Seco C-nucleoside analogs of the 1,2,4-triazole

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D-galacto-pentitol-1-yl)-1H-1,2,4-triazoles (6 and 7) were obtained in one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. The structures were confirmed by using 1H, 13C and 2D NMR spectra, DQFCOSY, HMQC and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.     

SECO C-NUCLEOSIDE ANALOGS OF THE 1,2,4-TRIAZOLE

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D-galacto-pentitol-1-yl)-1H-1,2,4-triazoles (6 and 7) were obtained in one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. The structures were confirmed by using ¹H, ¹³C and 2D NMR spectra, DQFCOSY, HMQC and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.     

A Novel Approach for the Synthesis of seco C-Nucleoside Analogues

Abstract

The synthesis of 4-amino-3-(D-gluco- or D-galacto-pentitol-1.yl)-5-mercapto-1,2,4-triazoles and their conversion to the respective 6-methyl-3-(1,2,3,4,5-penta-O-acetyl-pentitol-1-yl)1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles have been achieved. The vicinal coupling constants were used to deduce the favored conformations.     

Microwave-assisted organic synthesis of 3-(D-Gluco-pentitol-1-yl)-1H-1,2,4-triazole

The condensation of D-glucono- and D-galactono-1,5-lactone and thiocarbohydrazide to give 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 is accelerated by the use of microwave-assisted organic reaction (MAOS). The deamination and dethiolation of compound 4 to give 6 was also accelerated by the use of MAOS. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 8 and 9, respectively, within 4 min under microwave irradiation (MWI), whereas with ethyl chloroacetate the thioalkylated products 14 and 15 were obtained in 8 min. The structures of the synthesized compounds were confirmed by 1H NMR, 2D NMR, and mass spectra.     

NOVEL SYNTHESIS OF seco TYPE OF ACYCLO C-NUCLEOSIDES OF 1,2,4-TRIAZOLE AND 1,2,4-TRIAZOLO[3,4-b][1,3,4]THIADIAZINE

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D- galacto-pentitol-1-yl)-1H-1,2,4-triazoles (8 and 9) were obtained in a one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. Condensation of 1, 2, and 4-amino-3-(D-glycero-D-gulo-hexitol-1-yl)-5-mercapto-1,2,4-triazole (12) with phenacylbromide (11) afforded the corresponding 3-(D-gluco-, D-galacto-pentitol-1-yl) and 3-(D-glycero-D-gulo-hexitol-1-yl)-6-phenyl-7H-1,2,4- triazolo[3,4-b][1,3,4] thiadiazines (15, 16, and 17). Acetylation of 15–17 gave the penta- and hexa-O-acetyl derivatives 18–20, respectively. The structures were confirmed by using ¹H, ¹³C, and 2D NMR spectra, DQFCOSY, HMQC, and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.     

Microwave irradiation for accelerating the synthesis of acyclonucleosides of 1,2,4-triazole

The 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 can be successfully prepared using microwave irradiation. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 6 and 7, respectively. Reaction 4 and 5 with ethylchloroacetate gave the corresponding alkylated products 10 and 11. Better yields and much less time were the characteristic features of using the microwave heating over the conventional one. The structure of the prepared compounds was confirmed by 1H-NMR, 2D-NMR and mass spectra.     

Synthesis of some new [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles starting from 5-nitro-2-furoic acid and evaluation of their antimicrobial activity

New series of fused 1,2,4-triazoles such as, 6-(aryl)-3-(5-nitrofuran-2-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 4-8, 6-(alkyl/aryl amino)-3-(5-nitrofuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 9-13 and 6-(4-substituted phenyl)-3-(5-nitrofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 14-18 have been synthesized via the reaction of 4-amino-5-(5-nitrofuran-2-yl)-4H-1,2,4-triazole-3-thiol 3 with various reagents such as hetero aromatic aldehydes, alkyl/aryl isothiocyanates and 4-substituted phenacyl bromides, respectively. The structures of the newly synthesized compounds have been confirmed on the basis of elemental analysis and spectral studies. The newly synthesized triazolo derivatives have been investigated for their in vitro antibacterial activity. Most of the tested compounds showed interesting antibacterial activity against Staphylococcus aureus. Furthermore, the most potent antibacterial compounds 11-13 were evaluated for their in vitro cytotoxic activity against human cancer cell lines. It was found that compounds 11 and 13 showed higher cytotoxicity against Hep-G2 cell line as compared to standard.     

MICROWAVE IRRADIATION FOR ACCELERATING THE SYNTHESIS OF ACYCLONUCLEOSIDES OF 1,2,4-TRIAZOLE

The 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 can be successfully prepared using microwave irradiation. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 6 and 7, respectively. Reaction 4 and 5 with ethylchloroacetate gave the corresponding alkylated products 10 and 11. Better yields and much less time were the characteristic features of using the microwave heating over the conventional one. The structure of the prepared compounds was confirmed by ¹H-NMR, 2D-NMR and mass spectra.     

Synthesis of Triazole Schiff’s Base Derivatives and Their Inhibitory Kinetics on Tyrosinase Activity

In the present study, new Schiff’s base derivatives: (Z)-4-amino-5-(2-(3- fluorobenzylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (Y₁), (Z)-3-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y₂), (Z)-2-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y₃) and 3-((Z)-(2-(4- (((E)-3-hydroxybenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y₄) were synthesized and their structures were characterized by LC-MS, IR and ¹H NMR. The inhibitory effects of these compounds on tyrosinase activites were evaluated. Compounds Y₁, Y₂ and Y₃ showed potent inhibitory effects with respective IC₅₀ value of 12.5, 7.0 and 1.5 μM on the diphenolase activities. Moreover, the inhibition mechanisms were determined to be reversible and mixed types. Interactions of the compounds with tyrosinase were further analyzed by fluorescence quenching, copper interaction, and molecular simulation assays. The results together with the anti-tyrosinase activities data indicated that substitution on the second position of benzene ring showed superior ant-ityrosinase activities than that on third position, and that hydroxyl substitutes were better than fluorine substitutes. In addition, two benzene rings connecting to the triazole ring would produce larger steric hindrance, and affect the bonding between tyrosinase and inhibitors to decrease the inhibitory effects. The anti-tyrosinase effects of these compounds were in contrast to their antioxidant activities. In summary, this research will contribute to the development and design of antityrosinase agents.     

Double-headed acyclo C-nucleoside analogues. Functionalized 1,2-bis-(1,2,4-triazol-3-yl)ethane-1,2-diol

Reaction of L-tartaric acid with thiocarbohydcrazide afforded (1R, 2S)-1,2-bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)-ethane-1,2-diol (3). The functional groups in 3 allowed the construction of fused heterocycles on the 1,2,4-triazole rings, mainly of the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine type as in 4, 5, 7, 10, 13 and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole type as in 14.     

Synthesis,antibacterial and antifungal activities of 3-(1,2,4-triazol-3-yl)-4-thiazolidinones

A new series of 3-(1,2,4-triazol-3-yl)-4-thiazolidinone derivatives has been synthesized by the reaction of Schiff bases of 3-amino-1,2,4-triazoles with mercaptoacetic acid and 2-mercaptopropionic acid. Their antibacterial and antifungal activities were evaluated against S. aureus, S. epidermidis, C. albicans and C. glabrata     

Synthesis and Fungicidal Activity of 5-Aryl-1-(aryloxyacetyl)-3-(tert-butyl or phenyl)-4-(1H-1,2,4-triazol-1-yl)-4,5-Dihydropyrazole

A series of novel 5-aryl-1-(aryloxyacetyl)-3-(tert-butyl or phenyl)-4-(1H-1,2,4-triazol-1-yl)-4,5-dihydropyrazole 3a-3n were synthesized by the annulation of 2-aryloxyacetohydrazides with 3-aryl-1-t-butyl(or phenyl)-2-(1H-1,2,4-triazol-1-yl)prop-2-en-1-ones(1)in the presence of a catalytic amount of acetic acid.Compounds 2 were obtained by the Knoevenagel reactions of 1-t-butyl(or phenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone(2)with aromatic aldehydes in the presence of piperidine.Their structures were confirmed by IR,1H-NMR,ESIMS,and elemental analyses.The preliminary bioassay indicated that some compounds displayed moderate to excellent fungicidal activity.For example,compounds 31,3m,and 3n possessed100%inhibition against Cercospora arachidicola Hori at the concentration of 50 mg/L.     

3,4-Disubstituted-5-mercapto-1,2,4-triazoles and Related Compounds

3,4-Diaryl-5-mercapto-1,2,4-triazoles have been prepared by the cyclization of the corresponding 1-aroyl-4-Substituted thiosemicarbazide with alkali. The resulting mercapto triazoles were converted into 3,4-disubstituted-5-alkylthio-1,2,4-triazoles with the action of different alkyl halides and some of the sulphides were converted into sulphones by oxidation with aqueous potassium permanganate.     

1,2,4-Triazolo mercapto and aminonitriles as potent antifungal agents

A series of 3-mercapto-1,2,4-triazoles mono or disubstituted at 2-, 3- or 4-positions were synthesized and evaluated as antifungal agents. Many of these derivatives exhibit high activity against Candida albicans and Candida tropicalis.     

Synthesis of 3-alkyl(aryl)-4-alkylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-ones and 3-alkyl-4-alkylamino-4,5-dihydro-1H-1,2,4-triazol-5-ones as antitumor agents

A series of 3-alkyl-4-phenylethylidenamino- (8) and 3-alkyl-4-(3-phenylallylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (9) was synthesized from the reaction of the corresponding 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (1), with phenylacetaldehyde and cinnamaldehyde. 3-Alkyl-4-(2-phenylethylamino)- (10) and 3-alkyl-4-(3-phenylpropylamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (11) were obtained from the selective reduction of compounds (8) and (9) with NaBH₄. The in vitro antitumor activity of the novel compounds was screened and the highest inhibition of tree tumor cell lines was observed for the compounds containing phenylethylenamino and phenylethylamino groups at position 4 of 1,2,4-triazol ring.     

Inhibition of some hepatic glycosidases by the diseco nucleoside, 4-amino-3-(D-glucopentitol-1-yl)-5-mercapto-1,2,4-triazole and its 3-methyl analog

The in vivo and in vitro effects of 4-amino-3-(D-glucopentitol-1-yl)-5-mercapto-1,2,4-triazole and its 3-methyl analogue on alpha- and beta-glucosidases, beta-glucuronidase as well as alpha-amylase have been investigated. alpha-Glucosidase is the enzyme that is markedly affected in vivo and in vitro in a dose-dependent manner. The compounds showed a reversible inhibition of a competitive type for alpha-glucosidase. Moreover, they exert a relatively potent inhibition on alpha-glucosidase with a Ki magnitude of 3.6 x 10(-4), 9.5 x 10(-5) M.     

Synthesis and biological evaluation of (4H-1,2,4-triazol-4-yl)isoquinoline derivatives as selective glycine transporter 1 inhibitors

To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.     

Synthesis and antituberculosis activity of new 3-alkylsulfanyl-1,2,4-triazole derivatives

The increasing clinical importance of drug-resistant mycobacterial pathogens has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new alkylsulfanyltriazoles were synthesized and evaluated for antituberculosis activity. The reaction of thienyl-2-acetic acid with thiocarbohydrazide gave the mercaptotriazoles (II). The 4-amino-5-(2-thienylmethyl)-3-[1-(2-thienyl)-3-aryl) propion-3-yl] sulfanyl-4H-1,2,4-triazole (III) derivatives were synthesized by reacting the mercaptotriazoles with chalcones (I). Antituberculosis activities of the synthesized compounds were determined by broth microdilution assay, the Microplate Alamar Blue Assay, in BACTEC 12B medium and results were screened in-vitro, using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 microg/ml and the tested compounds showed considerable inhibition ranging from 58-84%.     

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.     

New Zn complexes based on 1,2,4-triazoles: Synthesis, structure and luminescence

The reaction of 3-(pyridin-2-yl)-5-(2-aminophenyl)-1H-1,2,4-triazole and salicylaldehyde or benzaldehyde leads a new type of 1,2,4-triazole’s derivats. Reactions of these ligands with zinc acetate in ethanol lead to the formation of two new complexes with azomethine or dihydrotriazaindolizine form of ligands. The structures of these complexes were investigated by X-ray analysis. The complexes showed strong green-blue luminescence in solid state.