

Molecular docking, pharmacokinetic studies, and in vivo pharmacological study of indole derivative 2-(5-methoxy-2-methyl-1H-indole-3-yl)-N′-[(E)-(3-nitrophenyl) methylidene] acetohydrazide as a promising chemoprotective agent against cisplatin induced organ damage

“…Though, by chemical modifications, the profile of its safety has been improved 18 . Studies have illustrated that modification by synthesis increased the probability to provide derivatives with noteworthy anti-inflammatory and lessen the chance of side effects 19 . The solution for the above-mentioned criteria has been limited by the COX-2 inhibitors 20 – 22 .…”