Synthesis, antimicrobial and anti-inflammatory activities of some 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines bearing trichlorophenyl moiety

The reaction of 2,3,5-trichlorobenzoic acid hydrazide with carbon disulfide and potassium hydroxide followed by treatment with hydrazine hydrate afforded 3-(2,3,5-trichlorophenyl)-4-amino-1,2,4-triazole-5-thione (6). Alternatively, this triazole was also synthesized by fusing 2,3,5-trichlorobenzoic acid with thiocarbohydrazide. Condensation of (6) with various aromatic carboxylic acids in the presence of phosphorous oxychloride or with phenacyl bromides afforded two series of fused heterocycles namely 6-(substituted aryl)-3-(2,3,5-trichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadizoles (7) and 6-(substituted aryl)-3-(2,3,5-trichlorophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines (8), respectively. The structures of these newly synthesized compounds are characterised by elemental analysis, IR, (1)H NMR and mass spectroscopic studies. All the synthesized compounds were screened for their antimicrobial and anti-inflammatory activities. Some of the compounds exhibited promising antimicrobial and anti-inflammatory activities.     

Heterocyclic system containing bridgehead nitrogen atom: synthesis and pharmacological activities of some substituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles

Several 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadizoles were prepared by the condensation of 4-amino-3-aryl/aralkyl substituted-5-mercapto-1,2,4-triazoles 3(a-c) with various substituted aromatic/hetero aromatic acids through a single step reaction. Elemental analysis, IR, 1H NMR and mass spectral data confirmed the structure of the newly synthesized compounds. Synthesized triazolo thiadiazoles investigated for their antibacterial, antifungal, anti-inflammatory and analgesic activities. Some of the tested compounds showed moderate antimicrobial activity against various tested bacterial and fungal strains. None of the synthesized compounds have significant anti-inflammatory and analgesic activities.     

Synthesis and antimicrobial evaluation of some fused heterocyclic [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives

A series of fused 1,2,4-triazoles with diphenylsulfone moiety are prepared utilizing 4-amino-5-[4-(4-X-phenylsulfonyl)phenyl]-4H-1,2,4-triazole-3-thiol 1 (X=H, Br). The latter on reaction with aromatic isothiocyanate in DMF, aromatic acid in POCl3 and CDI in dioxane gives five membered fused triazole derivatives 2a-c, 3a-c, 4a-g, 5a-g and 6a,b. The structures of newly synthesized compounds were confirmed on the basis of their elemental analysis and spectral data results (IR, 1H-and 13C NMR). New synthesized compounds were screened for their antimicrobial activities. The preliminary results revealed that some of the compounds exhibited promising antimicrobial activities.     

Studies on the synthesis and antibacterial activity of 3,6-disubstituted 1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles

Treating infections caused by drug-resistant bacterial strains constitutes one of the most essential challenges for medicine nowadays. A range of new derivatives of 1,2,4-triazolo[3,4-b]1,3,4-thiadiazole have been synthesized and evaluated for their in?vitro antimicrobial activity. Compounds 1-8 indicated high activity towards Gram-positive bacteria, which was up to 16 times more than currently used antibiotics. To the best of our knowledge, the derivatives obtained by us are the most active among the 3-aryl-6-arylamino-1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles known until now.     

Synthesis of some new 1,2,4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activities

4-Phenyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-thiol (3) was obtained in basic media via the formation of 2-isonicotinoyl-N-phenylhydrazinecarbothioamide (2), and converted to some alkylated derivatives (4a,b) and Mannich base derivatives (5a-c). 2-[(4-Phenyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]acetohydrazide (7) that was obtained by using compound 3 as precursor in two steps was converted to thiosemicarbazide derivative (8), Schiff base derivatives (9) and 5-{[(4-phenyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]methyl}-1,3,4-oxadiazole-2-thiol (10). Moreover, 5-{[(4-phenyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]methyl}-3-{[(2-morpholin-4-ylethyl)amino]methyl}-1,3,4-oxadiazole-2(3H)-thione (11) was synthesized via reaction of compound 10 with 2-(4-morpholino)ethylamine. The treatment of compound 8 with NaOH gave 4-(4-methylphenyl)-5-{[(4-phenyl-5-pyridine-4-yl-4H-1,2,4-triazol-3-yl)thio]methyl}-4H-1,2,4-triazole-3-thiol (12), while the acidic treatment of compound 8 afforded 5-{[(4-phenyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]methyl}-2(4-methylphenyl)-amino-1,3,4-thiadiazole (14). N-Methyl derivative of compound 14 and a Mannich base derivative of compound 12 were synthesized from the reactions of these precursors with methyl iodide and methyl piperazine, respectively. All newly synthesized compounds were screened for their antimicrobial activities. The antimicrobial activity study revealed that all the compounds screened showed good or moderate activity except compounds 3, 5c, 7, 9c, 9e, 9g, 9h, 11, and 13.     

New triazole and triazolothiadiazine derivatives as possible antimicrobial agents

Triazole and triazoles fused with six-membered ring systems are found to possess diverse applications in the fields of medicine, agriculture and industry. The new 1,2,4-triazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives were synthesized as novel antimicrobial agents. The reaction of 1H-indol-3-acetic acid with thiocarbohydrazide gave the 4-amino-3-mercapto-5-[(1H-indol-3-yl)methyl]-4H-1,2,4-triazole. The reaction of triazole with arylaldehydes in ethanol gave the 4-arylideneamino-3-mercapto-5-[(1H-indol-3-yl)methyl]-4H-1,2,4-triazoles (I). The 3-[(1H-indol-3-yl)methyl]-6-aryl-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (II) were obtained by condensing triazole with phenacyl bromides in absolute ethanol . The chemical structures of the compounds were elucidated by IR, (1)H NMR and FAB(+)-MS spectral data. Their antimicrobial activities against Micrococcus luteus (NRLL B-4375), Bacillus cereus (NRRL B-3711), Proteus vulgaris (NRRL B-123), Salmonella typhimurium (NRRL B-4420), Staphylococcus aureus (NRRL B-767), Escherichia coli (NRRL B-3704), Candida albicans and Candida glabrata (isolates obtained from Osmangazi University, Faculty of Medicine) were investigated and significant activity was obtained.     

Organoiodine (III)-mediated synthesis of 3-aryl/heteroaryl-5,7-dimethyl-1,2,4-triazolo[4,3-c]pyrimidines as antibacterial agents

Synthesis of 12 new 3-aryl/heteroaryl-5,7-dimethyl-1,2,4-triazolo[4,3-c]pyrimidines (3a-l) has been accomplished by the oxidation of pyrimidinylhydrazones (2a-l) of various aryl/heteroaryl aldehydes using 1.1equiv. of iodobenzene diacetate (IBD) in dichloromethane. All the compounds 3a-l tested in vitro for their antibacterial activity against two Gram-positive bacteria namely, Bacillus subtilis, Bacillus stearothermophilus and two Gram-negative bacteria Pseudomonas putida, Escherichia coli. Two compounds, namely 3-(2,4-dichlorophenyl)-5,7-dimethyl-1,2,4-triazolo [4,3-c]pyrimidine (3j) and 3-(4-hydroxy-2-methoxyphenyl)-5,7-dimethyl-1,2,4-triazolo[4,3-c]pyrimidine (3l) were found to be equipotent or more potent than the commercially available antibiotics (chloramphenicol and streptomycin).     

Studies on synthesis and pharmacological activities of 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and their dihydro analogues

Several 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole and their dihydro analogues were synthesized from hetero aromatic acids and hetero aromatic aldehydes, respectively, by microwave-assisted dry media and conventional methods. Elemental analysis, IR, (1)H NMR, (13)C NMR and mass spectral data elucidated the structures of all newly synthesized compounds. Synthesized compounds are studied for their antibacterial, antifungal, anti-inflammatory and analgesic activities. Some of the tested compounds showed significant pharmacological activities.     

Synthesis of 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines as novel analgesic/anti-inflammatory compounds

In this study, a new class of 4-amino-3-substituted-1,2,4-triazole-5-thiones (1–4) and their corresponding condensed derivatives 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (1a–4c) were synthesized and evaluated for their analgesic/anti-inflammatory activities. All synthesized compounds were also tested for their gastric toxicity and antioxidant activity on acute administration. Most of the compounds showed significant activity in both carrageenan-induced oedema and acetic acid-induced writhing tests besides negligible gastrointestinal toxicity. The compounds showing less ulcerogenic effect also showed less lipid peroxidation (LPO) level. Most promising results were obtained with the compounds that placed a fluoro or a chloride on the phenyl ring at the sixth position of the fused ring.     

Synthesis of new substituted azetidinoyl and thiazolidinoyl-1,3,4-thiadiazino (6,5-b) indoles as promising anti-inflammatory agents

Various N-({5-[(arylmethylene)amino]-1,3,4-thiadiazol-2-yl}methyl) [1,3,4] thiadiazino[6,5-b]indol-3-amine (6a-6h), 2-aryl-3-{5-[([1,3,4] thiadiazino[6,5-b]indol-3-ylamino)methyl]-1,3,4-thiadiazol-2-yl}-1,3-thiazolidin-4-one (7a-7h), and 3-chloro-4-aryl-1-{5-[{[1,3,4]thiadiazino[6,5-b]indol-3-ylamino]methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one (8a-8h) have been synthesized in the present study. The structure of these newly synthesized compounds were confirmed by their analytical and spectral data. These compounds were also evaluated for their anti-inflammatory, ulcerogenic and analgesic activities. Compound 8g has shown most active anti-inflammatory and analgesic activities with better ulcerogenic activity than phenylbutazone, while this compound was found to be associated with lesser degree of anti-inflammatory and analgesic activities as compared to indomethacin.     

Synthesis, cytotoxicity and effects of some 1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells

Novel derivatives of 4,5-substituted-1,2,4-triazole-thiones and 2,5-substituted-1,3,4-thiadiazoles were synthesized and evaluated for their cytotoxicity. The biological study indicated that compounds 4-ethyl-5-(4,5,6,7-tetrahydro-1-benzothien-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 13, N-ethyl-5-(4,5,6,7-tetrahydro-1-benzothien-2-yl)-1,3,4-thiadiazol-2-amine 16, 4-amino-5-(4,5,6,7-tetrahydro-1-benzothien-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 20 and 4-amino-5-(5-phenylthien-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 21 possessed high cytotoxicity in vitro against thymocytes. The corresponding IC(50) values were 0.46 microM, 5.2 x 10(-6)microM, 0.012 microM and 1.0 x 10(-6)microM. Most toxic against lymphocytes was compound 21, IC(50) - 0.012 microM. The tested compounds showed a general stimulation effect on B-cells' response.     

Synthesis, antifungal activity and CoMFA analysis of novel 1,2,4-triazolo[1,5-a]pyrimidine derivatives

In order to search novel agrochemicals with higher antifungal activity, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives bearing 1,3,4-oxadiazole moieties were designed and synthesized. Their antifungal activities against Rhizoctonia solani were evaluated in vitro. By determining the EC(50) values of all the newly synthesized compounds and 10 formerly synthesized compounds, compound 8r, 2-((5-(sec-butylthio)-1,3,4-oxadiazol-2-yl)-methylthio)-5-dimethyl-1,2,4-triazolo-[1,5-a]pyrimidine, was found to display the highest antifungal activity (EC(50)=6.57 microg mL(-1)). Based on the quantitative structure-activity relationships analyses, 2-(1-(5-(sec-butylthio)-1,3,4-oxadiazol-2-yl)ethylthio)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (9j) was designed and synthesized, which was found to display much higher activity (EC(50)=3.34 microg mL(-1)) than compound 8r and the control. To further explore the comprehensive structure-activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed and a statistically reliable model with good predictive power (r(2)=0.929, q(2)=0.588) was achieved on the basis of the common substructure-based alignment. According to the CoMFA model, the structure-antifungal activity relationship was explained reasonably.     

Synthesis of some novel thiourea derivatives obtained from 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIV and anti-tuberculosis agents

As a continuation of our previous efforts on N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and N-alkyl/aryl-N'-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, a series of novel 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones 23-26 and several related thioureas, N-alkyl/aryl-N'-{4-[(4-alkyl/aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]phenyl}thioureas 27-42 were synthesized for evaluation of their antiviral potency. Structures of the synthesized compounds were confirmed by the use of (1)H NMR, (13)C NMR and HR-MS data. All compounds 1-42 were evaluated in vitro against HIV-1 (IIIB) and HIV-2 (ROD) strains in MT-4 cells, as well as other selected viruses such as HSV-1, HSV-2, Coxsackie virus B4, Sindbis virus and Varicella-zoster virus using HeLa, Vero, HEL and E6SM cell cultures, and anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv. Compounds 4 and 5 showed weak activity against HSV-1, HSV-2 and TK(-) HSV, whereas eight compounds showed marginal activity against Coxsackie virus B4. The most active derivative in this series was compound 38 which showed moderate protection against Coxsackie virus B4 with an MIC value of 16 microg/ml and a selectivity index of 5. This compound was also active against thymidine kinase positive Varicella-zoster virus (TK(+) VZV, OKA strain) with an EC(50) value of 9.9 microg/ml. Compound 38 was the most active compound with 79% inhibition against M. tuberculosis H37Rv.     

Hypervalent iodine mediated synthesis of 1-aryl/hetryl-1,2,4-triazolo[4,3-a] pyridines and 1-aryl/hetryl 5-methyl-1,2,4-triazolo[4,3-a]quinolines as antibacterial agents

Oxidation of 2-pyridyl and 2-quinylhydrazones with iodobenzene diacetate (IBD) in dichloromethane yield 1-aryl/hetryl-1,2,4-trizolo-[4,3-a] pyridines (3a-f) and 1-aryl/hetryl-5-methyl-1,2,4-triazolo[4,3-a] quinolines (6a-f). Seven compounds were tested in vitro for their antibacterial activity. 1-(5'-Nitro-2-furyl)-5-methyl-1,2,4-triazolo[4,3-a]quinoline (6e) was associated with substantially higher antibacterial activity than some commercial antibiotics against Salmonella typhi at MIC i.e. 10 microg mL(-1).     

Synthesis of some new 4-styryltetrazolo[1,5-a]quinoxaline and 1-substituted-4-styryl[1,2,4]triazolo[4,3-a]quinoxaline derivatives as potent anticonvulsants

4-Methyltetrazolo[1,5-a]quinoxaline (3) was prepared by the azide cyclocondensation of 2-chloro-3-methylquinoxaline (2). The reaction of 3 with aromatic aldehydes furnished 4-styryltetrazolo[1,5-a]quinoxalines (4a-f). Compound 2, on treatment with hydrazine hydrate gave 2-hydrazino-3-methylquinoxaline (5). The ring closure of 5 was achieved by the reaction of orthoesters and trifluoroacetic acid to yield 4-methyl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (7a-c). Further, reaction of 7a-c with different aromatic aldehydes furnished the title compounds, 4-styryl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (8a-i) in good yield. In another scheme, the hydrazino compound 5 was treated with different aromatic aldehydes to yield corresponding N-arylidenehydrazino quinoxalines (6a-d). Further, the oxidative cyclization of hydrazones by nitrobenzene yielded 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines (7d-g), which on condensation with aromatic aldehydes gave the title compounds, 1-aryl-4-styryl[1,2,4]triazolo[4,3-a]quinoxalines (8j-u). The newly synthesized compounds have been characterized by FTIR, (1)H NMR, (13)C NMR and mass spectral data, followed by elemental analysis. Some of the compounds were screened for in vivo anticonvulsant activity. Few of them exhibited promising results.     

Organoiodine(III) mediated synthesis of 3,9-diaryl- and 3,9-difuryl-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidines as antibacterial agents

Nine 3,9-diaryl- and 3,9-difuryl-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidines (3a-i) have been synthesized by the oxidation of bis-2,4-pyrimidinylhydrazones of various araldehydes and furfural with 2equiv of iodobenzene diacetate (IBD) in dichloromethane and tested in vitro for their antibacterial activity. Three compounds, namely 3,9-di-(4'-fluorophenyl)-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidine (3f), 3,9-di-(4'-nitrophenyl)-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidine (3g) and 3,9-di-(5'-nitro-2'-furyl)-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidine (3i), were associated with substantially higher antibacterial activity than some commercial antibiotics against Gram-positive bacteria namely Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis; two Gram-negative bacteria namely Salmonella typhi and Escherichia coli at MIC (minimum inhibitory concentration) 10microg/ml.     

Organoiodine (III) mediated synthesis of 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines as antibacterial agents

Synthesis of some new 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines (3a-k) has been accomplished by the oxidation of 4,6-dimethyl-2-pyrimidinylhydrazones of various aldehydes with iodobenzene diacetate in dichloromethane. Nine new compounds (3b-g and 3i-k) were tested in vitro for their antibacterial activity. Two compounds, namely 3-(4'-pyridyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3k) and 3-(3',4'-dimethoxyphenyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3f), were associated with substantially higher antibacterial activity than some commercial antibiotics against Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Salmonella typhi at MIC (minimum inhibitory concentration) i.e. 10 microg/ml.     

Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid

Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.     

N- and S-alpha-l-arabinopyranosyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles. First synthesis and biological evaluation

First synthesis of N- and S-alpha-l-arabinopyranosyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles is described. Antimicrobial screening of two selected regioisomeric compounds against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis and Escherichia coli are compared.     

6-Benzylidenethiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted withibuprofen: synthesis, characterization and evaluation of anti-inflammatory activity

In this study, the synthesis of 3-[1-(4-(2-methylpropyl)phenyl)ethyl]-1,2,4-triazole-5-thione (2) and its condensed derivatives 6-benzylidenethiazolo[3,2-b]-1,2, 4-triazole-5(6H)-ones (2a-u) are described. The structures of the compounds were elucidated by spectral and elemental analysis. In the pharmacological studies, anti-inflammatory activities of these compounds have been screened. Among the compounds examined, the compounds 2 and 2g possessed the most prominent and consistent activity. In gastric ulceration studies the synthesized compounds were generally found to be safe at a 200 mg/kg dose level.