Synthesis, crystal structure and biological evaluation of some novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines.

Nitrogen-containing heterocycles are of particular interest and significant importance for the discovery of potent bioactive agents in pharmaceutical industry. The present study reports the synthesis of a library of new conjugated heterocycles including 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (4a-g and 5a-e) and 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazines (6a-h), by cyclocondensation reaction of 4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol 3 with various substituted aromatic acids and phenacyl bromides, respectively. The structures of newly synthesized compounds were characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy and in case of 4c by X-ray crystallographic analysis. Newly synthesized triazolothiadiazoles and thiadiazines were screened for acetyl- and butyryl-cholinesterases and alkaline phosphatase inhibition. Almost all of the compounds showed good to excellent activities against acetylcholinesterase more than the reference drugs. Compound 5d exhibited IC50 value 0.77 ± 0.08 µM against acetylcholinesterase and 4a showed IC50 9.57 ± 1.42 µM against butyrylcholinesterase. Among all the tested compounds, 4a also proved as excellent inhibitor of alkaline phosphatase with IC50 0.92 ± 0.03 µM. These heteroaromatic hybrid structures were also tested for their anticancer activity against lung carcinoma (H157) and kidney fibroblast (BHK-21) cell lines and leishmanias. Variable cell growth inhibitory activities were obtained and many compounds exhibit potent %inhibition.

Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives.

New series of 4,5-disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (8a-j) and 2,5-disubstituted-1,3,4-thiadiazoles (9a-h) were synthesized by dehydrative cyclization of hydrazinecarbothioamide derivatives (7a-k) by refluxing in 4N aqueous sodium hydroxide and by overnight stirring with polyphosphoric acid, respectively. The structures of the newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectroscopic studies and the synthesized compounds were screened for their antioxidant and urease inhibition activities. N-(2,4-Dimethylphenyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (9h) showed excellent antioxidant activity more than the standard drug whereas 4-(2,4-dimethylphenyl)-5-(3-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (8d) and 4-(2,3-dimethylphenyl)-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (8e) exhibited potent urease inhibitory activities.

Identification of novel urease inhibitors by high-throughput virtual and in vitro screening.

Ureases are important in both agriculture and human health. Bacterial ureases are directly involved in many farm-field problems and pathological conditions. Here, we report a structure-based virtual screening of an in-house compound bank of about 6000 molecular entities by computational docking and binding free energy calculations followed by in vitro screening. Applied protocol leads to the identification of novel urease inhibitors, which can serve as starting points for structural optimization.

2-(2-Fluoro-biphenyl-4-yl)-N'-(propan-2-yl-idene)propanohydrazide.

In the title compound, C(18)H(19)FN(2)O, the hydrazide side chain is approximately perpendicular to the central ring [dihedral angle = 76.80 (5)°]. The F atom is disordered over two positions with occupancies of 0.818 (2) and 0.182 (2). The packing consists of chains of mol-ecules parallel to the a axis, connected by a bifurcated N-H⋯(O,N) hydrogen bond and a weak C(phen-yl)-H⋯O hydrogen bond. The packing is extended to a layer structure parallel to the ab plane by a weak C(phen-yl)-H⋯F hydrogen bond.

3-(3-Bromo-benz-yl)-1H-isochromen-1-one.

In the title compound, C(16)H(11)BrO(2), the isocoumarin ring system is planar (r.m.s. deviation = 0.015 Å) and subtends a dihedral angle of 88.90 (2)° with the bromo-benzene ring. In the crystal, mol-ecules are linked, forming a three-dimensional packing pattern involving C-H⋯O inter-actions, Br⋯O contacts [3.4734 (10) Å] and π-π stacking inter-actions with centroid-centroid distances ranging from 3.667 (2) to 3.765 (2) Å.

3-(3-Bromo-benz-yl)isoquinolin-1(2H)-one.

In the title compound, C(16)H(12)BrNO, the ring systems subtend an inter-planar dihedral angle of 75.95 (3)°. In the crystal packing, mol-ecules are linked to form centrosymmetric pairs by pairs of classical N-H⋯O hydrogen bonds.

5-(2-Methoxy-benz-yl)-4-(2-methoxy-phen-yl)-4H-1,2,4-triazol-3-ol.

In the mol-ecule of the title compound, C(17)H(17)N(3)O(3), the triazole ring is oriented at dihedral angles of 88.09 (3) and 83.72 (3)° with respect to the 2-methoxy-benzyl and 2-methoxy-phenyl rings, respectively. The dihedral angle between the 2-methoxy-benzyl and 2-methoxy-phenyl rings is 52.95 (3)°. In the crystal structure, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers. There is a π-π contact between the 2-methoxy-phenyl rings [centroid-centroid distance = 3.811 (3) Å].

4-(3-Methoxy-phen-yl)-3-[2-(4-methoxy-phen-yl)eth-yl]-1H-1,2,4-triazol-5(4H)-one.

The asymmetric unit of the title compound, C(18)H(19)N(3)O(3), contains two crystallographically independent but similar mol-ecules. The triazole ring is oriented with respect to the benzene rings to form dihedral angles of 57.96 (6) and 7.01 (6)° in one mol-ecule, and 64.37 (5) and 10.73 (5)° in the other. The two independent mol-ecules are linked into a dimer by inter-molecular N-H⋯O hydrogen bonds.

3-(3-Fluoro-benz-yl)isochroman-1-one.

In the mol-ecule of the title compound, C(16)H(13)FO(2), the aromatic rings are oriented at a dihedral angle of 74.46 (4)°. The heterocyclic ring adopts a twisted conformation. In the crystal structure, there is a weak C-H⋯π inter-action.

4-(4-Methoxy-phen-yl)-3-[2-(2-methoxy-phen-yl)eth-yl]-1H-1,2,4-triazol-5(4H)-one.

The title compound, C(18)H(19)N(3)O(3), is a biologically active triazole derivative. The five-membered ring is oriented with respect to the six-membered rings at dihedral angles of 51.59 (4) and 61.37 (4)°. The crystal structure is stabilized by inter-molecular N-H⋯O hydrogen-bond inter-actions between centrosymmetrically related mol-ecules [the dihedral angle between the benzene rings is 47.44 (5)°].

3-Benzyl-isochroman-1-one.

In the mol-ecule of the title compound, C(16)H(14)O(2), the aromatic rings are oriented at a dihedral angle of 78.49 (3)°. The heterocyclic ring adopts a twist conformation. In the crystal structure, inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into chains along the c axis.

3-(4-Fluoro-benz-yl)-1H-isochromene-1-thione.

In the mol-ecule of the title compound, C(16)H(11)FOS, the benzene ring is oriented at a dihedral angle of 89.68 (3)° with respect to the planar [maximum deviation 0.009 (2) Å] isocoumarin ring system. An intra-molecular C-H⋯S inter-action results in the formation of a planar five-membered ring. In the crystal structure, inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into chains parallel to the c axis. A π-π contact between the isocoumarin rings [centroid-centroid distance = 3.818 (3) Å] may further stabilize the structure.

(E)-3-(3,5-Dimethoxy-phen-yl)acrylo-hydrazide.

In the title compound, C(11)H(14)N(2)O(3), the planar hydrazide group is oriented with respect to the benzene ring at a dihedral angle of 48.00 (3)°. In the crystal structure, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules.

Methyl 2,5-dichloro-benzoate.

In the mol-ecule of the title compound, C(8)H(6)Cl(2)O(2), the benzene ring is oriented with respect to the planar ester group at a dihedral angle of 39.22 (3)°.

3-(3-Chloro-benz-yl)-1H-isochromen-1-one.

The asymmetric unit of the title compound, C(16)H(11)ClO(2), a chemically synthesized isocoumarin, contains three independent mol-ecules. The benzopyran and benzene rings are approximately perpendicular to each other, forming dihedral angles ranging from 83.08 (14) to 87.43 (11)°. In the crystal structure, mol-ecules are linked by inter-molecular C-H⋯O hydrogen-bonding inter-actions, forming chains running parallel to the a axis.

5-(3-Methoxy-pheneth-yl)-4-(2-methoxy-phen-yl)-4H-1,2,4-triazol-3-ol.

In the mol-ecule of the title compound, C(18)H(19)N(3)O(3), the triazole ring is oriented with respect to the 3-methoxy-phenyl and 2-methoxy-phenyl rings at dihedral angles of 11.79 (3) and 89.22 (3)°, respectively. The dihedral angle between the two benzene rings is 85.95 (3)°. In the crystal structure, inter-molecular O-H⋯N and C-H⋯O hydrogen bonds link the mol-ecules. There is a π-π contact between the triazole and 3-methoxy-phenyl rings [centroid-centroid distance = 3.916 (3) Å]. There is a π-π contact between the triazole and one of the 3-methoxy-phenyl rings [centroid-centroid distance = 3.916 (3) Š]. C-H⋯π contacts are also found between the benzene ring and the methyl groups of their 3-methoxy-substituents.

2-[(4-Chloro-benz-yl)carbonyl-meth-yl]benzoic acid.

The title compound, C(16)H(13)ClO(3), is an important inter-mediate in the conversion of isocoumarin to 3,4-dihydro-isocoumarin. The two aromatic rings are oriented at a dihedral angle of 67.18 (3)°. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers. There is also a C-H⋯π contact between the benzoic acid and 4-chloro-benzyl rings.

3-(4-Ethoxy-benzo-yl)propionic acid.

The title compound, C(12)H(14)O(4), is an important inter-mediate in the synthesis of biologically active heterocyclic compounds. In the crystal structure, inter-molecular O-H⋯O and C-H⋯O hydrogen bonds link the mol-ecules. There are also C-H⋯π contacts between the benzene ring and the methyl-ene groups.

1-(3-Chloro-benz-yl)-5-iodo-indoline-2,3-dione.

In the title compound, C(15)H(9)ClINO(2), which possesses anticonvulsant activity, the iodo-indoline ring system is essentially planar (maximum deviation 1.245 Å) and is oriented with respect to the 3-chloro-benzyl ring at a dihedral angle of 76.59 (3)°. In the crystal, there is a π-π contact between iodo-indoline ring systems [centroid-centroid distance = 3.8188 (4) Å].

2-(2-Fluoro-benzoyl-meth-yl)benzoic acid.

In the title compound, C(15)H(11)FO(3), the aromatic rings are oriented at a dihedral angle of 69.26 (3)°. In the crystal structure, inversion dimers arise from pairs of inter-molecular O-H⋯O hydrogen bonds, and C-H⋯O hydrogen bonds further consolidate the packing. There are also C-H⋯π contacts between the benzoic acid and 2-fluoro-benzene rings.