oxadiazoles and Edema

1,3,4-thiadiazole (A), 1,3,4-oxadiazole (B) and 1,2,4-triazole (C) derivatives have been known for their immense pharmacotherapeutic potential. The current research article attempts to further explore and understand the probable biochemical mechanism related to antiinflammatory activity of derivatives.. The screened A, B and C derivatives were investigated for both in-vitro (Erythrocyte Membrane stabilization activity, Proteinase enzyme inhibitory activities) and in-vivo correlation using acute and chronic anti-inflammatory potential by carrageenan induced rats paw edema and cotton pellet granuloma methods, respectively. The activity was studied after interpreting acute toxicity studies results.. In vitro studies in the case of Erythrocyte Membrane stability and Proteinase enzyme inhibitory activities exhibited by A, B, and C at 100 ppm were found to be 48.89%, 51.08% and 50.08% and 66.78%, 76.91% and 57.41%, respectively. The maximum toxic dose was found to be 2000 mg/kg. The derivatives were studied for two-dose levels viz; Lower (100 mg/kg) and higher dose (200 mg/kg). In rat paw edema, maximum decrease was obtained for A (50.05%), B (50.05%) and C (51.06%) at lower and higher dose at 68.76%, 55.61%, and 65.26%, respectively for effect up to 24 h. In the chronic model of cotton pellet granuloma viz; higher and lower doses of A, B and C exhibited 38.15%, 33.19% and 30.25 % and 19.45%, 18.55% and 17.55 %, respectively.. The studied models depicted that derivatives A, B and C have the probable potential as anti-inflammatory agents. Further studies need to be undertaken to explore their potential in the different therapeutic areas.

Topics: Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Erythrocyte Membrane; Female; Male; Oxadiazoles; Peptide Hydrolases; Protease Inhibitors; Rats; Thiadiazoles; Triazoles

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Edema; Enzyme Inhibitors; Indomethacin; Inflammation; Macrophages; Male; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Nitric Oxide Synthase Type II; Oxadiazoles; RAW 264.7 Cells; Structure-Activity Relationship

There are several potential side and adverse effects are found to be associated with the anti-inflammatory drugs in clinical practice. The long-term use of these clinical agents highly unsafe. It encouraged the development of novel heterocyclic compounds with potential anti-inflammatory activity and low to no toxicity. In present investigation, a total of 12 indole functionalized pyrazole and oxadiazole derivatives were designed, synthesized and evaluated for the in-vivo anti-inflammatory and analgesic potential. These compounds displayed comparable anti-inflammatory and analgesic potential to the reference drugs. Finally, molecular docking analysis was performed considering different anti-inflammatory targets to determine the mechanistic target of the designed molecules. Detailed analysis suggested that the molecules inhibit COX-2, preferably over other anti-inflammatory targets. The results suggested that two compounds (15c and 15f) were found promising candidates for the development of novel anti-inflammatory agents.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Carrageenan; Cattle; Cyclooxygenase 2; Dose-Response Relationship, Drug; Edema; Female; Humans; Indoles; Male; Molecular Structure; Oxadiazoles; Picrates; Pyrazoles; Rats; Rats, Wistar; Structure-Activity Relationship

Novel isoxazoles (10, 12a&b, 15a-c) and the furoxan derivative (14) have been prepared as new safe anti-inflammatory agents from the hydroximoyl 9. All compounds were evaluated for COX-1\\COX-2 and most of them showed promising selectivity. The furoxan derivative 14 gave 59% inhibitory activity using carrageenan induced paw rat edema model. Ulcer index experiment and histo-pathological study of stomach samples were also included. Also the proposed binding mode of certain newly synthesized compounds with COX-2 isoform was briefly discussed.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Edema; Isoxazoles; Molecular Structure; Oxadiazoles; Rats; Rats, Wistar; Structure-Activity Relationship

The development of NSAIDs/iNOS inhibitor hybrids is a new strategy for the treatment of inflammatory diseases by suppression of the overproduction of PGE

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Celecoxib; Dinoprostone; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Humans; Indomethacin; Lipopolysaccharides; Male; Mice; Molecular Docking Simulation; Molecular Structure; Nitric Oxide; Nitric Oxide Synthase Type II; Oxadiazoles; Oximes; Rats; RAW 264.7 Cells

The prostaglandins (PG) a group of physiologically active lipid compounds having diverse hormone like effects are important mediators of the body's response to pain and inflammation, and are formed from essential fatty acids found in cell membranes. This reaction is catalyzed by cyclooxygenase, a membrane associated enzyme occurring in two isoforms, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of COX. In view of this, a series of novel benzophenones conjugated with oxadiazole sulphur bridge pyrazole moiety 8a-l were designed, synthesized, characterized and subsequently evaluated for anti-inflammatory and analgesic property. The investigation of novel analogues 8a-l for potential anti-inflammatory activity showed high levels of COX-1 and COX-2 inhibitory activity. Among the series, compound 8i with electron withdrawing fluoro group at the para position of the benzoyl ring of benzophenone was characterized by highest IC

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzophenones; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Edema; Formaldehyde; Humans; Mice; Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Pain; Pain Measurement; Pyrazoles; Rats; Structure-Activity Relationship

With the purpose to improve anti-inflammatory activity, the impact of introduction of 1,2,5- and 1,3,4-oxadiazole fragments to betulonic acid core as well as hybrids tethered with short ω-amino acids has been studied. The anti-inflammatory activity of synthesized compounds was tested in vivo using models of inflammation induced by concanavalin A and histamine. The majority of new compounds demonstrated higher anti-inflammatory activity compared with starting betulonic acid. To confirm the molecular targets of new derivatives in NRf2 and NFκB pathways the docking at Kelch and BTB active sites of Keap1 as well as IKK was done. The novelty of the present work is the development of new class of low toxic anti-inflammatory substances consisting of amino acid-linked betulonic acid - oxadiazole conjugates. These compounds can be considered as prospective chemopreventive agents.

Topics: Amino Acids; Animals; Anti-Inflammatory Agents; Computer Simulation; Concanavalin A; Disease Models, Animal; Edema; Female; Fibroblasts; Histamine; Inflammation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Molecular Docking Simulation; NF-E2-Related Factor 2; NF-kappa B; Oxadiazoles; Triterpenes

Chronic inflammation is pathologically associated with various clinical conditions such as rheumatoid arthritis. Several anti-inflammatory and analgesic drugs currently available in market presents a wide range of problems. Therefore, the current study was aimed to evaluate anti-inflammatory and analgesic activities of newly synthesized compound 2-(5-mercapto-1,3,4-oxadiazol-2-yl)-N-propylbenzenesulphonamide (MOPBS). Carrageenan and CFA-induced models were developed for evaluation of anti-inflammatory and analgesic activity. Quantitative real-time PCR (qRT-PCR) was performed to determine the mRNA expression levels of inflammatory mediators. Pain behaviours were evaluated by performing Von Frey, Randall Selitto, cold acetone and hot plate test respectively. X-ray imaging and haematoxylin and eosin (H&E) staining were performed for examination of soft tissues of treated mice paw. Additionally, Kodzeila's screen test and weight test were performed for determination of any side effects on motor function and muscle strength. Acute pretreatment of animals with MOPBS (1, 10, 50 and 100 mg/kg, i.p.) produced a significant reduction of paw oedema against carrageenan-induced acute inflammation as well as notable inhibition of mechanical hyperalgesia, allodynia and thermal hyperalgesia. Similarly, in chronic inflammation model, administration of MOPBS (50 mg/kg, i.p.) produced a remarkable reduction of paw oedema. Additionally, MOPBS pretreatment showed a significant inhibition of thermal hyperalgesia, mechanical allodynia, and mechanical hyperalgesia in chronic arthritis model. Several pro-inflammatory mediators such as nitric oxide (NO), vascular endothelial growth factor (VEGF), interleukins (IL-1β, IL-6) and tumor necrosis factor-α (TNF-α) were inhibited by MOPBS treatment in blood plasma and paw tissues, respectively. MOPBS also enhanced the mRNA expression levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), superoxide dismutase (SOD2) and heme oxygenase (HO-1) and in turn reduced arthritis severity and inflammation. Furthermore, anti-inflammatory data were confirmed by X-rays and histological analysis. MOPBS pretreatment did not produce any apparent toxic effect on gastric, kidney and liver function and on muscle strength and motor function. Hence, the present data suggest that MOPBS might be a candidate for several chronic inflammatory diseases such RA and other auto-immune diseases.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Hyperalgesia; Inflammation; Male; Mice; Oxadiazoles; Pain; Real-Time Polymerase Chain Reaction; Sulfonamides

Ten new 2(4-hydroxy-3-benzoyl) benzamide-5-phenyl-1,3,4-oxadiazole derivatives (10a-j) were synthesized by coupling 3-benzoyl-4-hydroxybenzoic acid (5) with 2-amino-5-phenyl-1,3,4-oxadiazoles (9a-j). The structures of these compounds were confirmed by IR,

Topics: Animals; Benzophenones; Chickens; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Humans; Inflammation; Male; Neovascularization, Physiologic; Oxadiazoles; Rats

A series of new 1,3,4-oxadiazole/oxime hybrids were synthesized and designed as potent COX inhibitors. The prepared compounds were evaluated for their anti-inflammatory, antioxidant and ulcerogenic activities. The results indicated that the prepared compounds exhibited remarkable anti-inflammatory activity with (69.60-109.60% of indomethacin activity) after 4h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Edema; Humans; Male; Molecular Structure; Oxadiazoles; Oximes; Rats; Sheep; Structure-Activity Relationship

In search of potential therapeutics for inflammatory disease, we report herein the synthesis, characterization and anti-inflammatory activities of a new series of 1-{(5-substituted-1,3,4-oxadiazol-2-yl)methyl}-2-(morpholinomethyl)-1H-benzimidazoles (5a-r). The anti-inflammatory activity of the compounds was evaluated using carrageenan induced rat paw edema test. Some compounds showed excellent anti-inflammatory activity in carrageenan induced rat paw edema test. 1-{(5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl}-2-(morpholinomethyl)-1H-benzimidazole (5g) showed maximum anti-inflammatory (74.17±1.28% inhibition) with reduced ulcerogenic and lipid peroxidation profile and also showed significant COX-2 inhibition with IC

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzimidazoles; Cyclooxygenase 2 Inhibitors; Edema; Male; Models, Molecular; Molecular Docking Simulation; Oxadiazoles; Rats, Wistar; Ulcer

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Edema; Granuloma; Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Oximes; Rats; Structure-Activity Relationship; 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 series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC(50)  = 5.28 μm). Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Design; Edema; Female; Humans; Male; Mice; Models, Molecular; Oxadiazoles; Pain; Phosphodiesterase 4 Inhibitors; Rats; Rats, Wistar

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 new group of derivatives of salicylic acid containing NO-donor furoxans, and the related des-NO-furazans, were synthesized and evaluated as new aspirin-like molecules. Their stability was assessed in acid (pH 1) and physiological solutions (pH 7.4), and in human serum. No compound exhibited COX-inhibitory activity against COX-1 and COX-2 isoforms, when tested up to 100μM, respectively, on isolated platelets and on monocytes. Phenylsulfonyl- and cyano-substituted furoxans inhibited platelet aggregation induced by collagen in human platelet-rich plasma, through a cGMP dependent mechanism. Furoxan derivatives displayed cGMP-dependent vasodilator activities, tested on rat aorta strips precontracted with phenylephrine. All products showed anti-inflammatory activity similar to that of ASA, tested on rats by the carrageenan-induced paw edema assay. Unlike ASA, all products showed markedly reduced gastrotoxicity in a rat lesion model.

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Collagen; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Drug Stability; Edema; Humans; Hydrogen-Ion Concentration; Nitric Oxide Donors; Oxadiazoles; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Salicylic Acid; Vasodilator Agents

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

Two novel series of oxadiazole and oxadiazoline analogs possessing an indole nucleus were synthesized for their potential anti-inflammatory activity. The structures of the compounds were elucidated by elemental and spectral (IR, (1)H-NMR, (13)C-NMR, and MS) analysis. Most of the test compounds demonstrated appreciable anti-inflammatory activities. The anti-inflammatory activity of oxadiazoles at doses of 100 mg/kg was shown by their ability to provide 27-66%, 14-32%, and 20-51%. protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the anti-inflammatory properties of oxadiazolines at doses of 100 mg/kg were reflected by their ability to provide 20-56%, 11-26%, and 25-47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. The ulcerogenic potential of the compounds was determined. Structure-activity relationships among synthesized compounds were also established.

Topics: Animals; Anti-Inflammatory Agents; Drug Design; Edema; Magnetic Resonance Spectroscopy; Mass Spectrometry; Oxadiazoles; Rats; Structure-Activity Relationship; Ulcer

We describe herein a convenient straightforward synthesis of 5-amino-substituted 1,2,4-oxadiazoles, upon the reactions of amidoximes with carbodiimides, as well as their further derivatization to acetamides, in good yields. Most of the compounds exhibited in general low interaction with the stable radical 1,1-diphenyl-2-picryl-hydrazyl. Compounds 32 and 39 inhibited significantly soybean lipoxygenase. Selected compounds were screened for their in vivo anti-inflammatory activity using the carrageenin paw edema model and showed significant anti-inflammatory activity (26, 51%). The ability of the compounds to release NO in the presence of a thiol factor has been also investigated.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Edema; Female; Glycine max; Lipoxygenase; Male; Molecular Structure; Oxadiazoles; Rats; Rats, Inbred F344; Stereoisomerism; Structure-Activity Relationship

A series of 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles (7a-7n) were synthesized and screened for analgesic and in vivo anti-inflammatory activities using acetic acid writhing in mice model and carrageenan-induced paw oedema method in mice, respectively. The analgesic activity of compounds 7i and 7m is superior while that of 7d, 7c, 7f and 7j is equal to the reference standard, diclofenac sodium. The anti-inflammatory activity of compounds 6, 7c, 7e, 7f, 7i, 7l, 7m and 7n is found to be superior than that of diclofenac sodium which is used as a reference, while compounds 7d and 7g are found to be equipotent with the reference compound.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Drug Evaluation, Preclinical; Edema; Mice; Oxadiazoles; Pain; Structure-Activity Relationship

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 series of novel ether-linked bis(heterocycle)s have been synthesized via [3+2]-cycloaddition reaction of nitrile oxide with allyl alcohol followed by intramolecular 1,3-diploar cycloaddition reaction of nitrile imine with carbonyl group. All the newly synthesized compounds were screened for their anti-inflammatory and analgesic activities. Among the list of compounds (7a-k) studied, 7d, 7g, 7j, and 7k exhibited excellent activity comparable to ibuprofen and aspirin at the similar dosages.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Edema; Female; Male; Mice; Molecular Structure; Oxadiazoles; Pain Measurement; Rats; Stomach; 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

The lymphatic vascular system regulates tissue fluid homeostasis and the afferent phase of the immune response, and it is also involved in tumor metastasis. There is increasing evidence that lymphatic vessels also mediate acute and chronic inflammation. However, the mechanisms and functional consequences of lymphangiogenesis under inflammatory conditions are largely unknown. Here, we show that lymphatic endothelial cells (LECs) specifically express the alpha1beta1 isoform of soluble guanylate cyclase (sGC), that vascular endothelial growth factor-A potently induces sGCalpha1beta1, and that nitric oxide (NO) -induced LEC proliferation, migration, and cGMP production in LECs are specifically dependent on sGCalpha1beta1. Moreover, the specific sGC inhibitor NS-2028 completely prevents ultraviolet B-irradiation-induced lymphatic vessel enlargement, edema formation, and skin inflammation in vivo. These findings identify a crucial role of the NO/sGCalpha1beta1/cGMP pathway in modulating lymphatic vessel function. The blockade of sGCalpha1beta1 signaling might serve as a novel therapeutic strategy for inhibiting lymphangiogenesis and inflammation, in addition to its effects on the blood vasculature.

Topics: Cell Movement; Cell Proliferation; Cells, Cultured; Cyclic GMP; Edema; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Guanylate Cyclase; Humans; Immunity, Cellular; Inflammation; Lymphatic Vessels; Nitric Oxide; Nitric Oxide Synthase Type III; Oxadiazoles; Oxazines; Receptors, Cytoplasmic and Nuclear; S-Nitroso-N-Acetylpenicillamine; Soluble Guanylyl Cyclase

Morphine can inhibit inflammatory edema in experimental animals. The mechanisms and sites by which opioids exert this effect are still under debate. Since the spinal level is a site for modulation of the neurogenic component of inflammation, we investigated the effect of intrathecal (i.t.) administration of morphine, and the involvement of spinal nitric oxide (NO)/cyclic-guanosine monophosphate-GMP pathway in carrageenan (CG)-induced paw edema.. Male Wistar rats received i.t. injections of drugs (20 microL) 30 min before paw stimulation with CG (150 microg). Edema was measured as paw volume increase (mL), and neutrophil migration was evaluated indirectly by myeloperoxidase (MPO) assay.. Morphine (37, 75, and 150 nmol) inhibited inflammatory edema, but had no effect on MPO activity. Coinjection with naloxone (64 nmol) reversed the effect of morphine. The corticosteroid synthesis inhibitor, aminoglutethimide (50 mg/kg, v.o.), administered 90 min before morphine injection did not modify its antiedematogenic effect. Low doses of the NO synthase inhibitor, N(omega)-nitro-L-arginine (L-NNA; 10 and 30 pmol) increased, while higher doses (3 and 30 nmol) inhibited edema. The guanylate cyclase inhibitor 1H-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 21 and 42 nmol) increased, while the phosphodiesterase type 5 inhibitor sildenafil (0.15 and 1.5 nmol) inhibited paw edema. Coadministration of a subeffective dose of L-NNA (3 pmol) or ODQ (10 nmol) with morphine prevented its antiedematogenic effect, but sildenafil (0.15 nmol) rendered a subeffective dose of morphine effective (18 nmol). ODQ also prevented the antiedematogenic effect of the NO donor S-nitroso-N-acetyl-penicilamine.. These results support the idea that morphine can act on opioid receptors at the spinal level to produce antiedematogenic, and that the NO/cGMP pathway seems to be an important mediator in this effect.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Guanylate Cyclase; Inflammation; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Neutrophil Infiltration; Neutrophils; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroarginine; Oxadiazoles; Peroxidase; Phosphodiesterase Inhibitors; Piperazines; Purines; Quinoxalines; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Signal Transduction; Sildenafil Citrate; Spinal Cord; Sulfones; Time Factors

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 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for antiinflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 micromol L(-1) and COX-1 enzyme inhibition of 44% at 88 micromol L(-1) concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 pmol L(-1)) and higher COX-1 enzyme inhibition (53% at 88 micromol L(-1)) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg(-1)) vs. celecoxib (48% at 12.5 mg kg(-1)). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

Topics: Animals; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Foot; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Oxadiazoles; Oxides; Rats; Rats, Sprague-Dawley; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared

A series of furoxan-based nitric oxide-releasing glucocorticoid derivatives was synthesized. The pharmacological assays indicated that three compounds, including I(4), I(5), and I(6), had anti-inflammatory activity. Furthermore compared with the leading compound hydrocortisone the safety of I(6) was greatly improved. Due to releasing NO in vivo the side effects of glucocorticoids, including hypertension and osteoporosis, were effectively avoided.

Topics: Alkaline Phosphatase; Animals; Animals, Newborn; Anti-Inflammatory Agents; Blood Pressure; Carrageenan; Cell Proliferation; Cotton Fiber; Dose-Response Relationship, Drug; Drug Design; Edema; Glucocorticoids; Heart Rate; Mice; Nitric Oxide; Osteoblasts; Osteoclasts; Oxadiazoles; Structure-Activity Relationship; Xylenes

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

The synthesis of some new 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k) has been described. Ethyl-6-methoxy-2-naphthoate (1) yielded on treatment with hydrazine hydrate to 6-methoxy-2-naphthoic acid hydrazide (2). Compound 2 reacted with substituted aromatic carboxylic acids (3a-k) in phosphorus oxychloride yielded 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k). Newly synthesized compounds were characterized by IR, (1)H-NMR and mass spectral data. All the compounds were screened for their anti-inflammatory and analgesic activity. Compound 4j exhibited promising anti-inflammatory and analgesic activities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Mice; Molecular Structure; Oxadiazoles; Pain; Pain Measurement; Rats; Structure-Activity Relationship

Naproxen, probenecid, diclofenac, ibuprofen and indomethacin were converted to hydrazide derivatives via their methyl ester by reacting with hydrazine hydrate, which were further condensed with beta-keto esters to get the pyrazolone derivatives. The hydrazide derivatives of probenecid and diclofenac were also reacted with biphenyl acetic acid while naproxen hydrazide was reacted with p-chloro benzoic acid besides biphenyl acetic acid to synthesize their oxadiazole analogues. Some selected members of the compounds prepared were screened for their anti-inflammatory and analgesic activity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Chromatography, Thin Layer; Edema; Female; Indicators and Reagents; Male; Mice; Naproxen; Oxadiazoles; Pain Measurement; Prodrugs; Pyrazoles; Rats

The synthesis of six 3-aryl-5-(n-propyl)-4,5dihydro-1,2,4-oxadiazoles 3a-f has been achieved in a facile manner by the reaction of an appropriate arylamidoxime 1a-f with butyraldehyde 2. Oxidation of 3a-f individually using MnO(2) in CH(2)Cl(2) or sodium hypochlorite in THF/H(2)O furnished 1,2,4-oxadiazoles 4a-f in good to excellent yields. Compounds 4a-f were also evaluated against inflammation. Except 4e, all of them reduced inflammation, however, 4c presented better antiinflammatory activity. A preliminary antimicrobial activity tests of 3a-f showed that these compounds possess activity against some microorganisms. In fact, 3c and 3f have been found to be more effective against Staphylococcus aureus, Mycobacterium smegmatis, and Candida albicans.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bacillus subtilis; Candida albicans; Edema; Enterobacter aerogenes; Escherichia coli; Mice; Microbial Sensitivity Tests; Mycobacterium smegmatis; Oxadiazoles; Saccharomyces cerevisiae; Spectrum Analysis; Staphylococcus aureus

The synthesis of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives and the results of anti-inflammatory activity in vivo are described. Most of the tested compounds exhibited anti-inflammatory activity and some of them were more active than acetylsalicylic acid.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bentonite; Carrageenan; Edema; Female; Hindlimb; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Morpholines; Oxadiazoles; Pyrimidines; Rats; Rats, Wistar; Toxicity Tests, Acute

To search for new derivatives of diclofenac (DC) having higher potency than the parent drug and lacking its undesirable effects.. Coupling DC with NO donor 3-hydroxymethyl-4-phenylfuroxan and its isomer through esterification, evaluating anti-inflammatory and analgesic activities, observing side effects in the rat gastrointestinal (GI) tract and assessing NO releasing ability both in vitro and in vivo.. Fifteen new compounds including nine target ones (II1-9) were synthesized, and their structures were determined by IR, 1HNMR, MS and elemental analysis. Compounds II3 and II9 showed anti-inflammatory activity comparable to DC. Compound II2 showed stronger anti-inflammatory and analgesic activities and less GI side effect than DC, and released NO in vivo.. Compound II2 is worthy to be intensively studied.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic N-Oxides; Diclofenac; Digestive System; Edema; Gastrointestinal Hemorrhage; Mice; Molecular Structure; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles; Pain Threshold; Rats; Structure-Activity Relationship

Sixteen 1-(1-naphthyloxy)acetyl-4-substituted-3-thiosemicarbazides, 2-substituted amino-5-(1-naphthyloxy)methyl-1,3,4-oxadiazoles, 2-substitutedamino-5-(1-naphthyloxy) methyl-1,3,4-thiadiazoles and 3-(1-naphthyloxy)methyl-4-substituted-1,2,4-triazole-5-thiones were synthesized. The structures of the compounds have been elucidated by UV, IR, 1H-NMR, 13C-NMR spectra and elemental analysis. The anti-inflammatory activities of the compounds were evaluated by carregeenan induced hind paw edema and air-pouch inflammation tests in mice. In carrageenan induced hind paw edema test, compounds 1a, 1d, 3d, 4a showed equivalent or higher activity compared to naproxen and phenylbutazone. In the air-pouch inflammatory model, compounds 1a, 1b, 1d, 2c, 3c, 3d, 4a and 4d showed marked anti-inflammatory activity. The ED50 values of these compounds ranged between 24-36 mg/kg. Side effects of the compounds on gastrointestinal system and kidneys were examined and none of the compound showed significant side effects.

Topics: Air; Animals; Anti-Inflammatory Agents, Non-Steroidal; Azides; Carrageenan; Crystallization; Edema; Foot; Male; Mice; Oxadiazoles; Spectrophotometry, Ultraviolet; Thiadiazoles; Triazoles

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Topics: Animals; Cells, Cultured; Chromones; Dermatitis, Atopic; Disease Models, Animal; Ear; Edema; Enzyme Inhibitors; Eosinophils; Hypersensitivity; Immunosuppressive Agents; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Oxadiazoles; Pyrimidinones; Skin; Tacrolimus; Th1 Cells; Th2 Cells

A new series of nonsteroidal antiinflammatory drugs (NSAIDs) obtained by linking ibuprofen to selected furoxan moieties and to related furazans were synthesized and tested for their antiinflammatory, antiaggregatory, and ulcerogenic properties. All the derivatives are endowed with antiinflammatory activity comparable to that of ibuprofen, but, unlike this drug, they display reduced acute gastrotoxicity. The masking of the ibuprofen-free carboxylic group seems to be principally at the basis of this reduced topical irritant action. The two furoxan derivatives 8 and 9 also trigger potent antiaggregatory effects, principally as a consequence of their NO-donor ability.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclic N-Oxides; Edema; Gastric Mucosa; Humans; Ibuprofen; In Vitro Techniques; Male; Nitric Oxide Donors; Oxadiazoles; Peptic Ulcer; Platelet Aggregation Inhibitors; Rats; Rats, Wistar

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

Various 5-[[(acetamidophen-4-yl)oxy]methyl]-2-(p-substituted phenylamino)-1,3,4-oxadiazoles (4a-4d) were synthesized by cyclization of the corresponding N1-[[(acetamidophen-4-yl)oxy]acetyl]- N4-(p-substituted phenylamino)-3-thiosemicarbazides (3a-3d). All four of the thiosemicarbazides [250 mg/kg, orally (p.o.)] and the corresponding oxadiazoles (250 mg, p.o.) possessed anti-inflammatory activity. In the Carrageenan-induced edema test in rat paw, the activity ranged from 28 to 47% for 3a-3d and 44 to 63% for 4a-4d, with indomethacin (10 mg/kg, p.o.), used as the standard reference drug, showing 88.5% protection. The compounds (1 mM) were also tested for the inhibition of bovine serum albumin denaturation, and this activity ranged from 27 to 68%. No correlation was seen between the anti-inflammatory activity of 3a-4d and the inhibition of denaturation of bovine serum albumin. The low toxicity of these compounds was reflected by their high approximate 50% lethal dose (LD50) values, ranging from 2000 to 2500 mg/kg.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Edema; Female; Indomethacin; Lethal Dose 50; Male; Mice; Oxadiazoles; Protein Denaturation; Rats; Serum Albumin, Bovine; Structure-Activity Relationship

Several 1-(4-biphenoxyacetyl)-4-substituted arylthiosemicarbazides and their corresponding cyclized 2-(4-biphenoxymethyl)-5-arylamino-1,3,4- oxadiazoles were synthesized and characterized by elemental analyses and IR, mass, and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carrageenin-induced edema in rat paw. The anti-inflammatory activity possessed by substituted thiosemicarbazides [100 mg/kg, intraperitoneal(ip)] ranged from 22 to 68%, whereas substituted 1,3,4-oxadiazoles (100 mg/kg, ip) provided protection of 10-76%. Hydrocortisone (10 mg/kg, ip) and oxyphenbutazone (40 mg/kg, ip), used as standard reference drugs, decreased edema in rat paw by 44.6 and 52.9%, respectively. All compounds (1 mM) possessed antiproteolytic activity that was reflected by their ability to cause in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin. This inhibition ranged between 43 and 72% for substituted thiosemicarbazides and 30 and 83% for substituted 1,3,4-oxadiazoles.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Chemical Phenomena; Chemistry, Physical; Edema; Female; Male; Oxadiazoles; Rats; Serum Albumin, Bovine; Thiosemicarbazones; Trypsin Inhibitors

N-Arylanthranilic acids, known generically as the fenamates, are nonsteroidal antiinflammatory drugs (NSAIDs) that block the metabolism of arachidonic acid by the enzyme cyclooxygenase (CO). Substitution of the carboxylic acid functionality of several fenamates with acidic heterocycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO) activities when tested in an intact rat basophilic leukemia (RBL-1) cell line. Compound 5b (IC50 = 0.77 microM (5-LO), 0.27 microM (CO)) which contains an 1,3,4-oxadiazole-2-thione replacement and 10b (IC50 = 0.87 microM (5-LO), 0.85 microM (CO)) which contains a 1,3,4-thiadiazole-2-thione are the most potent inhibitors of 5-LO and CO activities from these series. Both of these heterocyclic analogs of flufenamic acid are also active in carageenin-induced rat footpad edema (CFE), a model of acute inflammation. When dosed orally the ID50s for 5b and 10b in CFE are 8.5 and 4.7 mg/kg, respectively.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Edema; In Vitro Techniques; Lipoxygenase Inhibitors; Male; ortho-Aminobenzoates; Oxadiazoles; Rats; Rats, Wistar; Structure-Activity Relationship; Thiadiazoles; Triazoles; Tumor Cells, Cultured

Some novel 1,3,4-oxadiazoline and 1,3,4-oxadiazole derivatives have been synthesized from 3-hydroxy-5,6-diphenyl-1,2,4-triazine. Illucidation of the structures of the isolated products has been proved in the light of their elemental analysis, spectroscopic data and unambiguous synthesis in certain cases. Some derivatives have shown promising anti-inflammatory activity in comparison to phenylbutazone.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biotechnology; Drug Evaluation, Preclinical; Edema; Female; Male; Molecular Structure; Oxadiazoles; Rats; Structure-Activity Relationship

Various 2-(4-biphenoxymethyl)-5-arylamino-1,3,4-oxadiazoles were synthesized by cyclization of the corresponding 1-(4-biphenoxyacetyl)-4-substituted thiosemicarbazides. These compounds were characterized by their elemental analyses and infrared, mass, and nuclear magnetic resonance spectral data. All substituted thiosemicarbazides (100 mg/kg, ip) and cyclized substituted oxadiazoles (100 mg/kg, ip) possessed anti-inflammatory activity, as reflected by their ability to provide protection against carrageenin-induced edema in the rat paw which ranged from 28 to 68% and 36 to 76%, respectively. Cyclization of the substituted thiosemicarbazides, in general, resulted in an increase in the anti-inflammatory activity of their corresponding substituted oxadiazoles, with the exception of those containing 2,4-dimethyl and 3,4-dimethyl substituents in their molecular structure. Hydrocortisone (10 mg/kg, ip) and oxyphenbutazone (40 mg/kg, ip) were used as the standard reference drugs and these provided 45 and 53% protection, respectively. All compounds (1 mM) possessed antiproteolytic activity and the in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin ranged from 13 to 75% for substituted thiosemicarbazides and 39 to 70% for substituted oxadiazoles. There was no relationship between the anti-inflammatory activity of substituted thiosemicarbazides and substituted oxadiazoles and their antiproteolytic effectiveness. The low toxicity of these compounds was reflected by their high approximate LD50 values, ranging from 500 to 1000 mg/kg.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Female; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Mice; Oxadiazoles; Protease Inhibitors; Rats

Various new formazans of substituted oxadiazole 2(3H)-thiones were tested for their anti-inflammatory activity against carrageenin-induced paw oedema in albino rats. Among these, two most potent derivatives were evaluated in detail using cotton pellet implantation methods in albino rats of either sex. These two active analogues were also tested for their analgesic activity in albino mice and ulcerogenic liability in albino rats. The toxicity of the compounds was assessed by determination of their approximate LD50 value in albino mice. An attempt has also been made to establish the structure-activity relationship.

Topics: Aconitine; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Edema; Female; Gossypium; Lethal Dose 50; Male; Oxadiazoles; Phenylbutazone; Rats

Topics: Animals; Anti-Inflammatory Agents; Edema; Female; Male; Oxadiazoles; Rats; Sydnones

Topics: Benzyl Compounds; Blood Pressure; Diuresis; Edema; Female; Humans; Maternal-Fetal Exchange; Oxadiazoles; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinuria; Uterus

Seven 1-(naphth-1-ylacetyl)-4-substituted thiosemicarbazides were synthesized and cyclized to the corresponding 2-(naphth-1-ylmethyl)-5-arylamino-1,3,4-oxadiazoles. All compounds, with the exception of two slbstituted oxadiazoles, possessed low anti-inflammatory activity. The protection afforded by these compounds against carrageen-in-induced edema ranged from 3 to 43% where cyclization, in general, decreased anti-inflammatory activity. All compounds (1 mM), possessed antiproteolytic activity where in vitro protection of trypsin-induced hydrolysis of bovine serum albumin, in most cases was greater with oxadiazoles.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Drug Evaluation, Preclinical; Edema; Hydrocortisone; Hydrolysis; Oxadiazoles; Oxyphenbutazone; Rats; Serum Albumin, Bovine; Sodium Salicylate; Thiosemicarbazones; Trypsin

Eight 1-(naphth-1-ylacetyl)-4-substituted thiosemicarbazides and eight 2-(naphth-1-ylmethyl)-5-arylamino-1,3,4-oxadiazoles were synthesized and evaluated for antiinflammatory and antiproteolytic properties. All thiosemicarbazides (100 mg/kg) provided 14-43% protection against carrageenin-induced edema in rats. Cyclization of thiosemicarbazides to oxadiazoles resulted in significant reduction in the antiinflammatory activity. Some of these thiosemicarbazides also possessed low antiinflammatory activity against cotton-pellet-induced granuloma formation and formaldehyde-induced arthritis in rats. Hydrocortisone and oxyphenbutazone, used as reference drugs, exhibited greater antiinflammatory activity. All compounds possessed antiproteolytic activity. The in vitro protection of trypsin-induced hydrolysis of bovine serum albumin, unlike antiinflammatory activity, was greater with oxadiazoles (30-90%) than the precursor thiosemicarbazides (4-50%) at a final concentration of 1 mM.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Edema; Granuloma; Mice; Naphthalenes; Oxadiazoles; Rats; Semicarbazides; Trypsin Inhibitors

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