Dengke 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.

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.

Synthesis and Biological Evaluation of Substituted Desloratadines as Potent Arginine Vasopressin V2 Receptor Antagonists

Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

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-(2-Nitro­benz­yl)-1H-pyrrole-2-carbaldehyde

In the title compound, C12H10N2O3, the five- and six-membered rings form a dihedral angle of 83.96 (6)°. The nitro group is twisted by 5.92 (8)° from the plane of the attached benzene ring. In the crystal, weak intermolecular C—H⋯O hydrogen bonds link the molecules into columns in the [100] direction, with a short distance of 3.725 (3) Å between the centroids of benzene rings inside these columns.

Synthesis of the alkylated active metabolite of tipidogrel.

Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr-derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented.

5-(2-Cyano-benz-yl)-4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-2-yl acetate.

In the title molecule, C17H16N2O2S, the tetrahydropyridine ring exhibits a half-chair conformation. The mean planes of the ester chain and benzene ring are twisted by 5.5 (1) and 81.32 (5)°, respectively, from the plane of thiophene ring. In the crystal, weak C—H⋯O interactions link molecules related by translation along [100] into chains.

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.