Synthesis and in vitro antifungal and cytotoxicity evaluation of thiazolo-4H-1,2,4-triazoles and 1,2,3-thiadiazolo-4H-1,2,4-triazoles

The increasing clinical importance of drug-resistant fungal pathogens has lent additional urgency to microbiological and antifungal research. Various thiazolo(or 1,2,3-thiadiazolo)thiosemicarbazides (2a-2e), 3-thiono-1,4-dihydrotriazolothiazoles-(or 1,2,3-thiadiazoles) (3a-3e), their related substituted thio-4H-1,2,4-triazoles (4a-4p) and sulfones (5a-5o) were synthesized. Most of the compounds tested for antifungal activity exhibited significant effects against Cryptococcus neoofrmans and Sacchromyces cerevisiae at MIC ranges of 0.53 to 12.5 micrograms/mL, whereas their activities were moderate against Candida albicans and weak against Aspergillus fumigatus. At 10 ppm concentration, all compounds showed low toxicity on brine shrimps (higher than 80% survival), except compounds 4c and 2c. At 100 ppm concentration most of the compounds showed toxicity except compounds 2b, 2e, 3c, 3d, 3e, and 4e. Compounds 4b, 4c, and 4h showed in vitro cytotoxicity against Kbalb cell lines and compounds 4c and 4g against 143B cell lines at 0.1 mM concentration.     

Synthesis and in-vitro antimicrobial activity of new 1,2,4-triazoles

We have described the synthesis of new 1,2,4-triazoles and have evaluated their antimicrobial profile. Antitubercular activity was determined in triplicate using the Lowenstein-Jensen medium. A loopful of Mycobacterium tuberculosis suspension was inoculated on the surface of each Lowenstein-Jensen media containing the test compounds (100, 10 or 1 microg mL(-1)). To evaluate in-vitro antibacterial activity, compounds (50, 5 or 0.5 microg) were evaluated against B. subtilis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus typhi by the disc diffusion method. To evaluate antifungal activity Sabourauds Dextrose agar medium was used. Some of the compounds (5, 0.5 or 0.05 microg mL(-1)) were screened for activity against Aspergillus niger 88 and Aspergillus niger 90 and others were screened for activity against T. rubrum TR1, T. rubrum R6, T. rubrum R7 and T. mentagrophyte M1, using the cup plate method. Our results show that the triazoles with a pyrazine moiety at position 3 were more active as antitubercular and antifungal agents compared with the triazoles which had a pyrazine moiety at position 4 of the molecule.     

Synthesis, antibacterial and antifungal activity of some novel 3,5-disubstituted-1H-1,2,4-triazoles

A rapid and efficient one-pot condensation reaction of long-chain alkyl and alkenyl acid hydrazides and nitriles was carried out to afford 3,5-disubstituted-1H-1,2,4-triazoles. The compounds 5a-o were screened for in-vitro antibacterial activity against the representative panel of two Gram-positive and two Gram-negative bacteria. All the synthesized compounds were also tested for their inhibitory action against five strains of fungi. The various compounds show potent inhibitory action against test organisms. The compounds 5a-o were characterized on the basis of elemental analysis and spectral data.     

Synthesis of new 1,2,4-triazoles as anti-inflammatory and anti-nociceptive agents

A series of fifteen new substituted 1,2,4-triazoles (6a – 6o) have been synthesized in order to obtain new agents with potential anti-inflammatory and anti-nociceptive activity. The title compounds were synthesized using 4-methylbenzoic acid as a starting reactant. The synthesized compounds were characterized by spectroscopic methods (IR, ¹H NMR, ¹³ C NMR, FAB⁺ − MS) and elemental analysis (nitrogen analysis). The title compounds were evaluated for anti-inflammatory activity by the carrageenan induced paw edema method, and some compounds were evaluated for anti-nociceptive activity by the hot plate method and tail immersion method. Compounds N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-piperidin-1-ylacetamide (6f), 2-(4-benzylpiperazin-1-yl)-N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]acetamide (6i) and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) showed significant anti-inflammatory activity compared to other synthesized compounds, and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) exhibited superior anti-nociceptive activity.     

Synthesis and analgesic activity of new 1,3,4-oxadiazoles and 1,2,4-triazoles

A series of new 1,3,4-oxadiazoles and 1,2,4-triazoles were synthesized in order to obtain new compounds with potential analgesic activity. Compounds were evaluated for their analgesic activities by formalin-induced nociception test. Mefenamic acid (as the reference drug) did not show any activity in the early phase of the formalin test, while compounds 7b, 7c, 8c, and 9a significantly reduced the nociception in this phase. However in the late phase of formalin test all of the target compounds and mefenamic acid showed analgesic activity in comparison to control.     

Synthesis,analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles

Background

Long-term clinical employment of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant side effects including gastrointestinal (GI) lesions and kidney toxicity. In this paper we designed and synthesized new imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles by molecular hybridization of previously described anti-inflammatory compounds in the hope of obtaining new safer analgesic and anti-inflammatory agents.

Methods

The target structures were synthesized by preparation of 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 5. The reaction of hydrazine hydrate with this ester afforded the 5-methyl-1H-imidazole-4-carboxylic acid hydrazide 6 which was converted to target compounds 7-15 according to the known procedures. In silico toxicity risk assessment and drug likeness predictions were done, in order to consider the privileges of the synthesized structures as drug candidates.

Results and discussion

The analgesic and anti-inflammatory profile of the synthesized compounds were evaluated by writhing and carrageenan induced rat paw edema tests respectively. Compounds 8, 9 and 11-13 and 15 were active analgesic agents and compounds 8, 9 and 11-13 showed significant anti-inflammatory response in comparison with control. Compounds 11 and 13 were screened for their ulcerogenic activities and none of them showed significant ulcerogenic activity. The active Compounds 11 and 12 showed the highest drug likeness and drug score.

Conclusions

The analgesic and anti-inflammatory activities of title compounds were comparable to that of standard drug indomethacin with a safer profile of activity. The results revealed that both of oxadiazole and triazole scaffolds can be determined as pharmacophores. The in silico predictions and pharmacological evaluations showed that compounds 11 and 12 can be chosen as lead for further investigations.     

Synthesis and QSAR studies of some novel disubstituted 1,2,4-triazoles as antimicrobial agents

Disubstituted 1,2,4-triazoles 3a–k, 4a–k, and 6a–k have been synthesized from anthranilic acid and nicotinic acid, respectively, through a multi-step reaction sequence via their hydrazides. Synthesized compounds were evaluated for their in vitro antimicrobial activity against two gram-positive bacteria (S. aureus and B. subtilis), three gram-negative bacteria (E. coli, S. typhi, and K. pneumonia) as well as four fungi (A. niger, A. fumigatus, A. flavus, and C. albicans). To explore computational approach, structure–activity relationships were generated statistically using the synthesized compounds and their respective quantitative values of biological activities. These models can be used in future for predicting antimicrobial activity on similar class of compounds.     

Synthesis of some new s-alkylated 1,2,4-triazoles, their mannich bases and their biological activities

A series of 1‐(4‐methoxyphenyl)‐2‐[5‐{(biphenyl‐4‐yloxy)methyl}4‐(substituted phenyl)‐3‐mercapto‐(4H)‐1,2,4‐triazol‐3‐ylthio)] ethanones (6a–6s) and 4‐(substituted phenyl)‐3‐(morpholin/pyrrolidin‐4‐ylmethylthio)‐5‐(4‐phenylphenoxymethyl)‐4H‐1,2,4‐triazoles (7a–7e) were synthesized in order to obtain new compounds with potent anti‐inflammatory and analgesic activity with insignificant ulceration. Among the synthesized compounds, ( 6c), (6e), (6g) and (6l) from triazole series and ( 7b) and (7e) from Mannich base series were found to exhibit significant anti‐inflammatory activity with 59.69, 59.69, 64.69, 79.84, 54.54, 79.69% and 52.55, 57.50, 72.52, 83.03, 60.06, 84.08% inhibition of paw edema at 3 h and 5 h respectively, in comparison to the standard drug ibuprofen ( 7 8.93 and 82.58% at 3 h and 5 h). The active compounds were further tested for their analgesic activity and gastric ulceration study. Compounds 6g, 7b and 7e exhibited significant analgesic activity with reaction time ( 3.60, 3.22, 3.88 s ) respectively at 60 min. without causing any gastric irritation. These compounds were also screened for their in vitro antimicrobial activity, Compounds 6f, 6g, 6h, 6l, 6o, 6p, 7a, 7b and 7c showed significant zone of inhibition against various antimicrobial stains. It is concluded that the compounds 6g, 7b and 7e possess a good spectrum of activities. Compound 7e may be considered potent for development of better anti‐inflammatory agent. The antimicrobial activity revealed that most of the compounds showed moderate to significant activity. Compounds containing nitro, chloro, bromo and fluoro group showing better activity. All the compounds from 7a, 7b and 7e were active against gram positive bacteria (S. aureus).     

Synthesis, characterization, and antimicrobial evaluation of novel naphthalene-based 1,2,4-triazoles

In order to search for new bioactive molecules with significant antimicrobial action, a series of 1,2,4-triazole and naphthalene analogs bearing structurally diverse substituents, N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)(aryl)amides 3a–l were synthesized in good yield by a multi-step synthetic procedure. Their antimicrobial activity was screened against various Gram-positive and Gram-negative bacteria and fungi. Compounds 3a, 3f, 3g, 3j, and 3k exerted strong inhibition of the investigated bacterial and fungal strains compared to control antibiotic ampicillin and antifungal griseofulvin. On the basis of statistical analysis, it is observed that the compounds give significant co-relation. All the synthesized compounds have been characterized by IR, ¹H NMR, ¹³C NMR, and mass spectral data.     

Synthesis and antitumor activity of new furyl-2-substituted 1,3,4-thiadiazoles and 1,2,4-triazoles

A series of new furyl-2-substituted derivatives of 1,3,4-thiadiazole and 1,2,4-triaozle have been synthesized. The S-alkylation and aminomethylation of the latter leading to their 3-mercapto- and 2-aminomethylene-substituted derivatives have been studied. Results of antitumor activity testing of the synthesized compounds are presented and discussed.     

Synthesis and antitumor activity of 3,4,5-substituted 1,2,4-triazoles

Conditions for effective alkylation of new 3,4-substituted-5-mercapto-1,2,4-triazoles with various alkylating agents are established. Several compounds possessing pronounced antitumor activity have been found in experiments using two xenograft tumor models.     

Synthesis and antitumor activity of some benzofuryl-substituted 1,2,4-triazoles

A series of 3-benzofuryl-4-phenyl(allyl)-5-mercapto-1,2,4-triazoles have been synthesized by cyclization of the corresponding substituted thiosemicarbazides of benzofuran-2-carboxylic acid. S-alkylation of 5-mercaptotriazoles with various alkyl-, alkenyl-, and benzyl-substituted benzyl chlorides; chloroacetamides; and chloroacetic-, 2-bromopropionic-, and 2-bromocaproic acids has been studied. The antitumor activity of the synthesized compounds was tested.     

新双(β-二酮)钛配合物的合成

鉴于双 (β-二酮 )络钛配体中的平面芳香环是该类配合物抗肿瘤的重要活性基团 ,设计合成了 3个β-二酮钛配合物 :二乙氧基双〔1- ( 4 -吡啶基 ) - 3- ( 2 -噻吩基 ) - 1,3-丙二酮〕络钛 ( - A)、二乙氧基双〔1- ( 3-吡啶基 ) - 3-( 2 -噻吩基 ) - 1,3-丙二酮〕络钛 ( - B)、二乙氧基双〔1- ( 2 -呋喃基 ) - 3- ( 2 -噻吩基 ) - 1,3-丙二酮〕络钛 ( - C)。     

Synthesis and anticonvulsive activity of some new bisubstituted 1,3,4-oxadiazoles and 1H-1,2,4-triazoles

The synthesis of 7 new 2-[(2-alkoxy-3-methoxyphenyl) methyl]-5-arylamino-1,3,4 oxadiazoles by cyclisation of the corresponding thiosemicarbazides is described. Some of these were tested for anticonvulsant activity. The compound 2-[(2-butoxy-3-methoxy phenyl) methyl]-5-phenylamino 1,3,4-oxadiazole has shown significant anticonvulsant potency. A few new 3-phenyl-5-[(2-alkoxy-3-methoxy phenyl) methyl]-1H-1,2,4 triazoles have also been synthesized.     

Synthesis,in vitro cytotoxicity,and anti-microbial studies of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butanes

Synthesis and evaluation of cytotoxicity and anti-microbial activity of a series of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butane derivatives comprising thioether functionality and other pharmacophore modifications are described. All the newly synthesized compounds were characterized by IR, NMR, elemental analyses, and mass spectral studies. The compounds 4a–f, 5a–f, and 6a–f were evaluated for in vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29, and Breast Cancer MDA MB-231. All the compounds were subjected to in vitro anti-bacterial activity against Bacillus subtilus (ATCC 6633), Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922), and Pseudomonas aeruginosa (ATCC-27853) and their minimal inhibitory concentrations were determined.     

Synthesis and pharmacological activities of some new 3-substituted-4-amino-5-mercapto-1,2,4-triazoles

In this study, various 3-β-[(N-benzenesulphonyl/tosyl)-4-(un) substituted anilino]ethyl-4-amino-5-mercapto-4(H)-1,2,4-triazoles (5a-f), with biologically active 'sulphonamide' moiety as the side chain have been prepared. The structures of the newly synthesised compounds have been established on the basis of their spectral data and elemental analysis. All the compounds were evaluated for antimicrobial activities against Escherichia coli, Bacillus cirroflagellosus, Aspergillus niger and Colletotrichum capsici. Most of the compounds investigated exhibited significant antifungal activity against Colletotrichum capsici, even greater than fluconazole, the standard used. Only two compounds 3f (59%) and 5e (67%), have shown moderate antituberculosis activity. All the triazoles exhibited moderate degree of antiinflammatory activity and least ulcerogenecity. Most of the compounds have shown significant analgesic activity (81.02-120.72%) in comparison with aspirin (49.39%). In the MES method, only compound 3e exhibited a protection of 66.66%, whereas others exhibited minimum protection of (33.33%).     

Synthesis,antibacterial, antifungal and genotoxic activity of bis-1,3,4-oxadiazole derivatives

In the present investigation, four 1,3,4-bis-oxadiazole derivatives were synthesized as potential antimicrobial agents. The compounds are: 5,5'-dimercapto-bis-[1,3,4-oxadiazol-2-yl]propane (2a), 5,5'-dimercapto-bis-[1,3,4-oxadiazol-2-yl]butane (2b), 5,5'-dimercapto-bis-[1,3,4-oxadiazol-2-yl]octane (2c) and 5,5'-dibenzylthio-bis-[1,3,4-oxadiazol-2-yl]butane (3). The above newly synthesized compounds were investigated for their antibacterial, antifungal and mutagenic activities. The results of the biological activities revealed that the compounds 2a-c exhibited both antibacterial and antifungal activities against S. aureuss and B. subtilis. Compound 2a also showed activity against P. aeureoginosa. All the above compounds and compound 3 exhibited activity against C. albicans. Genotoxic studies showed that compound 2a had a weak base pair substitution mutagenicity but none of them exhibited a frameshift mutagenic action using Ames test.