Bingni Liu

Computational Approach to Drug Design for Oxazolidinones as Antibacterial Agents

A three dimensional Quantitative Structure Activity Relationship (3D-QSAR) model for a series of (S)-3-Aryl-5-substituted oxazolidinones was developed to gain insights into the design for potential new antibacterial agents. It was found that the Comparative Molecular Field Analysis (CoMFA) method yielded good results while the Comparative Molecular Similarity Indices Analysis (CoMSIA) was less satisfactory. The CoMFA method yielded a cross-validated correlation coefficient q(2) = 0.681, non-cross-validated R(2) = 0.991, SE (Standard Error ) = 0.054, and the value of statistical significance measure F = 266.98. The relative steric and electrostatic contributions are 0.542 and 0.458, respectively. These results indicate that the model possesses a high predictivity. Guided by this model, three new compounds were synthesized. All these compounds exhibit inhibitory activity; two of them were shown having high activity (MIC = 1.0 microg/ml). The activity observed by experiments was in good agreement with the theoretical one. It is anticipated that the present model would be of value in facilitating design of new potent antibacterial agents.

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents.

A series of novel pazopanib derivatives, 7a-m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by (1)H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC50 values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.

N-(2-Chloro-pyrimidin-4-yl)-N,2-di-methyl-2H-indazol-6-amine.

In the title compound, C13H12ClN5, which is a derivative of the antitumor agent pazopanib {systematic name: 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide}, the indazole and pyrimidine fragments form a dihedral angle of 62.63 (5)°. In the crystal, pairs of molecules related by twofold rotational symmetry are linked into dimers through π–π interactions between the indazole ring systems [centroid–centroid distance = 3.720 (2) Å]. Weak intermolecular C—H⋯N hydrogen bonds further assemble these dimers into columns propagated in [001].

2-Methyl-6-nitro-2H-indazole.

In the title compound, C8H7N3O2, the molecular skeleton is almost planar with a maximum deviation of 0.0484 (9) Å for the methyl C atom. In the crystal, weak intermolecular C—H⋯N and C—H⋯O hydrogen bonds help to establish the packing.

Crystal structure of 9-(4-bromo­but­yl)-9H-fluorene-9-carb­oxy­lic acid

The title compound, C18H17BrO2, is a key intermediate in the synthesis of lomitapide mesylate, a microsomal triglyceride transfer protein inhibitor. Its asymmetric unit contains two independent molecules with slightly different conformations; the mean planes of the 4-bromobutyl and carboxylate groups in the two molecules form dihedral angles of 24.54 (12) and 17.10 (18)°. In the crystal, carboxylate groups are involved in O—H⋯O hydrogen bonding, which leads to the formation of two crystallographically independent centrosymmetric dimers. Weak intermolecular C—H⋯O interactions further link these dimers into layers parallel to the bc plane.

1,3-Dimethyl-1H-indazol-6-amine.

The molecular skeleton of the title compound, C9H11N3, is almost planar, with a maximum deviation of 0.0325 (19) Å for the amino N atom. In the crystal, N—H⋯N hydrogen bonds establish the packing.

2-(Thio­phen-2-yl)ethyl 4-methyl­benzene­sulfonate

In the title molecule, C13H14O3S2, the thiophene and benzene rings form a dihedral angle of 13.86 (13)°. In the crystal, weak intermolecular C—H⋯O hydrogen bonds link the molecules into layers parallel to the ab plane.

Methyl 5-chloro-2-nitro-benzoate.

In the title compound, C8H6ClNO4, the nitro and acetoxy groups attached to the benzene ring at neighbouring positions are twisted from its plane by 29.4 (1) and 49.7 (1)°, respectively. In the crystal, weak C—H⋯O hydrogen bonds link molecules into layers parallel to (101). The crystal packing exhibits short intermolecular C⋯O distances of 2.925 (3) Å.