Synthesis, biological evaluation and 3D-QSAR studies of 1,2,4-triazole-5-substituted carboxylic acid bioisosteres as uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia associated with gout.

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC50 = 0.032 µM for 1g against human URAT1 vs 7.20 µM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher's randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.

5-(4-Ethoxy-benzyl)-1H-tetra-zole.

In the title mol-ecule, C(10)H(12)N(4)O, the tetra-zole and benzene rings form a dihedral angle of 67.52 (2)°. In the crystal, inter-molecular N-H⋯N hydrogen bonds link the mol-ecules into chains along the a axis. The relatively short distance of 3.760 (3) Šbetween the centroids of the tetra-zole rings suggests the existence of π-π inter-actions.

2-[(2,6-Dichloro-benz-yl)amino]-N-(4-methyl-thia-zol-2-yl)acetamide.

In the title compound, C(13)H(13)Cl(2)N(3)OS, the thia-zole and benzene rings are roughly parallel to one another in two layers [dihedral angle = 5.08 (2)°] because the N-C-C-N-C chain that links the two rings is folded [N-C-C-N torsion angle = 12.0 (2)°] rather than fully extended. An intra-molecular N-H⋯N inter-action occurs. In the crystal, weak inter-molecular N-H⋯N and C-H⋯O inter-actions are present and π-π inter-actions are indicated by the short distances [3.507 (3)-3.665 (2) Å] between the centroids of the thia-zole and benzene rings.

(3-Phenyl-isoxazol-5-yl)methanol.

In the title compound, C(10)H(9)NO(2), the isoxazole and phenyl rings form a dihedral angle of 25.82 (3)°. In the crystal, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into ribbons propagating along [001]. The crystal packing is further stabilized by weak C-H⋯O and C-H⋯N inter-actions.

1-(3-tert-Butyl-4-hy-droxy-phen-yl)ethanone.

The title compound, C(12)H(16)O(2), is approximately planar (r.m.s. deviation = 0.030 Å), apart from two methyl groups of the tert-butyl unit [deviations of the C atoms = 1.140 (2) and -1.367 (1) Å]. In the crystal, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into hexa-meric rings with R(6) (6)(48) graph-set motifs.

(5-Bromo-2-methyl-phen-yl)(4-eth-oxy-phen-yl)methanone.

In the title compound, C(16)H(15)BrO(2), the dihedral angle between the benzene rings is 68.5 (2)°. In the crystal structure, mol-ecules are linked by weak C-H⋯O hydrogen bonds into chains parallel to the b axis.

Ethyl 6-methyl-2-p-tolyl-pyrazolo[1,5-a]pyridine-5-carboxyl-ate.

In the title mol-ecule, C(18)H(18)N(2)O(2), the bicyclic ring system and the benzene ring form a dihedral angle of 13.45 (3)°. In the crystal structure, weak inter-molecular C-H⋯O hydrogen bonds link mol-ecules into chains propagated along [201].

Ethyl 6-methyl-sulfanyl-2-phenyl-1H-imidazo[1,2-b]pyrazole-7-carboxyl-ate monohydrate.

The title compound, C(15)H(15)N(3)O(2)S·H(2)O, has been obtained in a search for new imidazo[1,2-b]pyrazole derivatives with better biological activity. The 1H-imidazo[1,2-b]pyrazole plane forms a dihedral angle of 16.90 (3)° with the benzene ring. π-π inter-actions are indicated by the short distance of 3.643 (2) Šbetween the centroids of the benzene and imidazole rings. The crystal structure also involves inter-molecular O-H⋯N hydrogen bonds.

[5-(4-Bromo-phenoxy-meth-yl)-1,3,4-thia-diazole-2-thiol-ato]triphenyl-tin(IV).

In title compound, [Sn(C(6)H(5))(3)(C(9)H(6)BrN(2)OS(2))], the Sn atom is five-coordinated and the 1,3,4-thia-diazole-2-thiol ligand acts as an S,N-bidentate chelating ligand. The five-coordinate Sn(IV) atom forms four primary bonds, three to the phenyl groups and one to the S atom. Thus, the title complex has a distorted cis-trigonal bipyramidal geometry with the S atom and two C atoms occupying the equatorial plane, whereas the N atom and another C atom are in axial positions. In addition, there is a weak intramolecular Sn⋯N interaction. The crystal structure involves weak intra-molecular C-H⋯N and inter-molecular C-H⋯Br hydrogen bonding.

tert-Butyl N-(5-bromo-1H-imidazo[4,5-b]pyridin-2-ylmeth-yl)carbamate.

In the mol-ecule of the title compound, C(12)H(15)BrN(4)O(2), the imidazole and pyridine rings are strictly coplanar [maximum deviation 0.006 (3) Å]. In the crystal structure, mol-ecules are linked into chains running parallel to the a axis by inter-molecular N-H⋯O hydrogen bonds. Centrosymmetrically related chains are further connected by N-H⋯N hydrogen-bonding inter-actions to form a two-dimensional layer structure parallel to the ab plane.