Search

Indomethacin suffers from the general side effects of NSAIDs. The study aimed to retard the adverse effects of gastrointestinal (GI) origin. Two conjugates of indomethacin were synthesized by esterification with flavonoids namely, naringenin and hespertin. Purified synthesized mutual prodrugs were characterized by m.p., TLC, elemental analyzes, FTIR, NMR and MS. Synthesized conjugates were subjected for antiinflammatory, analgesic and antiulcer activity. These conjugates showed retention of antiinflammatory activity with reduced ulcerogenic side effects. These results indicated that indomethacin–flavonoid conjugates have the potential to be developed as safer NSAIDs.

A novel mutual prodrug consisting of 4-biphenylacetic acid (BPA) and quercetin tetramethyl ether (QTME) has been synthesized as a gastrosparing NSAID, devoid of ulcerogenic side effects. The physicochemical properties, including aqueous solubility, partition coefficient, chemical stability and enzymatic hydrolysis of synthesized derivative have been studied to assess its prodrug potential. Its antiinflammatory, antiulcer and analgesic activities were also evaluated. The results indicated that BPA-QTME derivative is chemically stable, biolabile and possesses optimum lipophilicity. The synthesized compound also exhibited retention of antiinflammatory activity with reduced ulcerogenicity. Based on these observations, the therapeutic potential of this mutual prodrug is discussed.

The present study was designed to investigate the antioxidant, anti-inflammatory and analgesic potential of Citrus decumana peel extract. Antioxidant activity of Citrus decumana peel extract in four solvent systems was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH(.)) and hydrogen peroxide (H(2)O(2)) radical scavenging methods. Ethyl acetate peel extract of Citrus decumana (EtCD) was studied for its anti-inflammatory and analgesic activities at a dose level of 100, 200 and 300 mg/kg. Anti-inflammatory activity was performed using carrageenan-induced paw edema in rats. Analgesic activity was evaluated for its central and peripheral pharmacological actions in mice. EtCD showed significant antioxidant activity in a dose-dependent manner when compared with ascorbic acid. EtCD at the dose of 300 mg/kg produced significant decrease in paw volume and pain when compared with reference drug diclofenac and morphine, respectively. The Citrus decumana peel extract may be useful as a natural antioxidant in the treatment of inflammation and pain.

The partially purified catechin fraction isolated from green tea extract was treated with a variety of acylating agents (acyl anhydrides/chloride) to obtain (−)-epigallocatechin-3-gallate (EGCG) O-acyl derivatives in 20−25.4% yields. The (−)-EGCG O-acyl derivatives were characterized by physical data and spectral studies. These compounds were evaluated for their antitumor activity by use of a two-stage carcinogenesis model in 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)--induced cancer in Swiss albino mice. The study showed that there was a significant decrease in the antitumor activity with the increase in size and branching of the chain length of acyl groups. The results indicated that these O-acyl derivatives of (−)-EGCG have the potential to be developed as cancer chemopreventive agents. Keywords: Green tea; catechins; (−)-EGCG O-acyl derivatives; antitumor activity

Various glycolamide ester prodrugs of 6-MNA (I), an active metabolite of nabumetone (II), were synthesised to obtain NSAIDs with improved therapeutic index. To assess their suitability as prodrugs, these derivatives were evaluated for physicochemical properties, chemical stability and enzymatic hydrolysis in 80% human plasma. A number of these ester derivatives possessed physicochemical properties required for oral absorption (log P ≥ 2, solubility ≥ 10 μg / ml ). These esters were sufficiently stable in 0.05 M phosphate buffer of pH 7.4 at 37°C (half-lives 16–473 h). The disubstituted glycolamide esters XII-XXII were more stable than monosubstituted glycolamide esters IV-XI. Compound XII was also subjected to hydrolytic studies over the pH range 1.2–9.0 at 70°C and from the pH-rate profile, the pH of maximum stability was found to be 4.34 (4–5). At pH 4.5 compound XII showed a shelf life of 1.12 years at 20°C as determined from accelerated studies using the Arrhenius equation. The ester derivatives were quantitatively converted to 6-MNA very rapidly in human plasma at 37°C and pH 7.4 Comparison with chemical stability data shows that the intrinsic reactivity of esters has no effect on their enzymatic reactivity. The chemically most stable N,N-disubstituted glycolamide esters were better substrates for plasma enzymes (half-lives 7–83 s) compared to the monosubstituted glycolamide esters (half-lives 168–809 s). It is concluded that these derivatives possess many of the ideal properties of prodrugs and esterification of 6-MNA with substituted 2-hydroxyacetamides may be a potentially useful prodrug approach.

(-)-Epicatechin-3-gallate (1) is one of the principal catechins of green tea and exhibits cancer-preventive activities in various animal models. However, this compound is unstable in neutral or alkaline medium and, therefore, has a poor bioavailability. To improve its stability, O-acyl derivatives of 1 were prepared by isolating the partially purified tea catechin fraction from green tea extract and treating it with a variety of acylating agents. The resulting derivatives, compounds 2-6, were screened for their antitumor potential against 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced squamous cell carcinogenesis of skin in mice. The results showed that the antitumor activity decreased with the increase in size of the chain length of the acyl groups, i.e., from compound 2, derivative with an Ac group, to compound 6, possessing a valeryl group. Moreover, the C(4) derivative with a branched acyl chain, 5, had a lower activity than the linear C(4) derivative 4. This reduction in the inhibitory activity may be due to the steric hindrance by the two Me groups. Moreover, significant increases in the protein levels analyzed by ELISA of c-Jun, p65, and p53 were observed in the skin of DMBA/TPA treated mice, whereas mice treated with 2 and DMBA/TPA had a similar expression of these transcription factors than the control mice. The prodrug potential of the O-acyl derivatives 2-6 showed that they were adequately stable to be absorbed intact from the intestine, more stable at gastric pH, and suitable for oral administration.

The present study was designed to investigate the effect of 7,8-dimethoxycoumarin (DMC) isolated from ethyl acetate extract of Citrus decumana peels on gastritis in rats. Isolation of 7,8-DMC from ethyl acetate extract of C. decumana peels was done by column and preparative thin layer chromatography using different solvents on polarity basis. Furthermore, effect of 7,8-DMC (50, 75, and 100 mg/kg, i.p.) in pyloric ligation-induced gastritis was studied in rats. The highest dose of 7,8-DMC showed significant decrease in the gastric volume, total acidity, ulcerative index, thiobarbituric acid reactive species levels, and myeloperoxidase activity, whereas there was an increase in the glutathione level. However, the lowest and medium doses did not produce significant results as compared to omeprazole and N-acetyl cysteine-treated groups. Compound 7,8-DMC (100 mg/kg) showed ameliorative effect on gastric inflammation and may be used as a therapeutic agent in the treatment of gastritis.