Non-carboxylic analogues of naproxen: design, synthesis, and pharmacological evaluation of some 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives

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.     

Synthesis and pharmacological evaluation of N-(6-chlorobenzo[d]thiazol-2-yl)hydrazine carboxamide derivatives of benzothiazole

A series of 6-substituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole (6a–g) and 1,3,4-oxadiazole (7a–g, 8) derivatives of benzothiazole were synthesized in satisfactory yield and pharmacologically evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation activities by known experimental models. All the synthesized compounds were in good agreement with elemental and spectral data. Some of the synthesized compounds have significant anti-inflammatory and analgesic activities. Ulcerogenic and irritative action on the gastrointestinal mucosa, in comparison with standard are low.     

Synthesis of some new 2-(2-fluoro-4-biphenylyl)propionic acid derivatives as potential anti-inflammatory agents

The synthesis of a group of 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,3,4-thiadiazoles and 1,2,4-triazine derived from 2-(2-fluoro-4-biphenylyl) propionic acid is described. The structures of new compounds are supported by IR, 1H NMR and MS data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug flurbiprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. Five out of seventeen new compounds, showed very good anti-inflammatory activity in the carrageenan induced rat paw edema test with negligible ulcerogenic action. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA), which is one of the byproducts of lipid peroxidation. The study showed that the compounds inhibit the induction of gastric mucosal lesions and it can be suggested from our results that their protective effects may be related to an inhibition of lipid peroxidation in the gastric mucosa.     

Studies on fused heterocyclic 3,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazoles: synthesis and biological evaluation

In this study, a series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (5a–t) were synthesized by condensing 4-amino-3-mercapto-(4H)-1,2,4-triazoles (4a–c) with different aromatic or aroyl acids through one-pot reaction. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation actions. Some of the newly synthesized compounds showed very good anti-inflammatory activity with low GI toxicity and reduced lipid peroxidation. These compounds also showed interesting profile of analgesic activity in acetic acid-induced writhing test. The findings of the study indicate that the synthesized compounds have superior GI safety profile along with reduction in lipid peroxidation as compared to that of the standard.     

Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones

Sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-oxadiazole, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thiadiazole and 5-(2-naphthyloxymethyl)-4-substituted-1,2,4-triazole-3thione derivatives have been prepared and evaluated as orally active anti-inflammatory agents with reduced side-effects. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin and phenylbutazone. In carrageenan-induced foot pad edema assay, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole, 5-(2-naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione and 5-(2-naphthyloxymethyl)-4-ethyl-1,2,4-triazole-3-thione showed an interesting anti-inflammatory activity. In the air-pouch test, 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives reduced total number of leukocytes of the exudate that indicates excellent inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, liver and stomach and none of the compounds showed significant side effects compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs).     

Synthesis and Biological Evaluation of ��-Aroylpropionic acid based 1,3,4-Oxadiazoles

In the present investigation, two new series, 1-(4-benzylphenyl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)-1-propanone and 1-(4-ethylphenyl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)-1-propanone from β-(4-benzylbenzoyl)propionic acid and β-(4-ethylbenzoyl)propionic acid, respectively, were synthesized and tested for antiinflammatory, analgesic, lipid peroxidation, ulcerogenic and antibacterial actions. A fair number of compounds were found to have good antiinflammatory activity in carrageenan-induced rat paw edema test, while a few compounds showed significant antibacterial activity. The newly synthesized compounds showed very low ulcerogenic action.     

Design and one-pot and microwave-assisted synthesis of 2-amino/5-aryl-1,3,4-oxadiazoles bearing a benzimidazole moiety as antioxidants

In this study, two new series of 2-amino-1,3,4-oxadiazoles and 5-aryl-1,3,4-oxadiazoles carrying a benzimidazole moiety were synthesized. The antioxidant properties of these compounds were investigated in vitro by the determination of the microsomal NADPH-dependent inhibition of lipid peroxidation levels (LP), the microsomal ethoxyresorufin O-deethylase activity (EROD), and DPPH radical scavenger effects. Among the tested compounds, 2-[(2-(4-chlorophenyl)-1H-benzo[d]imidazole-1-yl)methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (9) was found to be the most active compound in all three in vitro systems.     

Synthesis and Evaluation of Antiinflammatory, Analgesic and Ulcerogenic Potential of NSAIDs Bearing 1,3,4-Oxadiazole Scaffold

Synthesis of 1,3,4-oxadiazole derivatives of diclofenac and mefenamic acid are described. The target compounds 5-[2-(2,6-dichloroanilino)benzyl]-2-aryl-1,3,4-oxadiazole (3a-3e) and 5-[2-(2,3-dimethylanilino)phenyl]-2-(aryl)-1,3,4-oxadiazole (6a-6e) were obtained by treating 2 and 5 with various aromatic acids using POCl₃ as dehydrating agent. They were purified and characterized by IR, ¹H-NMR and elemental analysis. These compounds were further subjected to antiinflammatory, analgesic and acute ulcerogenic activity. Compound 3c and 6d exhibited good antiinflammatory activity and compounds 3c, 3e, 6c, 6d, 6e were found to be non ulcerogenic.     

Synthesis and local anesthetic activity of some novel N-[5-(4-substituted)phenyl-1,3,4-oxadiazol-2-yl]-2-(substituted)-acetamides

A novel series of acetamides carrying substituted-1,3,4-oxadiazole moiety were synthesized from reaction of 5-aryl-2-chloroacetamido-1,3,4-oxadiazoles with different secondary amines. The local anesthetic potential of the compounds was investigated using rabbit corneal reflex method and guinea pig's wheal derm method. The present work is the only one of its kind reporting local anesthetic activity in acetamide system combined with 1,3,4-oxadiazole nucleus. Lidocaine was selected as standard drug in evaluation of local anesthetic activity of synthesized oxadiazole analogues. Compound 19 was found to possess significant local anesthetic activity in both the models employed for evaluation of local anesthetic activity. Compound 20, 23, 28, 29 and 35 also demonstrated marked local anesthetic activities. Structure-activity relationships among synthesized compounds were also established.     

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents

The synthesis of new indole derivatives bearing isoxazoline moiety (3a–d and 4a–d) has been described. IR, ¹H NMR, and mass spectral data supported the structures of synthesized compounds. The compounds were tested in vivo for their anti-inflammatory activity by carrageenin-induced rat paw edema method. The compounds that showed good anti-inflammatory activity were screened for their ulcerogenic and lipid peroxidation activities. The most active compound of this series is 3-[3-(4-methoxyphenyl)- 4-morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-5yl]-1H-indole 4d.     

Synthesis and evaluation of anti-inflammatory and analgesic activity of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones

A novel series of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-one (7a–i) were synthesized by the condensation between the appropriately substituted 5-substituted-1,3,4-oxadiazolyl-2-thione (4a–i) derived from various existing NSAIDs and 3-(2-bromoacetyl)-2H-chromen-2-one (6) under reflux in the presence of sodium ethoxide. Structure of the synthesized compounds was established on the basis of physicochemical, elemental analysis, and spectral data. The title compounds were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg bw. Among the series, four compounds 7c, 7e, 7f, and 7h were found to possess a significant anti-inflammatory and analgesic activity profile. In addition, these compounds were also found to possess a less degree of ulcerogenic potential as compared to standard NSAIDs.     

Synthesis and characterization of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene) benzenamine derivatives as potent antifungal agents

In the present study, a series of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene)benzenamine derivatives have been synthesized and characterized by IR, 1H NMR and 13C NMR spectra. All the synthesized compounds were evaluated for their antifungal activity and were compared with the standard drug, clotrimazole. The compounds demonstrated excellent to weak antifungal activity. Among the synthesized derivatives, 4f and 4h showed significant activity and 4c exhibited moderate activity against Candida albicans, Candida tropicalis and Aspergillus niger as compared with the standard antifungal agent - clotrimazole. The minimum inhibitory concentration of the compounds was in the range of 1.62-25 microg/mL against fungi. Furthermore, the substitution of chloro, nitro and methoxy groups at para position of benzene moiety play an important role in enhancing the antifungal activity of this class of compounds.     

Synthesis and pharmacological evaluation of some 3-(2-methylphenyl)-2-substituted amino-quinazolin-4(3H)-ones as analgesic and antiinflammatory agents

A variety of novel 3-(2-methylphenyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one was synthesized from 2-methyl aniline. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. Among these, the compound 2-(1-ethylpropylidene)-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one emerged as the most active compound for analgesic activity, while the compound 2-(1-methylbutylidene)-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one showed most potent anti-inflamma-tory activity of the series and was moderately more potent in its anti-inflammatory activity when compared to the reference standard diclofenac sodium (CAS 15307-86-5). Interestingly, the test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid (CAS No: 50-78-2).     

Synthesis and in vitro antimicrobial 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

A series of 6-substituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole (3a-g) and 1,3,4-oxadiazole (4a-g, 5) derivatives of isoniazid were synthesized in satisfactory yield and pharmacologically evaluated for their in vitro antimicrobial activity. All the synthesized compounds were in good agreement with elemental and spectral data. A majority of the tested compounds showed good to moderate antimicrobial activity against all tested pathogenic bacterial and fungal strains.     

2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a novel series of anti-inflammatory and analgesic agents

2-Amino-5-sulfanyl-1,3,4-thiadiazole derivatives were synthesized via the interaction of 2-amino-5-sulfanyl-1,3,4-thiadiazole, Ar-Cl, and benzene sulfonamide/benzene sulfonyl chloride. Twelve compounds were synthesized, out of which six compounds show significant anti-inflammatory and analgesic activity and were devoid of gastrointestinal side effects (ulcerogenic effect), which zre the most frequent adverse reactions associated with orally ingested anti-inflammatory or antiarthritic agents.     

Pharmacological screening of few new 2-(substituted acetyl) amino-5-alkyl-1,3,4-oxadiazoles.

Nine new 2-(substituted acetyl) amino-5-alkyl-1,3,4-oxadiazoles were synthesised and confirmed on the basis of IR and nitrogen analysis. These were screened for spasmolytic, anti-inflammatory and their effects on blood pressure after determining ALD50. Compounds GK-4 i.e. 2-(diethylaminoacetyl)- amino-5-methyl-1,3,4-oxadiazole and GK-8 i.e. 2-(din-propylamino acetyl)-amino-5-ethyl-1,3,4-oxadiazole were found to be spasmolytic. Compound GK-6 i.e. 2-(diethylaminoacetyl)-amino-5-n-propyl-1,3,4-oxadiazole was found to be a potent hypotensive agent with the effect lasting for more than two hours.     

Synthesis and Reactions of 2(5)-[Benzyl or Cyanomethyl]-1,3,4-oxadiazoles

A series of five membered heterocycles, namely 5-(benzyl or cyanomethyl)-3-acetyl-2,2-disubstituted-1,3,4-oxadiazolines ( 3a-e ), 2,5-disubstituted-1,3,4-oxadiazoles ( 4a, b ), 2-hydroxy-5-(benzyl or cyanomethyl)-1,3,4-oxadiazoles ( 5a, b ), 1,2,5-trisubstituted-1,3,4-triazoles ( 6a, b ), and 2-(benzyl or cyano-methyl)-1,3,4-oxadiazole-5-thiols ( 10a, b ), were synthesized. Also 5-chloro-2-benzyl-1,3,4-oxadiazole 7 was prepared. Reaction of amines, hydrazines, and sodium azide with 7 gave the corresponding 2-arylamino ( 8a, b ), 5-hydrazino or phenylhydrazino ( 8c, d ) and 2-azido derivatives 9 , respectively. Mannich bases ( 11a, b ) were prepared by the reaction of sec. amines with 9a . 5-Carboxymethylthio-1,3,4-oxadiazoles ( 12a, b ) and their ethyl esters ( 13a, b ) were also prepared. The ester 13a reacted with amines and hydrazines to give the corresponding amides ( 14a-d ).     

Antimicrobial activity of Schiff bases of coumarin-incorporated 1,3,4-oxadiazole derivatives: an in vitro evaluation

A series of 3-{5-[(E)-(substituted benzylidene) amino]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-ones (4a–r) were synthesized by the reaction of 3-(5-amino]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one with different substituted benzaldehydes to form Schiff bases of coumarin-incorporated 1,3,4-oxadiazole derivatives. The structures of the compounds were confirmed on the basis of their elemental analysis and spectral data. The compounds were screened against bacterial strains Staphylococcus aureus NCTC (10418), Escherichia coli NCTC (6571), and fungal strain Candida albicans ATCC (10231). Ciprofloxacin and Ketoconazole were used as standards. The test compounds and standards were evaluated at 100 μg/ml concentration. DMF (N,N-dimethylformamide) was used as solvent and control. Most of the synthesized compounds possess significant antimicrobial activity. Compound (4m) without any substitution of the phenyl ring which is attached to 1,3,4-oxadiazole moiety showed highly significant in vitro growth inhibition against S. aureus and E. coli, while as compound (4g) with para N(CH₃)₂ showed highly significant in vitro growth inhibition against C. albicans.     

Synthesis and pharmacological evaluation of some 3-(4-methylphenyl)-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents

A variety of 3-(4-methyl phenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-methyl phenyl)-3H-quinazolin-4-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(4-methyl phenyl)-3H-quinazolin-4-one was synthesized from 4-methyl aniline. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic index activities. While the test compounds exhibited significant activity, compounds Al, A2, and A3 showed more potent analgesic activity and the compound A3 showed more potent anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

Synthesis and antiviral evaluation of novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines and their sugars, 1,2,4-triazoles, tetrazoles and pyrazolyl derivatives

A number of new N-arylaminomethyl-1,3,4-oxadiazole derivatives 2, 3a,b, and 9-12a,b were prepared. Sugar (5-N-arylaminomethyl-1,3,4-oxadiazol-2-yl) hydrazones 4-6a,b were synthesized by the reaction of the hydrazino derivatives 3a,b with the corresponding monosaccharides. The novel acyclo-C-nucleosides 7, 8a,b were prepared by heterocyclization of the sugar hydrazones 4, 5a,b with acetic anhydride. A number of the synthesized compounds were tested for their antiviral activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBBcell culture-adapted strain). The results revealed that the sugar hydrazones 6a,b showed higher antiviral activity compared to the other hydrazones and their acetylated derivatives.