Synthesis, gastroprotective and acute toxicity of bio-isosteric derivative of diclofenac

Dana Ameen

doi:10.15218/zjms.2020.017

Authors

Dana Ameen Department of Pharmaceutical Chemistry, College of Pharmacy, Hawler Medical University, Erbil, Iraq.

DOI:

https://doi.org/10.15218/zjms.2020.017

Keywords:

NSAIDs, Diclofenac, Diarylether, Bio-isostere, Gastroprotective

Abstract

Background and objective: Non-steroidal anti-inflammatory drugs (such as diclofenac1) had been widely prescribed for the treatment of different types of pain; however, they are not devoid of adverse effects. Therefore, synthesis of new bio-isosteric analogs4a-e of diclofenac1 with greater COX II selectivity and less gastrointestinal side effect is demanded. This study aimed to evaluate the acute toxicity and gastroprotective activity of the bio-isosteric derivative of diclofenac against ethanol-induced gastric ulceration in rats.

Methods: 2-Cumaranone 2 had been utilized to prepare amides 3a-e then after the bio-isosteric derivatives 4a-esynthesized from them then used to study the biological activity by testing whether high doses of the prototype compound 4c are toxic or not on albino mice and measuring the gastroprotective effect on albino rats. Rats were divided into four groups. Group 1 orally administered with Tween 20; group 2 was orally administered with 20 mg/kg esomeprazole; groups 3 and 4 received 100 and 200 mg/kg of the compound, respectively. Absolute ethanol was given orally to the groups, and rats were sacrificed after one hour.

Results: Few diarylethers 4a-ebio-isosteric to diclofenac had been prepared and fully characterized (including ¹HNMR, ¹³CNMR, and IR spectroscopy). Serum biochemical parameters were reported to be normal. Hematological analysis of kidney and liver did not elicit any remarkable changes in the treated group compared to the control group. Thus, the 50% oral lethal dose (LD₅₀) for the male and female mice was greater than 5 g/kg body weight. Anti-ulcer data showed a gastroprotective effect of the bio-isosteric diclofenac derivative 4c and presented the ulcer area inhibition, low stomach pH, and preserve the mucous content.

Conclusion: Many bio-isosteric derivatives of diclofenac had been prepared with good yields. The synthesized derivative4c showed no toxicity, and the gastroprotective effect may possibly be due to the preservation of gastric wall mucus.

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