oxadiazoles and Stomach-Ulcer

A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 μM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Formaldehyde; Kinetics; Mice; Molecular Dynamics Simulation; Molecular Structure; Oxadiazoles; Pain; Rats; Stomach Ulcer; Structure-Activity Relationship; Triazines

A novel series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized for selective COX-2 inhibition with potent anti-inflammatory activity. Among the compounds tested, 9g (2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazole) was found to be the most potent inhibitor of COX-2 with IC50 of 0.31 μM showing promising degree of anti-inflammatory activity in the carrageenan-induced rat paw edema model with ED50 of 74.3 mg/kg. The lead compound 9g further showed suppression of acetic acid-induced writhes comparable to that of aspirin and gastro-sparing profile superior to the aspirin. Molecular docking analysis displayed higher binding affinity of ligands towards COX-2 than COX-1.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemistry Techniques, Synthetic; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Humans; Male; Mice; Molecular Docking Simulation; Oxadiazoles; Protein Conformation; Rats; Stomach Ulcer; Structure-Activity Relationship; Substrate Specificity

New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Carrageenan; Cell Line, Tumor; Cell Survival; Computer-Aided Design; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Humans; Inflammation; Inhibitory Concentration 50; Lipid Peroxidation; Male; Molecular Docking Simulation; Molecular Structure; Neoplasms; Oxadiazoles; Rats, Wistar; Risk Assessment; Stomach Ulcer; Structure-Activity Relationship

Several 2,5-disubstituted-1,3,4-oxadiazoles (4a-f) and 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (7a-f) were synthesized and characterized by elemental analyses and spectral data. These compounds were screened for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities. Compound 7c showed excellent anti-inflammatory and remarkable analgesic activity with reduced ulcerogenic and lipid peroxidation activity when compared with ibuprofen.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Oxadiazoles; Spectroscopy, Fourier Transform Infrared; Stomach Ulcer; Thiazoles

A series of substituted azole derivatives (3a-e, 4a-e and 5a-e) were synthesised by the cyclisation of N(1)(diphenylethanoyl)-N(4)-substituted phenyl thiosemicarbazides under various reaction conditions. 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 5-(diphenylmethyl)-N-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3b) and 5-(diphenylmethyl)-N-(3-chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3c) emerged as the most active compounds of the series, and were moderately more potent than the standard drug, ibuprofen. (This abstract was published in Inflammation Research, Supplement 2, Volume 56, page A101, 2008.).

Topics: Acetates; Analgesics; Animals; Anti-Inflammatory Agents; Drug Design; Gastric Mucosa; Ibuprofen; Inflammation; Lipid Peroxidation; Mice; Models, Animal; Oxadiazoles; Pyrazoles; Rats; Rats, Wistar; Semicarbazides; Severity of Illness Index; Stomach Ulcer

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Edema; Enzyme Inhibitors; Lipid Peroxidation; Lipoxygenases; Oxadiazoles; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Stomach Ulcer; Structure-Activity Relationship

A series of novel 2-[4-aryl-5-{(quinolin-8-yloxy)methyl}-4H-1,2,4-triazol-3-ylthio]-1-arylethanones (6a-6j) and 8-{(5-aryl-1,3,4-oxadiazol-2-yl)methoxy}quinolines (7a-7d) were synthesized from the corresponding 4-arnyl-1-(2- quinolin-8-yloxy)acetyl) thiosemicarbazides (4a-4d) and hydrazides (3) respectively. The prepared compounds were screened for their anti-inflammatory, analgesic, ulcerogenic and antimicrobial activities. The anti-inflammatory activities were determined by carrageenan induced rat paw edema method. Compounds 6c, 6d, 6f 6j, 7b and 7e significantly inhibited the rat paw edema depending upon the dose employed. These compounds exhibited insignificant ulceration compared to the standard drug Indomethacin. The compounds were also evaluated for their in vitro antimicrobial activity. Some compounds have shown moderate to good activity whereas compound 7b has shown significant zone of inhibition compared to the standard drug Ampicillin against gram negative microorganisms.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Edema; Gram-Negative Bacteria; Microbial Sensitivity Tests; Molecular Structure; Oxadiazoles; Quinolones; Rats; Rats, Wistar; Stomach Ulcer; Structure-Activity Relationship; Triazoles

Synthesis and biological evaluation of various aroylpropionic acid derivatives containing 1,3,4-Oxadiazole nucleus is reported here. The compounds (3a-w) were synthesized by cyclization of 3-aroylpropionic acids into 1,3,4-oxadiazole nucleus by treating with various aryl acid hydrazides in the presence of POCl(3). The structures of new compounds are supported by IR, (1)H NMR and MS data. These compounds were tested in vivo for their anti-inflammatory activity. All the compounds tested showed anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic and lipid peroxidation activities. Seven (3c, g, i, j, m, o, p) out of 23 new compounds showed very good anti-inflammatory activity in the carrageenan-induced rat paw edema test with very less ulcerogenic action. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA), which is one of the byproducts of lipid peroxidation. Compound 3i and o 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. The study showed that the cyclization of carboxylic group of aroylpropionic acids into an oxadiazole nucleus resulted in compounds having good anti-inflammatory and analgesic effects with reduced gastric irritation.

Topics: Acute Disease; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclization; Drug Design; Drug Evaluation, Preclinical; Edema; Ibuprofen; Lipid Peroxidation; Mice; Molecular Structure; Oxadiazoles; Propionates; Rats; Rats, Wistar; Stereoisomerism; Stomach Ulcer

A novel series of 2-[3-(4-bromophenyl)propan-3-one]-5-(substituted phenyl)-1,3,4-oxadiazoles (4a-n) have been synthesized from 3-(4-bromobenzoyl)propionic acid (3) with the aim to get better anti-inflammatory and analgesic agents with minimum or without side effects (ulcerogenicity). Compound 3 was reacted with several aryl acid hydrazides (2a-n) in phosphorous oxychloride to obtain the title compounds. Structures of the synthesized compounds were supported by means of IR, 1H NMR and mass spectroscopy. Title compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antibacterial activities. Antibacterial activity was expressed as the corresponding minimum inhibitory concentration (MIC). A fair number of compounds were found to have significant anti-inflammatory and analgesic activities, while a few compounds showed appreciable antibacterial activity. The newly synthesized compounds showed very low ulcerogenic action. The findings of the present study indicate that cyclization of the carboxylic group of 3 into novel 1,3,4-oxadiazole nucleus resulted in increased anti-inflammatory and analgesic activities with a significant decrease of ulcerogenic activity.

Topics: Acetic Acid; Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Drug Design; Escherichia coli; Female; Inflammation; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Oxadiazoles; Pain; Rats; Rats, Wistar; Staphylococcus aureus; Stomach Ulcer; Structure-Activity Relationship

Several 5-(3,4-dichlorophenyl)-2-(aroylmethyl)thio-1,3,4-oxadiazoles were synthesized and characterized by elemental analyses, IR and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carregeenan-induced edema in rat paw. In addition, ulcerogenic activity was determined. The anti-inflammatory data scoring showed that compounds 5e, 5f and 5g, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5f was comparable to that of the reference drug indometacin (CAS 53-86-1).

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Crystallography, X-Ray; Drug Design; Edema; Foot; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Oxadiazoles; Rats; Rats, Sprague-Dawley; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared; Stomach Ulcer; Thiones

Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase. Sildenafil, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy. Activation of ATP-sensitive potassium channels (K(ATP)) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage.. Rats were treated with L-NAME (1 or 3 mg kg(-1), i.p.) or with L-arginine (200 mg kg(-1), i.p.) + L-NAME (3 mg kg(-1), i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg(-1), i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg(-1), i.p.) or with glibenclamide (1 mg kg(-1), i.p.) + diazoxide (3 mg kg(-1), i.p.). After thirty minutes, the rats received sildenafil (1 mg kg(-1), by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg(-1)) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin.. Sildenafil significantly reduced ethanol-induced gastric damage in rats. L-NAME alone, without L-arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol-induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil.. Sildenafil had a protective effect against ethanol-induced gastric damage through the activation of the NO/cGMP/K(ATP) pathway.

Topics: Animals; Arginine; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diazoxide; Disease Models, Animal; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Glutathione; Glyburide; Guanylate Cyclase; Hemoglobins; KATP Channels; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Peptic Ulcer Hemorrhage; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Stomach Ulcer; Sulfones

Diclofenac sodium is being used for its anti-inflammatory actions since 28 years, but as all the NSAIDs are suffering from the deadlier GI toxicities, diclofenac sodium is also not an exception to these toxicities. The free -COOH group is thought to be responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main motto was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. In this paper, the results of synthesis and pharmacological screening of a series of S-substituted phenacyl 1,3,4-oxadiazoles and Schiff bases derived from 2-[(2,6-dichloroanilino) phenyl] acetic acid (diclofenac acid) are described. The 1,3,4-oxadiazoles and diclofenac moieties are important because of their versatile biological actions. In the present studies, the oxadiazole system has been functionalized onto the diclofenac acid moiety and 18 compounds in this series were synthesized. The structures of new compounds are characterized by TLC, FTIR, 1H NMR and Mass spectral data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds, which showed significant activity (comparable to the standard drug diclofenac sodium), were screened for their analgesic activity and to check their ability to induce ulcers by ulcerogenicity and histopathology studies. Eight new compounds, out of 18, were found to have significant anti-inflammatory activity in the carrageenan induced rat paw oedema model, with significant analgesic activity in the acetic acid induced writhing model with no ulcerogenicity. The compounds, which showed negligible ulcerogenic action, also showed promising results in histopathology studies, that is, they were found to be causing no mucosal injury.

Topics: Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Design; Drug Evaluation, Preclinical; Oxadiazoles; Rats; Schiff Bases; Stomach Ulcer; Structure-Activity Relationship; Sulfhydryl Compounds

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.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Antioxidants; Carrageenan; Diphenylacetic Acids; Drug Evaluation, Preclinical; Edema; Female; Gastric Mucosa; Lipid Peroxidation; Liver; Male; Mice; Molecular Structure; Oxadiazoles; Rats; Rats, Wistar; Stereoisomerism; Stomach Ulcer; Thiadiazoles; Triazoles

A series of substituted 1,3,4-oxadiazole (2-7 and 14-19), 1,2,4-triazole (20-25), and 1,3,4-thiadiazole (26-31) derivatives of naproxen have been synthesized by cyclization of 2-(6-methoxy-2-naphthyl)propanoic acid hydrazide 1 and N(1)[2-(6-methoxy-2-naphthyl) propanoyl]-N(4)-alkyl/aryl-thiosemicarbazides (8-13) under various reaction conditions. All the compounds were screened for their anti-inflammatory activity by carrageenan-induced rat paw edema test method. Compounds showing high anti-inflammatory activity were also tested for their analgesic, ulcerogenic, and lipid peroxidation. Few of the synthesized compounds showed significant anti-inflammatory and analgesic activities along with reduced ulcerogenic effect and lipid peroxidation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Design; Edema; Liver; Liver Function Tests; Male; Mice; Molecular Structure; Naproxen; Oxadiazoles; Pain; Rats; Stomach Ulcer; Thiadiazoles; Triazoles

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Ulcer Agents; Benzimidazoles; Drug Design; Helicobacter pylori; Indomethacin; Microbial Sensitivity Tests; Molecular Structure; Nitric Oxide Donors; Omeprazole; Oxadiazoles; Rabeprazole; Rats; Stomach Ulcer; Structure-Activity Relationship

The reaction of the 2-amino-substituted 1,3,4-oxadiazoles 9, 10 and the benzothiazoles 11, 12 with ethyl cyanoacetate is described. The obtained cyanoacetamide derivatives 13-16 gave the benzylidene derivatives 18-21 by condensation with benzaldehyde. 2-Phenyl-5-amino-1,3,4-oxadiazolo[3,2-a]pyrimidin-7-one (17) was also obtained. Moreover, the preparation of 6,7,8,9-tetraydro-5H-1,3,4-thiadiazolo[2,3-b]quinazolin++ +-5-thio-derivatives 22-25 and N-(1,3,4-thiadiazol-2-yl-5-substituted)-3,4-5,6-tetrahydro-anthran ilic acids 26-29 is also described. All above compounds and compounds, related to them, 1-8 were tested for their analgesic and antiinflammatory activities and the pharmacological screening results are reported and discussed.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Benzothiazoles; Carrageenan; Edema; Lethal Dose 50; Male; Mice; Oxadiazoles; Pain Measurement; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Thiadiazoles; Thiazoles

The syntheses of some acetamides (II) and phenylureas (III) derived from 2-amino-5-alkoxyphenyl-1,3,4-oxa(thia)diazoles (I) and some 2-alkoxyphenyl-6-phenyl-1,3,4-oxa(thia)diazole-[3,2-a]-s- triazin-5,7-diones (IV) are described. Pharmacological tests showed antiinflammatory and analgesic activities of bicyclic derivatives. A probable influence of alkoxyphenyl substituents, present in three kinds of structures, was observed.

Topics: Acetamides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical Phenomena; Chemistry; Lethal Dose 50; Male; Mice; Oxadiazoles; Rats; Rats, Inbred Strains; Reaction Time; Spectrophotometry, Infrared; Stomach Ulcer; Thiadiazoles; Triazines; Urea

Topics: Adult; Aged; Anti-Inflammatory Agents; Duodenal Ulcer; Female; Humans; Male; Middle Aged; Oxadiazoles; Peptic Ulcer; Stomach Ulcer

Topics: Animals; Bronchial Spasm; Edema; Gastrointestinal Motility; Oxadiazoles; Rats; Stereoisomerism; Stomach Ulcer