Syntheses and evaluation of anti-inflammatory, analgesic and ulcerogenic activities of 1,3,4-oxadiazole and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives

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.     

Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives of isoniazid

The significance of this study was to prepare various isoniazid derivatives by introducing the isoniazid core into several molecules to explore the possibilities of some altered biological activities. Series of 6-substituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole (3a–g) and 1,3,4-oxadiazole (4a–g and 5) derivatives of isoniazid were synthesized in satisfactory yield and pharmacologically evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation activities by known experimental models.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

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.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

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.     

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.     

Design,synthesis and pharmacological evaluation of novel azole derivatives of aryl acetic acid as anti-inflammatory and analgesic agents

A series of substituted azole derivatives (3a–e, 4a–e and 5a–e) were synthesised by the cyclisation of N¹(diphenylethanoyl)-N⁴-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.)     

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis,docking studies and investigation of anti-inflammatory,ulcerogenic liability and analgesic activities

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC₅₀s of 0.75–70.50 μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.     

Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of naproxen

Some 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a-f and 5a-d) have been synthesized by cyclisation of 4-amino-5-[1-(6-methoxy-2-naphthyl)ethyl]-3-mercapto-(4H)-1,2,4-triazole (3) with various substituted aromatic acids and aryl/alkyl isothiocyanates, through a single step reaction. The target compounds were pharmacologically evaluated for their anti-inflammatory and analgesic potentials by known experimental models. Several of these showed significant activity. Very low ulcerogenic index was observed for potent compounds.     

Synthesis and biological evaluation of some new pyridazinone derivatives

A series of pyridazinone derivatives (19-34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48-77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen.     

Synthesis and biological evaluation of some new pyridazinone derivatives

A series of pyridazinone derivatives (19–34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48–77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen.     

3-Arylsulphonyl-5-arylamino-1,3,4-thiadiazol-2(3H)ones as anti-inflammatory and analgesic agents

Two series of 3-arylsulphonyl-5-arylamino-1,3,4-thiadiazol-2(3H)ones 2 with potential anti-inflammatory and analgesic activity were prepared and tested. Pharmacological results revealed that all the title compounds, endowed with an arylsulphonyl side chain, possess good antalgic activity and fair anti-inflammatory properties. The analgesic profile of the two series, evaluated by the acetic acid writhing test, showed that compounds 2c, 2f and 2h, in particular, were the most active. Structure-activity relationships are briefly discussed.     

Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives

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.     

Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory,analgesic and antimicrobial agents

The synthesis of two groups of structure hybrids comprising basically the antipyrine moiety attached to either polysubstituted thiazole or 2,5-disubstituted-1,3,4-thiadiazole counterparts through various linkages is described. Twelve out of the newly synthesized compounds were evaluated for their anti-inflammatory activity using two different screening protocols; namely, the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays, using diclofenac Na as a reference standard. The ulcerogenic effects and acute toxicity (ALD₅₀) values of these compounds were also determined. Meanwhile, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity. In general, compounds belonging to the thiazolylantipyrine series exhibited better biological activities than their thiadiazolyl structure variants. Collectively, compounds 6, 10, 26, and 27 proved to display distinctive anti-inflammatory and analgesic profiles with a fast onset of action. All of the tested compounds revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD₅₀ > 3.0 g/kg). Meanwhile, compounds 7, 10, 11, and 23 are considered to be the most active broad spectrum antimicrobial members in this study. Compound 10 could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic and antibacterial profile.     

New 1,3,4-oxadiazole/oxime hybrids: Design,synthesis, anti-inflammatory,COX inhibitory activities and ulcerogenic liability

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 4 h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC₅₀ of (1.10–0.94) and (2.30–5.00) µM on both COX-1 and COX-2 respectively. Compound 7h was found to inhibit both COXs non-competitively with K_i values of 73 µM and 89 µM. Most of the tested compounds showed ulcer-free stomachs compared to indomethacin.     

New 1,3,4-thiadiazole derivatives endowed with analgesic and anti-inflammatory activities

Two series of N-[5-oxo-4-(arylsulfonyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl]-amides were synthesized and tested in vivo for their analgesic and anti-inflammatory activities. All the new compounds possess good antalgic action in the acetic acid writhing test and some terms of the series showed also fair anti-inflammatory activity in the carrageenan rat paw edema test. Ulcerogenic and irritative action on the gastrointestinal mucose, in comparison with indomethacin is low.     

In vivo anti-inflammatory activity and docking study of newly synthesized benzimidazole derivatives bearing oxadiazole and morpholine rings

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 IC₅₀ values of 8.00 μM. Compounds 5o and 5q were also found to exhibit good COX-2 inhibition with IC₅₀ values of 11.4 and 13.7 μM concentrations. Molecular docking study showed that morpholine and oxadiazole rings linked to the benzimidazole nucleus play an important role in binding with the COX-2.     

Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity,anti-inflammatory activity and gastric safety profile

Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO₂Me or/and SO₂NH₂) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED₅₀ = 15.06, 42.51 and 50.43 μmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED₅₀ = 82.2 μmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72–3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.     

A facile regioselective synthesis of novel spiro-thioxanthene and spiro-xanthene-9',2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents

The 1,3-dipolar cycloaddition of nitrile imines to 9H-thioxanthone-9-thione and 9H-xanthone-9-thione afforded novel spiro-thioxanthene-9',2-[1,3,4]thiadiazoles 6a-g and spiro-xanthene-9',2-[1,3,4]thiadiazoles 7a-g in good yields. Some of the newly synthesized compounds were tested for anti-inflammatory and analgesic activities comparable to ibuprofen. Compounds 6a,d,e and 7a,d,e showed significant activity compared to standard drug. The toxicity studies revealed that neither death nor other behavioral or toxicological changes were observed on rats up to a dose as high as 200 mg/kg.     

Fluorine bearing sydnones with styryl ketone group: synthesis and their possible analgesic and anti-inflammatory activities

In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a-i, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mg\kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution.     

Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents

A series of 3-(4-biphenyl)-5-substituted phenyl-2-pyrazolines (2a-h) and 1-benzoyl-3-(4-biphenyl)-5-substituted phenyl-2-pyrazolines (3a-h) were synthesized by condensation of chalcones with hydrazine hydrate in solvent system ethanol and DMF. The newly synthesized compounds were screened for their anti-inflammatory and analgesic activity, and were compared with standard drug. Among the compounds studied, compound 2e showed more potent anti-inflammatory and analgesic activity than the standard drug, along with minimum ulcerogenic index.