Synthesis, Characterization and Biological Activities of New Symmetric Bis-1,2,3-Triazoles with Click Chemistry.

BACKGROUND: 1,2,3-Triazole and its derivatives have important biological activities such as antimicrobial, anti-allergic, analgesic, anti-HIV, antiinflammatory, anticancer, antimalarial and antituberculosis. Other significant triazole derivatives are 1,2,4-triazoles which play a very important role in the medicinal chemistry due to the antiinflammatory, antimicrobial, antimigraine, anticancer, antimicrobial and antimycotic activities. In this study, we aimed to synthesize a new series of bis-1,2,3-triazole derivatives including 1,2,4-triazole to obtain more effective biological activities. METHODS: In this study, a new series of bis-1,2,3-triazole compounds (9,10,11) were synthesized. Antimicrobial Activity: Disc diffusion method was used. Enzyme Inhibition: α-Glucosidase Inhibition was investigated. Antioxidant Activities: DPPH Radical Scavenging, Phosphomolybdenum- Reducing Antioxidant Power (PRAP) and Ferrous Ion-Chelating methods were used. RESULTS: Compounds 9a, 9c, 9e, 9f, 10a, 10b, 10d, 11a, 11b and 11f showed significant antibacterial and antifungal activity against all the strains tested. Compound 9g exhibited the highest AChE inhibition. Compounds 10f, 11a and 11g showed remarkable activity against the BuChE enzyme. Compound 10f has the highest antioxidant activities. CONCLUSION: The compounds 9a, 9c, 9e, 9f, 10a, 10b, 10d, 11a, 11b and 11f exhibit the best antimicrobial activity against the bacteria and fungi C.albicans, Y. enterocolitica, E. coli, Candida albicans, Yersinia enterocolitica. Compound 9g exhibit the highest AChE inhibition with 72.67 ± 3.92% at 100 µg/mL. Compounds 10f, 11a and 11g showed remarkable activity against the BuChE enzyme compared to galantamine. Many of the compounds exhibited significant α-glucosidase inhibition activities. Compound 10f has the highest antioxidant activities (DPPH, PRAP, ferrous ionchelating) with 27.71 ± 0.85%, 0.689 ± 0.005, 42.07 ± 2.48 at 100 µg/mL, respectively.

Synthesis of new 1,2,4-triazole compounds containing Schiff and Mannich bases (morpholine) with antioxidant and antimicrobial activities.

Compound 2 was synthesized by reacting CS2/KOH with compound 1. The treatment of compound 2 with hydrazine hydrate produced compound 3. Then, compound 3 was converted to Schiff bases (4a-d) by the handling with several aromatic aldehydes. The treatment of triazole compounds 4a-d containing Schiff base with morpholine gave compounds 5a-d. All compounds were tested for their antioxidant and antimicrobial activities. The antioxidant test results of DPPH• radical scavenging and ferric reducing/antioxidant power methods showed good antioxidant activity. The triazole-thiol (3) was the most active, and the effect of the substituent type of the thiophene ring on the activity was same for both Schiff bases (4a-d) and Mannich bases (5a-d). Among the newly synthesized triazole derivatives, the Schiff base 4d and the Mannich base 5d carrying nitro substituent on the thiophene ring showed promising antibacterial and antifungal activity, with lower MIC values than the standard antibacterial ampicillin.

Synthesis of Novel Symmetrical 1,4-Disubstituted 1,2,3-Bistriazole Derivatives via 'Click Chemistry' and Their Biological Evaluation.

A series of symmetric bis-1,2,3-triazole compounds 2-5(a-f) were synthesized as potential antioxidant agents via click chemistry. Their structures were confirmed by ¹H-NMR and (13)C-NMR. All of the synthesized compounds were subjected to antioxidant and antimicrobial assays. The antioxidant activity of these compounds (AChE inhibition, DPPH and SOD activities) was evaluated. Compound 2f was found to show the highest AChE inhibition activity of all compounds, while compound 3b showed a strong inhibitory effect on DPPH radical and compound 2a was the most effective of all compounds for SOD activity. All synthesized compounds were found to possess moderate antibacterial activity against the bacteria E. coli and Y.pseudotuberculosis.

New thiophene-1,2,4-triazole-5(3)-ones: highly bioactive thiosemicarbazides, structures of Schiff bases and triazole-thiols.

Key compound 2-(4-amino-5-oxo-3-(thiophene-2-ylmethyl)-4,5-dihydro-1,2,4-tiazole-1-yl) acetohydrazide (3) was synthesized by reacting hydrazine hydrate with ethyl-2-(4-amino-5-oxo-3-(thiophene-2-ylmethyl)-4,5-dihydro-1,2,4-tiazole-1yl)acetate (2), obtained in basic media from 4-amino-5-(thiophene-2-ylmethyl)-2H-1,2,4-triazole-3(4H)-one (1). Compound 3 was converted to thiosemicarbazide derivatives (4a-d) and Schiff base derivatives 6a-e and 7a-e. The treatment of compound 4 with NaOH gave 4-amino-2-((4-(4-aryl)-5-mercapto-4H-1,2,4-triazole-3-yl)methyl)-5-(thiophene-2-ylmethyl)-2H-1,2,4-triazole-3(4H)-ones (5a-d). All newly compounds, well characterized by elemental analyses, IR, (1)H NMR, (13)C NMR and mass spectral studies were tested for their antioxidant and antimicrobial activities. Thiosemicarbazide derivatives (4a-d) were highly active in two antioxidant tests with 69.0-88.2% DPPH· scavenging and 503-1257 µM TEAC values, while the others showed lower or no activity. The results of the two antioxidant tests correlated well. Moreover, Thiosemicarbazide derivatives (4a-d) also showed antibacterial activity against Staphylococcus aureus, Bacillus cereus, and Mycobacterium smegmatis. Thiosemicarbazide group deserves attention in the synthesis of bioactive compounds.

Synthesis and biological properties of novel triazole-thiol and thiadiazole derivatives of the 1,2,4-Triazole-3(5)-one class.

2,2'-(4,4'(Butane-1,4-diyl/hexane-1,6-diyl)bis(3-methyl-5-oxo-4,5-dihydro-1,2,4- triazole-4,1-diyl)) diacetohydrazides 3a,b were obtained via the formation of diethyl 2,2'-(4,4'(butane-1,4-diyl/hexane-1,6-diyl)bis(3-methyl-5-oxo-4,5-dihydro-1,2,4-triazole-4,1- diyl))diacetates 2a,b, obtained starting from di-[3(methyl-2-yl-methyl)-4,5-dihydro-1H-[1,2,4]-triazole-5-one-4yl]-n-alkanes 1a,b in two steps. The synthesis of the compounds 7a,b-9a,b incorporating the 1,3,4-thiadiazole, and 10a,b-11a,b with a 1,2,4-triazole-thiol nucleus as the second heterocycle, was performed by the acidic or basic treatment of compounds 4a,b-6a,b which were obtained from the reaction of 3a,b with several isothiocyanates. Newly synthesized compounds were screened for antimicrobial activities and their antioxidant properties by the 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging method. Compounds 4a,b, 5a,b, and 6a,b were found to possess good antioxidant properties. Almost all compounds have significant antimicrobial activities.

Synthesis, structural characterization and comparison of experimental and theoretical results by DFT level of molecular structure of 4-(4-methoxyphenethyl)-3,5-dimethyl-4H-1,2,4-triazole.

4-(4-Methoxyphenethyl)-3,5-dimethyl-4H-1,2,4-triazole (3) was synthesized from the reaction of ethyl N'-acetylacetohydrazonate (1) with 2-(4-methoxyphenyl)ethanamine (2). The structure of the title compound 3 has been inferred through IR, (1)H/(13)C NMR, mass spectrometry, elemental analyses and combination of X-ray crystallography and theoretical methods. In addition to the molecular geometry from X-ray determination, the molecular geometry and vibrational frequencies of the title compound 3 in the ground state, were calculated using the density functional method (B3LYP) with the 6-31G(d) basis set. The calculated results show that the optimized geometry can well reproduce the crystal structure and the theoretical vibrational frequencies show good agreement with experimental values. The nonlinear optical properties are also addressed theoretically. The predicted nonlinear optical properties of 3 are greater than ones of urea. In addition, DFT calculations of molecular electrostatic potentials and frontier molecular orbitals of the title compound were carried out at the B3LYP/6-31G(d) level of theory.

Experimental and DFT computational studies on 5-benzyl-4-(3,4-dimethoxyphenethyl)-2H-1,2,4-triazol-3(4H)-one.

The triazole compound, 5-benzyl-4-(3,4-dimethoxyphenethyl)-2H-1,2,4-triazol-3(4H)-one, has been synthesized and characterized by (1)H-NMR, (13)C-NMR, IR, and X-ray single-crystal determination. The compound crystallizes in the monoclinic space group P2(1) with a = 11.8844(3) A, b = 17.5087(4) A, c = 17.3648(6) A, beta = 99.990(2) and Z = 8. In addition to the molecular geometry from X-ray experiment, the molecular geometry, vibrational frequencies and gauge including atomic orbital (GIAO) (1)H- and (13)C-NMR chemical shift values of the title compound in the ground state have been calculated using the density functional method (B3LYP) with 6-31G(d,p) basis set. The calculated results show that the optimized geometries can well reproduce the crystal structure and the theoretical vibrational frequencies and chemical shift values show good agreement with experimental ones. Besides, molecular electrostatic potential (MEP), natural bond orbital (NBO), and frontier molecular orbitals (FMO) analysis of the title compound were performed by the B3LYP/6-31G(d,p) method.

2-Benzoylmethyl-4-[(2-benzylidene-ethylidene)amino]-5-(2-thienylmethyl)-2H-1,2,4-triazol-3(4H)-one.

In the mol-ecule of the title compound, C(24)H(20)N(4)O(2)S, the dihedral angle between the triazole and thio-phene rings is 66.80 (4)° and the dihedral angle between the two benzene rings is 63.37 (4)°. An intra-molecular C-H⋯O inter-action results in the formation of a six-membered ring. A π⋯π contact between the benzene rings, [centroid-centroid distance = 3.918 (2) Å] may stabilize the structure. Weak C-H⋯π inter-actions are also present. The S, C and H atoms of the thiophene ring are disordered over two positions and were refined with occupancies of 0.654 (3) and 0.346 (3).

Synthesis and characterization of some new tetraaldehyde and tetraketone derivatives and X-ray structure of 1,1'-(4,4'-(2-(1,3-bis(4-acetylphenoxy)propan-2-ylidene)propane-1,3-di-yl)bis(oxy)bis(4,1-phenylene))diethanone.

Tetraketone and tetraaldehyde derivatives 2a-d were synthesized via the reaction of ethene-1,1,2,2,-tetra-yl-tetramethylene tetrabromide (1) with hydroxyketone and aldehyde derivatives. The molecular structures were identified by IR, (1)H-NMR, (13)C-NMR and MS analysis. The crystal structure of the title compound 2a, C(38)H(36)O(8), is reported. Its crystal data are: monoclinic, space group P 2(1)/n with cell dimensions of a=9.0395(12) A, b=12.6114(17) A, c=13.8166(18) A, beta=95.875(3), V=1566.8(4) A(3), F.W.=620.67, rho(calc)=1.316 gcm(3) for Z=2, mu=0.092 mm(-1).

4,4'-Butane-1,4-diylbis[3-ethyl-1H-1,2,4-triazol-5(4H)-one] and 4-hydroxy-3-n-propyl-1H-1,2,4-triazol-5(4H)-one.

The title compounds, C12H20N6O2, (I), and C5H9N3O2, (II), display the characteristic features of 1,2,4-triazole derivatives. Compound (I) lies about an inversion centre which is at the mid-point of the central C-C bond. Compound (II) also contains a planar 1,2,4-triazole ring but differs from (I) in that it has a hydroxy group attached to the ring. Molecules of (I) are held together in the crystal structure by intermolecular N-H...O contacts and by weak pi-pi stacking interactions between the 1,2,4-triazole moieties. Compound (II) contains intermolecular O-H...O and N-H...O hydrogen bonds.

Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo- [1,2,4]triazole derivatives.

Acetic acid ethyl esters containing 5-oxo-[1,2,4]triazole ring (2) were synthesized by the condensation of compounds 1a-f with ethyl bromoacetate in basic media. The reaction of compounds 2a-f with hydrazine hydrate led to the formation of acid hydrazides (3a-f). The treatment of compounds 3 with two divers aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (4a,c,e,f, 5a,e,f). The thiosemicarbazide derivatives (6a,c,d,f) were afforded by the reaction of corresponding compounds 3 with phenylisothiocyanate. The treatment of compounds 6a,c,d,f with sulfuric acidic caused the conversion of side-chain of compounds 6a,c,d,f into 1,3,4-thiadiazol ring; thus, compounds 7a,c,d,f were obtained. On the other hand, the cyclization of compounds 6a,c,d,f in the presence of 2 N NaOH resulted in the formation of compounds 8a,c,d,f containing two [1,2,4]triazole rings which are linked to each other via a methylene bridge. Compounds 4a, f, 5a, 7a, d, f, 8a and d have shown antimicrobial activity against one or more microorganism, but no antifungal activity has been observed against yeast like fungi. Also inhibitory effect on mycelial growth by compounds 4e, 7d and 8f has been observed. Compounds 4c and 5f were found to possess antitumor active towards breast cancer.