Abstract
This study was aimed to design novel diclofenac hydrazones having anti-inflammatory and analgesic activity with gastric sparing effect. A new series of 2-[2-(2,6-dichloroanilino)phenyl]-N’-[(substituted phenyl) methylidene] acetohydrazide derivatives (1−14) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activity. The compounds were identified and confirmed by elemental analysis and spectral data. During anti-inflammatory activity by carrageenan-induced paw edema method, compounds (2, 3, 7, 8, 11, and 13) were found to be most promising. Compounds 3, 8, and 13 have been found to have significant analgesic activity compared to the reference drug diclofenac in analgesic activity by both the hot plate method and acetic acid-induced writhing method. The compounds which presented highly significant anti-inflammatory and analgesic activity were further tested for their ulcerogenic activity. Compounds 3 and 8 showed maximum ulcerogenic reduction activities. Compound 8 was found to have LD50 of 168 mg/kg. Compound 8 with 3,5-dimethoxy-4-hydroxyphenyl substitution was found to be the most promising anti-inflammatory and analgesic agent with gastric sparing activity. Molecular docking of compounds was performed for COX−1/COX−2 binding site. Lead compound 8 showed better binding affinities of −9.4 kJ/mol with both COX-1 and COX-2 as compared to the standard drug, diclofenac with binding affinities of −6.6 kJ/mol and −8.1 kJ/mol for COX−1 and COX−2, respectively.
Highlights
Diclofenac is a phenyl acetic acid derivative with anti-inflammatory, analgesic, and antipyretic activity
To synthesize various substituted diclofenac hydrazones, the hydrazide of diclofenac (III) was used as a starting material [28]. e diclofenac hydrazide was obtained from diclofenac ester (methyl [2-(2,6-dichloroanilino)phenyl]acetate (II), which was reacted with hydrazine hydrate 99% in absolute ethanol
The structures were characterized by spectroscopic methods, elemental analysis, and mass spectrometry. e structure of the diclofenac hydrazide (III) has presented an identical NMR splitting pattern as that of diclofenac. e structures of the diclofenac acid hydrazide derivatives were confirmed on the basis of 1H NMR analysis, which was established by the disappearance of–NH2 protons at δ 1.97 ppm
Summary
Diclofenac is a phenyl acetic acid derivative with anti-inflammatory, analgesic, and antipyretic activity. It is a widely used NSAID for the treatment of chronic inflammatory diseases. Diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal effects. Prolonged use of diclofenac has caused gastric ulcer and bleeding. E pharmacological activity of diclofenac is the cyclooxygenase enzyme inhibition, resulting in the inhibition of prostaglandin biosynthesis from arachidonic acid [1]. Diclofenac is a nonselective COX inhibitor with complete absorption and extensive metabolism. Selective COX-2 inhibitors like celecoxib, rofecoxib, and etoricoxib are reported to have less gastrointestinal side effects [2]
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