Design and Synthesis of Novel Anti-inflammatory/Anti-ulcer Hybrid Molecules with Antioxidant Activity.

BACKGROUND: NSAIDs are the most widely prescribed medications worldwide for their anti-inflammatory, antipyretic, and analgesic effects. However, their chronic use can lead to several adverse drug events including GI toxicity. The selective COX-2 inhibitors developed as gastrosparing NSAIDs also suffer from serious adverse effects which limit their efficacy. OBJECTIVE: Local generation of reactive oxygen species is implicated in NSAID-mediated gastric ulceration and their combination with H2 antagonists like famotidine reduces the risk of ulcers. The objective of this work was to design and synthesize novel methanesulphonamido isoxazole derivatives by hybridizing the structural features of NSAIDs with those of antiulcer drugs (ranitidine, famotidine, etc.) to utilize a dual combination of anti-inflammatory activity and reducing (antioxidant) potential. METHODS: The designing process utilized three dimensional similarity studies and utilized an isoxazole core having a potential for anti-inflammatory as well as radical scavenging antioxidant activity. The compounds were assayed for their anti-inflammatory activity in established in vivo models. The in vitro antioxidant activity was assessed in potassium ferricyanide reducing power (PFRAP) assay employing ascorbic acid as the standard drug. RESULTS: Compounds 5, 6, 9 and 10 showed antiinflammatory activity comparable to the standard drugs and were also found to be non-ulcerogenic at the test doses. Compounds 6-10 exhibited good antioxidant effect in the concentration range of 1.0- 50.0 µmol/ml. The test compounds were also found to comply with the Lipinski rule suggesting good oral absorption. CONCLUSION: A new series of isoxazole based compounds is being reported with good antiinflammatory activity coupled with antioxidant potential as gastro-sparing anti-inflammatory agents.

Thermogelling chitosan-based polymers for the treatment of oral mucosa ulcers.

Current treatments for oral mucosa-related ulcers use drugs to relieve pain and promote healing, but rarely consider drug resistance to bacterial infection in the microenvironment of the oral cavity or the prevention of bleeding from gingival mucosa ulcers. We herein report an injectable, thermogelling chitosan-based system to address these concerns. An aqueous solution of chitosan-based conjugates (chitosan-g-poly(N-isopropylacrylamide) [CS-g-PNIPAAM] including 1a [CS-g-PNIPAAM with less PNIPAAM] and 1b [CS-g-PNIPAAM with more PNIPAAM], and chitosan-g-poly(N-isopropylacrylamide)-g-polyacrylamide [CS-g-PNIPAAM-g-PAM] 3) could reversibly form semi-solid gels at physiological temperatures for easy application to oral cavity ulcer sites by injection. The chitosan-based conjugate thermogels prepared could inhibit both Gram-positive and Gram-negative bacteria and the two with higher chitosan and poly(N-isopropylacrylamide) contents (1a and 1b) promoted proliferation of gingival fibroblasts in vitro. These two thermogels also exhibited improved blood clotting in an in vivo rat study. Thermogels 1a and 1b effectively promoted ulcer healing and shortened ulcer healing times in an oral gingival mucosa ulcer model using Sprague Dawley (SD) rats. These thermogels showed no obvious toxicity to the main organs of SD rats undergoing gingival ulcer treatment. These results suggest that this antibacterial biomaterial could be a promising injectable therapeutic agent for the treatment for oral mucosa ulcers.

Lipid Nanoemulsions of Rebamipide: Formulation, Characterization, and In Vivo Evaluation of Pharmacokinetic and Pharmacodynamic Effects.

Rebamipide has low oral bioavailability (10%) due to its low solubility and permeability. Lipid nanoemulsions (LNEs) were prepared in order to improve its oral bioavailability. Rebamipide-loaded lipid nanoemulsions were formulated by hot homogenization and ultrasonication method. Olive oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. The lipid nanoemulsions were evaluated for various parameters. The globule size, polydispersity index (PDI), and zeta potential (ZP) of the formulations ranged from 230.3 ± 3.88 to 279.8 ± 5.76 nm, 0.204 ± 0.008 to 0.246 ± 0.029, and - 27.7 ± 2.05 to - 31.0 ± 1.87 mV, respectively. Entrapment efficiency and assay values ranged from 99.90 ± 0.006 to 99.92 ± 0.002% and 99.3 ± 0.808 to 99.6 ± 0.360, respectively. Physical stability test results revealed that the optimized LNEs were stable for 2 months at both room (25°C) and refrigerated temperature (4°C). The optimized LNE showed 4.32-fold improvement in the oral bioavailability in comparison to a marketed tablet suspension. In vivo anti ulcer activity of rebamipide LNE was studied by testing the prophylactic effect in preventing the mucosal damage in stomach region. The mucosa of stomach in animals was damaged by per oral administration of 80% alcohol. Maximum prophylactic antiulcer activity was observed by per oral delivery of rebamipide as LNE. Our results indicated that LNEs were a promising approach for the oral delivery of rebamipide for systemic effects along with local effects in protecting gastric region, which gets damaged during peptic ulcers.

Synthesis and Biological Evaluation of 3, 8-dimethyl-5-isopropylazulene Derivatives as Anti-gastric Ulcer Agent.

Recent studies showed that Guaiazulene (GA) and Sodium guaiazulene sulfonate (GAS-Na) have good anti-gastric ulcer effect. Here, two series of GA derivatives were synthesized and evaluated for their anti-gastric ulcer activity. The data obtained from in vivo testing of these compounds in a rodent ethanol-induced stomach injury model are discussed. Among the tested compounds, A1, A4, and A9 (ulcer index: 1.125 ± 1.246**, 1.714 ± 0.756*, 1.875 ± 1.126*) exhibited better anti-gastric ulcer activity than the positive control Omeprazole (2.005 ± 1.011*). The information got from these studies and the results of 3D-SAR investigation may be useful in the design of novel anti-gastric ulcer agents.

Synthesis, molecular docking and biological evaluation of 3-arylfuran-2(5H)-ones as anti-gastric ulcer agent.

3-Arylfuran-2(5H)-one derivatives show good antibacterial activity and were determined as tyrosyl-tRNA synthetase (TyrRS) inhibitors. In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to treat infections caused by Helicobacter pylori. Twenty 3-arylfuran-2(5H)-ones were synthesized and evaluated for anti-H. pylori, antioxidant and anti-urease activities which are closely interconnected with H. pylori infection. The results displayed that some of the compounds show excellent antioxidant activity, and good anti-H. pylori and urease inhibitory activities. Out of these compounds, 3-(3-methylphenyl)furan-2(5H)-one (b9) showed the most potent antioxidant activity (IC50=8.2 µM) and good anti-H. pylori activity (MIC50=2.6 µg/mL), and it can be used as a good candidate for discovering novel anti-gastric ulcer agent.

Synthesis, anti-inflammatory and anti-ulcer evaluations of thiazole, thiophene, pyridine and pyran derivatives derived from androstenedione.

The reaction of androstenedione with bromine gave the 16-bromo derivative 2. The latter reacted with either cyanothioacetamide or thiourea to give the 2-cyanomethylthiazole derivative 4 and the 2-aminothiazole derivative 13. Compound 4 and 13 were used underwent some condensation, coupling and heterocyclization reactions to give thiophene, pyridine and pyran derivatives. The anti-inflammatory and anti-ulcer evaluations of the newly synthesized products were evaluated and the results showed that 23f showed the maximum antiulcer activity. In addition, toxicity of the most active compounds was studied against shrimp larvae and showed that compounds 2, 23c and 23f showed non-toxicity against the tested organisms.

Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of new 2-(4-isobutylphenyl)propanoic acid derivatives.

Synthesis and pharmacological evaluation of various 2-(4-isobutylphenyl)propanoic acid derivatives containing 1,3,4-thiadiazole and thiadiazolo[3,2-a][1,3,5]triazine-5-thione nucleus is reported here. The structures of new compounds are supported by IR, (1)H & (13)C NMR data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA). Compound 4i and 5f showed 89.50 and 88.88% of inhibition in paw edema, 69.80 and 66.25% protection against acetic acid-induced writhings and 0.7 and 0.65 of severity index, respectively, compared to 90.12, 72.50 and 1.95 values of ibuprofen.

Synthesis and antigastric ulcer activity of novel 5-isoproyl-3,8-dimethylazulene derivatives.

5-Isoproyl-3,8-dimethylazulene derivatives were synthesized and evaluated for antigastric ulcer activity in vivo. Some of them possess the best activity against gastric ulcer with ulcer index values lower than the drug reference (omeprazole). The structure-activity relationship (SAR) shows that the lipophilic flat structure contributes to quite potent antigastric ulcer activity.

Gastroprotective effect and cytotoxicity of labdeneamides with amino acids.

Semisynthetic aromatic amides from ARAUCARIA ARAUCANA diterpene acids have been shown to display a relevant gastroprotective effect with low cytotoxicity. The aim of this work was to assess the gastroprotective effect of amino acid amides from imbricatolic acid and its 8(9)-en isomer in the ethanol/HCl-induced gastric lesions model in mice as well as to determine the cytotoxicity of the obtained compounds on the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), and liver hepatocellular carcinoma (Hep G2). The diterpenes 15-acetoxyimbricatolic acid, its 8(9)-en isomer, 15-hydroxyimbricatolic acid, and the 8(9)-en derivative, bearing a COOH function at C-19, were used as starting compounds. New amides with C-protected amino acids were prepared. The study reports the effect of a single oral administration of either compound 50 min before the induction of gastric lesions by ethanol/HCl. Some 20 amino acid monoamides were obtained. Dose-response experiments on the glycyl derivatives showed that at a single oral dose of 100 mg/kg, the compounds presented an effect comparable to the reference drug lansoprazole at 20 mg/kg and at 50 mg/kg reduced gastric lesions by about 50%. All derivatives obtained in amounts > 30 mg were compared at a single oral dose of 50 mg/kg. The best gastroprotective effect was observed for the exomethylene derivatives bearing a valine residue at C-19 either with an acetoxy or free hydroxy group at C-15. The tryptophanyl derivative from the acetate belonging to the 8,9-en series presented selective cytotoxicity against hepatocytes. The glycyl amide of 15-acetoxyimbricatolic acid was the most cytotoxic and less selective compound with IC50 values between 47 and 103 µM for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes.

1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties.

A series of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid were synthesized in order to obtain new compounds with potential anti-inflammatory activity, analgesic activity and lower ulcerogenic potential. All compounds were evaluated for their anti-inflammatory activity by the carrageenan induced rat paw edema test method. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic, ulcerogenic and antioxidant activities. Out of all tested compounds, the compounds 3, 7, 17 and 20, showed significant reduction in rat paw edema induced by carrageenan treatment. These compounds showed significant analgesic effect and at an equimolar oral doses relative to flurbiprofen were also found to be non-gastrotoxic in rats. Compound 17 was evaluated as the lead compound having more anti-inflammatory activity (81.81%) than the reference drug (79.54%), low ulcerogenic potential and protective effect on lipid peroxidation.

Anti-inflammatory and gastroprotective properties of some chalcones.

The synthesis of 1,3-diaryl propen-1-ones (chalcones) by the Claisen-Schmidt condensation between acetophenones and benzaldehydes in potassium hydroxide/methanol medium at room temperature yielded: 1-(4-nitrophenyl)-3-(2,4,6-trimethoxyphenyl)propen-1-one (3a), 1-(4-nitrophenyl)-3-(3-bromophenyl)propen-1one (3b), 1-(4-methoxyphenyl)-3-(3-bromophenyl)propen-1-one (3c), 1-(4-methoxyphenyl)-3-(2,4,6-trimethoxyphenyl)propen-1-one (3d), 1-(2,4-dihydroxyphenyl)-3-(phenyl)propen-1-one (3e), 1-(4-nitrophenyl)-3-(4-chlorophenyl)propen-1-one (3f) which were evaluated for anti-inflammatory activity at doses of 20, 40 and 80mg/kg. The compounds were found to be effective inhibitors of carrageenan-induced rat paw edema in Wistar rats and this activity was dose dependent and increased between the third and fourth hour. The gastroprotective activity of the compounds was investigated (using 200 mg/kg acetylsalicylic acid-induced ulceration) in Wistar rats at a single dose of 100 mg/kg for all the compounds synthesized and compound 3d had significant activity (p<0.001) comparable to cimetidine. The compounds were found to have anti-inflammatory and anti-ulcer activities at the doses employed.

Protective effects of polygodial and related compounds on ethanol-induced gastric mucosal lesions in rats: structural requirements and mode of action.

The methanolic extract from the leaves of Tasmannia lanceolata was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, three known sesquiterpenes, polygodial, polygodial 12 alpha-acetal, and polygodial 12 beta-acetal, and a new sesquiterpene, methyl isodrimeninol, were isolated as the active constituents. Among them, polygodial showed very potent gastroprotective effects (ED(50)=0.028 mg/kg, po). From the gastroprotective effects of various reduction and oxidation derivatives of polygodial, the dialdehyde or diacetal structure was found to be essential for the strong activity. Since the gastroprotection of polygodial was attenuated by pretreatment with indomethacin, N-ethylmaleimide, N(G)-nitro-L-arginine methyl ester and ruthenium red, endogenous prostaglandins, sulfhydryl compounds, nitric oxide and vanilloid receptors may be involved in the protective activity.

The influence of commonly prescribed synthetic drugs for peptic ulcer on the pharmacokinetic fate of glycyrrhizin from Shaoyao-Gancao-tang.

The influence of synthetic drugs prescribed for peptic ulcer on the pharmacokinetic fate of glycyrrhizin (GL) from Shaoyao-Gancao-tang (SGT, a traditional Chinese formulation, Shakuyaku-Kanzo-to in Japanese) was investigated in rats. Co-administration of histamine H2-receptor antagonist (cimetidine) and anticholinergic drug (scopolamine butyl bromide) with SGT didn't influence the area under the plasma concentration-time curves (AUC) of glycyrrhetic acid (GA), an active metabolite derived from GL in SGT. The AUC of GA from SGT were significantly reduced by co-administration of synthetic drugs commonly used for peptic ulcer in a triple therapy (OAM), a combination of a proton pump inhibitor (omeprazole) and two antibiotics (amoxicillin and metronidazole). We found that the reduction of AUC in OAM treatment was due to the antibacterial effect of amoxicillin and metronidazole on intestinal bacteria in rat which lead to the decrease of GL-hydrolysis activity. The present study suggests that it may not be a proper way to use triple therapy containing antibiotics simultaneously with SGT for healing of chronic ulcers.

Synthesis of a model compound related to an anti-ulcer pectic polysaccharide.

A stereocontrolled synthesis of the model compound for an anti-ulcer active polysaccharide (Bupleuran 2IIc) is described. Glycosidation of the disaccharide acceptor, 2-O-acetyl-3-O-benzyl-4-O-(p-methoxybenzyl)-alpha-L-rhamnopyranosyl-(1-- >4)-2,3,6-tri-O-benzyl-alpha-D-galactopyranosyl trichloroacetimidate, with the disaccharide receptor, allyl 3,4-di-O-benzyl-alpha-L-rhamnopyranosyl-(1-->4)-2,3,6-tri-O-benzyl-beta- D-galactopyranoside, using silver triflate (AgOTf) as a promoter gave the desired tetrasaccharide derivative, which was transformed into the acidic tetrasaccharide, corresponding to a segment of the rhamnogalacturonan (Bupleuran 2IIc) polysaccharide, propyl alpha-L-Rha-(1-->4)-alpha-D-GalA-(1-->2)-alpha-L-Rha-(1-->4)-beta-D-GalA , via removal of the corresponding ether and ester protecting groups, followed by oxidation.

Synthesis and pharmacological screening of novel non-acidic gastroprotective antipyretic anti-inflammatory agents with anti-platelet properties. 5-Alkyl/cycloalkylamino substituted 2-amino-5H-[1]benzopyrano[4,3-d] pyrimidines.

The preparation and screening of antipyretic, anti-inflammatory, analgesic, gastroprotective and antiplatelet activities of original non-acidic aminobenzo-pyranopyrimidine derivatives are described. Major and dose-dependent analgesic and antipyretic properties were detected in all the compounds after oral administration (6.25-100 mg kg-1) in the mouse writhing test and in the E. coli lipopolysaccharide-induced fever in the rat, respectively. Unlike the reference drug indometacin (ED50 ulcer = 9.1 mg kg-1), no gastrolesivity was displayed by all the new compounds up to 150 mg kg-1 so that therapeutical indices equal or higher than that of indometacin were calculated. Furthermore, at 100 mg kg-1 they were able to prevent ethanol-induced gastric mucosal injury in rats. At a 1 mmol/l concentration the compounds under study were as effective as acetylsalicylic acid in inhibiting in vitro platelet aggregation induced by adenosine diphosphate.

Soft drugs. 21. Design and evaluation of soft analogs of propantheline.

The soft drug approach was applied to synthesize seven soft analogs of propantheline, which by design display predictable and controllable decomposition to inactive metabolites. Their synthesis involved the quatemization of several different amine groups with the chloromethyl ester of 9-methylxanthene-9-carboxylic acid. The rates of disappearance were measured for all of the compounds and were found to be more rapid than that of propantheline bromide in a variety of chemical and biological media under in vitro conditions. One of the soft analogs was found to be equipotent with propantheline in an in vitro assay. This soft analog was found to be equipotent with propantheline, in vivo, in protecting the rats against indomethacin-induced gastric ulceration and in inducing mydriasis in rabbits on intravenous administration. The pupil sizes returned faster to predrug levels with the soft analog than with propantheline, indicating increased metabolic lability of the soft analog. The equipotency of this soft analog coupled with increased metabolic lability proves the rationality of the soft drug approach for the design of safer therapeutic agents with higher therapeutic indices.

Biological activity of some Schiff bases and their metal complexes.

Schiff bases derived from salicylaldehyde and 2-substituted aniline and their metal chelates with Cu(II), Ni(II), and Co(II) ions were synthesized and screened for the antiinflammatory and antiulcer activity. The compound salicylidene-anthranilic acid (SAA) was found to possess the antiinflammatory and antiulcer activity. The copper complexes showed an increased antiulcer activity. The SAA is perhaps acting by influencing prostaglandin biosynthesis.

The synthesis of benzindene prostacyclin analogs as potential antiulcer agents.

Two new diastereomeric benzindene prostacyclin analogs (U-72,382 and U-72,383) related to the potent antiulcer agent U-68,215 have been synthesized. These cyclohexyl ring modified analogs of U-68,215 were prepared to determine how the gastrointestinal and hypotensive endpoints observed for U-68,215 would be affected.