Abstract
The design, synthesis, and development of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are respectable area of research. Novel Diclofenac Schiff's bases (M1, M2, M4, M7, and M8) were designed and synthesized, and their respective chemical structures were deduced using various spectral tools (IR, 1H NMR, 13C NMR, and MS). The compounds were synthesized via Schiff's condensation reaction and their anti-inflammatory activity was investigated applying the Carrageenan-induced paw edema model against Diclofenac as positive control. Percentage inhibition of edema indicated that all compounds were exhibiting a comparable anti-inflammatory activity as Diclofenac. Moreover, the anti-inflammatory activity was supported via virtual screening using molecular docking study. Interestingly compound M2 showed the highest in vivo activity (61.32% inhibition) when compared to standard Diclofenac (51.36% inhibition) as well as the best binding energy score (-10.765) and the virtual screening docking score (-12.142).
Highlights
IntroductionDiclofenac is a phenyl acetic acid derivative and belongs to the non-steroidal anti-inflammatory drugs (NSAIDs) family [1]
Diclofenac is a phenyl acetic acid derivative and belongs to the non-steroidal anti-inflammatory drugs (NSAIDs) family [1].Despite the huge prescription of NSAIDs, most of them exhibit shared set of adverse effects including gastrointestinal complications [2,3,4,5,6] that are generally attributed to the primary local irritation following the direct contact of carboxylic acid functionality of NSAID with GI mucosal cells and the reduced cytoprotection effect resulting from decreased tissue prostaglandin production [6]; further studies were carried out in order to achieve innovative compounds with lower side effects
The size of active site in cyclooxygenase enzyme COX-2 is larger than cyclooxygenase enzyme COX-1; the extension in ligand size may increase the selectivity toward COX-2 enzyme [15]
Summary
Diclofenac is a phenyl acetic acid derivative and belongs to the non-steroidal anti-inflammatory drugs (NSAIDs) family [1]. Despite the huge prescription of NSAIDs, most of them exhibit shared set of adverse effects including gastrointestinal complications [2,3,4,5,6] that are generally attributed to the primary local irritation following the direct contact of carboxylic acid functionality of NSAID with GI mucosal cells and the reduced cytoprotection effect resulting from decreased tissue prostaglandin production [6]; further studies were carried out in order to achieve innovative compounds with lower side effects. Amide modification of carboxylic acid group of the existing NSAIDs such as Indomethacin, Meclofenamic acid, and Ketoprofen conferred the compounds greater selectivity for COX-2 over the COX-1 enzyme resulting in GI sparing effect [8]. Isatin (indoline-2,3-dione) is synthetically versatile substrate serving as raw material for drug synthesis that can be modified into various heterocyclic compounds including Indoles and Quinolones [10]. The size of active site in cyclooxygenase enzyme COX-2 is larger than cyclooxygenase enzyme COX-1; the extension in ligand size may increase the selectivity toward COX-2 enzyme [15]
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