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Dive into the research topics where Zhi-Long Wang is active.

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Featured researches published by Zhi-Long Wang.


Bioorganic & Medicinal Chemistry | 2015

Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists.

Suwen Hu; Zhi-Long Wang; Tingjun Hou; Xiaodong Ma; Jing Li; Tao Liu; Xin Xie; Yongzhou Hu

Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10μM.


Journal of Medicinal Chemistry | 2017

Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis

Ying Shi; Yan-Hui Duan; Yue-Yang Ji; Zhi-Long Wang; Yan-Ran Wu; Hendra Gunosewoyo; Xiao-Yu Xie; Jian-Zhong Chen; Fan Yang; Jing Li; Jie Tang; Xin Xie; Li-Fang Yu

Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.


RSC Advances | 2014

Design, synthesis, and biological evaluation of a new class of MT2-selective agonists

Xuan Zhang; Zhi-Long Wang; Qingqing Huang; Yu Luo; Xin Xie; Wei Lu

A novel class of chiral 2,3-dihydro-1H-indene derivatives were designed and synthesized as melatonergic ligands. Most of the reported MT2-selective ligands behave as antagonists. By contrast, our exploration of 2,3-dihydro-1H-indene showed that the introduction of a lipophilic group at the 2- or 3-position of this scaffold could afford highly selective MT2 agonists. Among all these synthesized molecules, compounds 10b, 12a, 17a, 20a exhibited powerful MT2 agonistic activity (EC50 < 50 nM) as well as excellent MT2 selectivity (more than 2200-fold).


ACS Medicinal Chemistry Letters | 2017

Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as Agonists of Cannabinoid Receptor Type 2

Hai-Yan Qian; Zhi-Long Wang; You-Lu Pan; Li-Li Chen; Xin Xie; Jian-Zhong Chen

Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.


Royal Society Open Science | 2018

Ligand-based pharmacophore model for the discovery of novel CXCR2 antagonists as anti-cancer metastatic agents

Jin-Xin Che; Zhi-Long Wang; Haichao Sheng; Feng Huang; Xiaowu Dong; Youhong Hu; Xin Xie; Yongzhou Hu

Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with the HipHop program by screening a database containing compounds which were designed based on the known structure–activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Compound 1a bearing the novel skeleton was selected from database screening and subjected to the in vitro biological test which showed a moderate CXCR2 antagonist potential. With further modification and exploration of SAR, compound 1e demonstrated improved CXCR2 antagonist activity with an IC50 value of 14.8 µM. Furthermore, wound healing assay using the NCI-H1299 cell line indicated that 1e showed an excellent anti-cancer metastatic effect (72% inhibition in cell migration at 50 µg ml−1).


RSC Advances | 2018

Bicyclo[2.2.1]heptane containing N,N′-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents

Jin-Xin Che; Zhi-Long Wang; Xiaowu Dong; Youhong Hu; Xin Xie; Yongzhou Hu

CXCR1 and CXCR2 are CXC chemokine receptors (CXCRs), corresponding to cytokines of the CXC chemokine family. CXCR2 was found to be 77% homologous to CXCR1. Antagonism of the chemokine receptor CXCR2 has been proposed as a new strategy for the treatment of metastatic cancer. In order to find a CXCR2 selective antagonist, a bicyclo[2.2.1]heptane containing N,N′-diarylsquaramide (compound 2e) was identified by introducing a bridge ring system into the N,N′-diarylsquaramide skeleton, and it exhibited good CXCR2 antagonistic activity (CXCR2IC50 = 48 nM) and good selectivity (CXCR1IC50/CXCR2IC50 = 60.4). Furthermore, an in vitro biological assay of compound 2e also demonstrated its good anti-cancer metastatic effect against the pancreatic cancer cell line CFPAC1. In addition, compound 2e showed an extremely high stability in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF), as well as in rat and human plasma, but not in rat and human liver microsomes. In vivo pharmacokinetic studies in rats indicated that 2e has an excellent PK profile (10 mg kg−1 po, Cmax = 2863 ng mL−1, t1/2 = 2.58 h). Moreover, molecular docking was further implemented to propose the preponderant configuration of compound 2e, providing important and useful guidelines for further development.


Journal of Medicinal Chemistry | 2018

Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus–Cell Interface

Adel A. Rashad; Li-Rui Song; Andrew P. Holmes; Kriti Acharya; Shiyu Zhang; Zhi-Long Wang; Ebony N. Gary; Xin Xie; Vanessa Pirrone; Michele Kutzler; Ya-Qiu Long; Irwin M. Chaiken

To address the urgent need for new agents to reduce the global occurrence and spread of AIDS, we investigated the underlying hypothesis that antagonists of the HIV-1 envelope (Env) gp120 protein and the host-cell coreceptor (CoR) protein can be covalently joined into bifunctional synergistic combinations with improved antiviral capabilities. A synthetic protocol was established to covalently combine a CCR5 small-molecule antagonist and a gp120 peptide triazole antagonist to form the bifunctional chimera. Importantly, the chimeric inhibitor preserved the specific targeting properties of the two separate chimera components and, at the same time, exhibited low to subnanomolar potencies in inhibiting cell infection by different pseudoviruses, which were substantially greater than those of a noncovalent mixture of the individual components. The results demonstrate that targeting the virus-cell interface with a single molecule can result in improved potencies and also the introduction of new phenotypes to the chimeric inhibitor, such as the irreversible inactivation of HIV-1.


Journal of Medicinal Chemistry | 2018

Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists

Panfeng Peng; Huan Chen; Ya Zhu; Zhi-Long Wang; Jian Li; Rong-Hua Luo; Jiang Wang; Liang Chen; Liu-Meng Yang; Hualiang Jiang; Xin Xie; Beili Wu; Yong-Tang Zheng; Hong Liu

CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 μM, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.


ChemMedChem | 2018

Design, Synthesis, and SAR Studies of Heteroarylpyrimidines/Heteroaryltriazines to be CB2R Ligands

Jian-Zhong Chen; Hai-Yan Qian; Zhi-Long Wang; Li-Li Chen; You-Lu Pan; Xiao-Yu Xie; Xin Xie

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline‐2,4(1H,3H)‐diones as CB2R‐selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2R in calcium mobilization assays, and four displayed CB2R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2R (EC50=7.53±3.15 nm) had a selectivity over CB1R of more than 1328‐fold. Moreover, structure–activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2R.


Bioorganic & Medicinal Chemistry | 2018

Discovery and synthesis of 6,7,8,9-tetrahydro-5 H -pyrido[4,3- c ]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy

Li-Huai Qin; Zhi-Long Wang; Xin Xie; Ya-Qiu Long

The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure-activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.

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Xin Xie

Chinese Academy of Sciences

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Youhong Hu

Chinese Academy of Sciences

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