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Indomethacin has been conjugated with different antioxidants having antiulcerogenic activity with the objective of obtaining indomethacin–antioxidant codrugs as gastrosparing NSAIDs devoid of ulcerogenic side effects. Purified synthesized codrugs have been characterized by m.p., TLC, elemental analyses, FTIR, NMR, MS. The synthesized derivatives have been screened for their antiinflammatory, analgesic, and antiulcer activity. The codrugs showed retention of antiinflammatory activity with reduced ulcerogenic side effects. These results indicated that indomethacin–antioxidant codrugs have the potential to be developed as gastrosparing NSAIDs. Indomethacin has been conjugated with different naturally occurring antioxidants having antiulcerogenic properties with the objective of obtaining indomethacin–antioxidant codrugs as gastrosparing NSAIDs, devoid of ulcerogenic side effects .

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

Five new derivatives of the pentacyclic triterpenoid lantadene A (= 22beta-angeloyloxy-3-oxoolean-12-en-28-oic acid; 1) from the leaves of Lantana camara L. were synthesized, characterized, and screened for their cytotoxicities against four human cancer cell lines. The three most-potent compounds, i.e., 1, 4, and 6, with IC50 values in the range of ca. 20-29 microM, were further studied for their in vivo tumor-inhibitory potential upon oral administration in two-stage squamous cell carcinogenesis, using female Swiss albino mice, papilloma being induced by 7,12-dimethylbenz[a]anthracene (DMBA), and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). The results are discussed in terms of structure-activity relationship.

Lantana (Lantana camara Linn) is a noxious weed that grows in many tropical and subtropical parts of the world. Ingestion of lantana foliage by grazing animals causes cholestasis and hepatotoxicity. Both ruminants and nonruminant animals such as guinea pigs, rabbits, and female rats are susceptible to the hepatotoxic action of lantana toxins. The hepatotoxins are pentacyclic triterpenoids called lantadenes. Molecular structure of lantadenes has been determined. Green unripe fruits of the plant are toxic to humans. Lantana spp. exert allelopathic action on the neighboring vegetation. The allelochemicals have been identified as phenolics, with umbelliferone, methylcoumarin, and salicylic acid being the most phytotoxic. In addition to phenolics, a recent report indicates lantadene A and B as more potent allelochemicals. Management of lantana toxicosis in animals is achieved by drenching with activated charcoal and supportive therapy. Recent reports on the bilirubin clearance effect of Chinese herbal tea Yin Zhi Huang (decoction of the plant Yin Chin, Artemisia capillaries, and three other herbs) or its active ingredient 6,7-dimethylesculetin, in jaundice are very exciting and warrant investigations on its, possible, ameliorative effects in lantana intoxicated animals. Research is being conducted on new drug discovery based on natural products in different parts of the lantana plant.

Eupatorium genus grows wild in many parts of the world. A number of species of Eupatorium are toxic to grazing animals. Milk sickness in humans is caused by ingestion of milk of the animals reared on the pastures infested with Eupatorium rugosum (white snakeroot). While some information is available on the toxins in various species of Eupatorium, ambiguities still persist in extrapolation of the data to field incidence of toxicosis. Eupatorium genus has been used for its medicinal properties for many decades. A number of bioactive natural products have been reported in the extracts of Eupatorium spp. and the genus is a promising bioresource for preparation of drugs and value-added products. Copyright © 1998 John Wiley & Sons, Ltd.

Ageratum has encroached upon a large expanse of land area in many parts of the world affecting crops, livestock and overall ecology. A number of chemical constituents including flavonoids, benzofurans, chromenes and terpenoids have been reported from different species of Ageratum. Various preparations of this plant are used in indigenous systems of medicine in manv countries. Chemical compounds and extracts of Ageratum have been found to possess insecticidal and insect repellent properties. This review presents a comprehensive account of the chemical constituents and biological properties of Ageratum and brings out “action‐plan” for future R&D areas for drugs, biocides, and value‐ added products.

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.

4-Biphenylacetic acid (4-BPA), the active metabolite of NSAID fenbufen has been modified using prodrug approach. A number of glycolamide ester derivatives of 4-BPA have been synthesized as potential prodrugs by masking the free carboxyl group which is mainly responsible for gastric damage, in order to obtain NSAIDs with improved therapeutic index. The structures of these derivatives have been established on the basis of spectral analysis.

Three taxa of the lantana plant (Lantana camara var.Aculeata) I (white-pink), II (yellow-pink), and III (yellow-red)-differed in the content of lantadenes and compounds X, Y, and Z. Lantadene A, lantadene B, and lantadene C were the major lantadenes of taxon III. It contained small amounts of lantadene D. Taxa I and II contained very small amounts of lantadene A and lantadene B. Compounds X, Y, and Z were the major constituents of taxa I and II, and they constituted 59% and 92% of the total constituents in these taxa, respectively. Ingestion of lantana leaf powder of taxon III by male guinea pigs caused severe hepatotoxicity. Taxon I elicited mild hepatotoxicity in one out of six animals while taxon II was nontoxic. The biological and ecological significance of the presence of high amounts of compounds X, Y, and Z in taxa I and n is not known.