Zicheng Li

Discovery of (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione, a readily available and orally active glitazone for the treatment of concanavalin A-induced acute liver injury of BALB/c mice.

A large amount of evidence suggests that monocytes/macrophages infiltration is implicated in a variety of inflammatory diseases including acute liver injury. Monocyte chemoattractant protein 1 (MCP-1) plays a crucial role in the process of macrophages recruitment. We herein presented a small-molecule library and a feasible quick screening method of evaluating potency of inhibition of chemotaxis of RAW264.7 cells stimulated by MCP-1. Fifty-three small molecules were synthesized and screened, and four compounds (2g, 2h, 4f, and 6h) showed inhibitory effects with IC(50) values range from 0.72 to 20.47 microM, with compound 4f being the most efficient. Further in vivo studies demonstrated that oral administration of 2g, 2h, 4f, or 6h decreases, most significantly for 4f, the serum levels of alanine aminotransaminase (ALT) and asparate aminotransaminase (AST) in ConA-induced acute livery injury BALB/c mice. Histopathological evaluation liver sections confirmed 4f as a potent, orally active compound for hepatoprotective effects against ConA-induced acute liver injury in BALB/c mice.

Synthesis and evaluation of 2-[2-(phenylthiomethyl)-1H-benzo[d] imidazol-1-yl)acetohydrazide derivatives as antitumor agents.

A novel class of acetylhydrazone derivatives (5a-x) containing 2-(phenylthiomethyl)-1H-benzo-[d]-imidazole moieties are synthesizer, and their antitumor activities against A549, HCT116, HepG2, PC-9, and A375 were determined by the MTT assay. Among them are N-(2,4-dihydroxybenzylidene)-2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide (5a) and N-(5-bromo-2-hydroxy-benzylidene)-2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide (5d) which displayed excellent cancer inhibitory activity against the tested cancer cells (IC(50) 4-17 μM), compared with 5-FU and SU11248. The others have moderate to weak inhibitory activity against the tested cancer cell lines.

Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido(2,3-d)pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents

A series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives was readily synthesized and their anti-proliferative activities on five types of tumor cells were evaluated through a cell-based phenotypic screening approach. Compound 3k was found to be potent on human colon cancer SW620 cells with an IC50 value of 12.5 μM. Structural optimization of compound 3k led to compound 4a with improved anti-proliferative potency on SW620 cells with an IC50 value of 6.9 μM. Further cell-cycle analyses suggested that compound 4a induced apoptosis of SW620 cells in a concentration-dependent manner.

Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents

A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H(37)Rv by a microdilution method, with MIC values ranging from 4 to 64μg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R(2) group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4μg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.

Synthesis, antiproliferative activities and in vitro biological evaluation of novel benzofuransulfonamide derivatives.

In a cell-based screen of novel antiproliferative agents, the hit compound 1a, which bears a benzofuransulfonamide scaffold, exhibited broad-spectrum antiproliferative activities against a panel of tumor cell lines. The promising in vitro antiproliferative activity and structural novelty of 1a prompted us to investigate the synthesis of five analogs of 1a and test their antiproliferative activities. The most potent analogue, 1h, exhibited enhanced antiproliferative activities compared with the parent 1a, and exhibited an IC(50) value against NCI-H460 cells of 4.13 μM compared with 4.52 μM for the positive control cisplatin. Flow cytometric analysis revealed that 1h induces significant levels of apoptosis in NCI-H460 cells in vitro at low micromolar concentrations. These results suggest that 1a and analogs based on its benzofuransulfonamide scaffold may constitute a novel class of antiproliferative agents, which deserve further study.

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

Identification of Novel BACE1 Inhibitors by Combination of Pharmacophore Modeling, Structure-Based Design and In Vitro Assay

The protease β-secretase plays a critical role in the synthesis of pathogenic amyloid-β in Alzheimers disease. In this study, pharmacophore constructed from receptor-ligand complex was used to screen Chemdiv and Zinc database and the resulting hits were subjected to docking experiments using LiandFit and CDOCKER programs. Molecules with high consensus scores and good interaction patterns in docking programs were retained. Drug-likeness assay including Lipinskis rule of five and ADMET properties filters were further used to identify BACE1 inhibitor. Finally, 13 compounds with novel scaffolds were selected and, considering of the nature of relative high LogP value of many marketed AD drugs, three of them with top 3 predicted LogP value were evaluated for their IC50 values in vitro by BACE1 enzymatic activity study. We believe that compound 13 with an IC50 value of 136 µM can be a lead compound with great potential in BACE1 inhibition and increasing activity by subsequently structure modification or optimization. At the same time, we found that the interaction between the residues Asp228, Asp32 of BACE1 and ligands is significant through analyzing the binding mode of 13 candidate compounds.

Facile microwave-assisted synthesis of substituted benzofuran derivatives

A series of benzofuran derivatives have been synthesized by use of a microwave-assisted process. Substituted or unsubstituted ο-hydroxyacetophenone and salicylaldehyde reacted with ethyl bromoacetate, ω-bromoacetophenone, or chloroacetone under the action of potassium carbonate in DMF to yield substituted benzofuran derivatives. Compared with conventional heating, this microwave-assisted synthetic process has the advantages of more convenient operation, shorter reaction time, and higher yield.

Synthesis and evaluation of 2-(2-((4-substituted-phenoxy)methyl)-1H-benzo[d] imidazol-1-yl)acetohydrazone derivatives as antitumor agents

Abstract Twelve 2-(2-((4-substituted-phenoxy)methyl)-1H-benzo[d]imidazol-1-yl)-acetylhydrazone derivatives were synthesized. These synthesized compounds have been tested for their antitumor activity in vitro against A549, MDA-MB-231, A375, and HCT116 cancer cells using the MTT assay. Among them, the compounds containing hydroxyl on position 2 at phenyl of hydrazone displayed a good anticancer activity, especially those containing two hydroxyl on 2 and 4 place at phenyl of hydrazone, for example, N′-(2,4-dihydroxybenzylidene)-2-(2-((p-tolyloxy)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide 7b, N′-(2,4-dihydroxybenzylidene)-2-(2-(phenoxymethyl)-1H-benzo[d]imidazol-1-yl) acetohydrazide 7f, 2-(2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazol-1-yl)-N′-(2,4-dihydroxybenzylidene)acetohydrazide 7j, have excellent antitumor activity. The results revealed that hydroxyl on position 2 at phenyl of hydrazone was necessary for anticancer activity, and another hydroxyl group on 4 place at phenyl can increase the inhibitory activity. An electron-withdrawing substituent at position 4 on phenyl ring of 2-phenoxylbenzimidazole was favorable to increasing anticancer activity toward MDA-MB-231, A375, and HCT116 cells.

Alkynylation of aldehydes mediated by zinc and allyl bromide: a practical synthesis of propargylic alcohols

A practical synthesis of propargylic alcohols was developed by alkynylation of aldehydes mediated by zinc and allyl bromide. Aromatic, aliphatic and vinyl aldehydes react with phenylacetylene or 1-hexyne to obtain various propargylic alcohols at room temperature in up to 98% yield. This method is characterized with inexpensive materials, wide substrate scope, and mild reaction conditions, and is also easy to scale up. In addition, this protocol is applicable to the alkynylation of α-ketone esters and epoxides to generate α-tertiary-hydroxy esters and α-alkynyl alcohols, respectively.Graphical Abstract