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Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit.

ABSTRACT: A series of anti-inflammatory derivatives containing an N-acyl hydrazone subunit (4a-e) were synthesized and characterized. Docking studies were performed that suggest that compounds 4a-e bind to cyclooxygenase (COX)-1 and COX-2 isoforms, but with higher affinity for COX-2. The compounds display similar anti-inflammatory activities in vivo, although compound 4c is the most effective compound for inhibiting rat paw edema, with a reduction in the extent of inflammation of 35.9% and 52.8% at 2 and 4 h, respectively. The anti-inflammatory activity of N-acyl hydrazone derivatives was inferior to their respective parent drugs, except for compound 4c after 5 h. Ulcerogenic studies revealed that compounds 4a-e are less gastrotoxic than the respective parent drug. Compounds 4b-e demonstrated mucosal damage comparable to celecoxib. The in vivo analgesic activities of the compounds are higher than the respective parent drug for compounds 4a-b and 4d-e. Compound 4a was more active than dipyrone in reducing acetic-acid-induced abdominal constrictions. Our results indicate that compounds 4a-e are anti-inflammatory and analgesic compounds with reduced gastrotoxicity compared to their respective parent non-steroidal anti-inflammatory drugs.

SUBMITTER: de Melo TR

PROVIDER: S-EPMC4013598 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit.

de Melo Thais Regina Ferreira TR Chelucci Rafael Consolin RC Pires Maria Elisa Lopes ME Dutra Luiz Antonio LA Barbieri Karina Pereira KP Bosquesi Priscila Longhin PL Trossini Gustavo Henrique Goulart GH Chung Man Chin MC dos Santos Jean Leandro JL

International journal of molecular sciences 20140404 4

A series of anti-inflammatory derivatives containing an N-acyl hydrazone subunit (4a-e) were synthesized and characterized. Docking studies were performed that suggest that compounds 4a-e bind to cyclooxygenase (COX)-1 and COX-2 isoforms, but with higher affinity for COX-2. The compounds display similar anti-inflammatory activities in vivo, although compound 4c is the most effective compound for inhibiting rat paw edema, with a reduction in the extent of inflammation of 35.9% and 52.8% at 2 and ...[more]

PMID: 24714090

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Project description:Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug.

Project description:Background & aimsNonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested to protect against esophageal adenocarcinoma (EAC). This study examined the effect of NSAIDs on the risk of developing Barrett's esophagus (BE), the precursor lesion to EAC.MethodsWe conducted a case-control study among eligible patients scheduled for either elective esophagogastroduodenoscopy (EGD) or recruited from primary care clinics to undergo a study EGD. We compared 323 patients with BE (296 nondysplastic and 27 dysplastic) with 2 separate control groups: 1347 patients from the elective EGD group (endoscopy controls) and 502 patients from the primary care group (primary care controls) with no endoscopic or histopathologic BE. Use of aspirin products and 23 nonaspirin NSAIDs was ascertained from detailed, self-reported questionnaires. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models.ResultsThere were no significant differences in self-reported NSAID use between all BE cases and all controls (58.2% vs 54.6%; P = .33); this was seen for aspirin products (43.0% vs 37.4%; P = .08) and nonaspirin NSAIDs (7.7% vs 8.9%; P = .46). These findings persisted in the multivariable model for any NSAIDs (adjusted OR, 0.89; 95% CI, 0.75-1.28), aspirin (adjusted OR, 1.16; 95% CI, 0.90-1.51), and nonaspirin NSAIDs (adjusted OR, 0.88; 95% CI, 0.55-1.39). Use of a combination of aspirin and nonaspirin NSAIDs was reported in 7.4% of cases and 8.3% of controls, and a nonsignificant inverse association with BE was seen (adjusted OR, 0.70; 95% CI, 0.44-1.11). There was no significant association between BE and daily NSAID use (adjusted OR, 1.03; 95% CI, 0.78-1.37). Similar findings were observed for comparisons involving nondysplastic or dysplastic BE cases, and endoscopy or primary care control groups separately or combined.ConclusionsThe use of NSAIDs was not associated with a reduced risk of BE. It is likely that the protective mechanism of NSAIDs on EAC occurs subsequent to the development of BE.

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Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit.

Publications

Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit.

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