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European Journal of Medicinal Chemistry

Haydi Saher ElBordiny, Mostafa Mahmoud El-Miligy, Shaymaa Emam Kassab, Hoda Daabees, Soad Abdelhamid Mohamed El-Hawash, Waleed Ali Mohamed Ali
New candidates of 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives (4-7) were designed combining the pyrazoline/isoxazoline heterocycles and 2-phenylindole to explore its potential as 15-lipoxygenase (15-LOX) inhibitors. The design of the new derivatives was based on utilizing the antioxidant properties of pyrazoline, 2-phenylindole and the good 15-LOX inhibition properties of indolylpyrazoline. The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields...
January 10, 2018: European Journal of Medicinal Chemistry
Xuan Xiao, Xing-Xing Zhang, Mei-Miao Zhan, Kai Cheng, Shiyu Li, Zhouling Xie, Chenzhong Liao
Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH2-, -SCH2-, -OCH2CH2-, -OCH2CH2O-, -OCH2CH2CH2O- were tried...
January 10, 2018: European Journal of Medicinal Chemistry
Qun Wei, Jun-Ya Ning, Xi Dai, Yuan-Di Gao, Le Su, Bao-Xiang Zhao, Jun-Ying Miao
Heat shock protein 90 (HSP90) inhibition has aroused increasing enthusiasm in antitumor strategies in recent years. According to our previous studies, we synthesized a series of coumarin pyrazoline compounds HCP1-HCP6 that might be HSP90 inhibitors. Interactions between HCP1-HCP6 and HSP90 were examined and antitumor activities of them were investigated in A549 lung cancer cells. Results showed that all the six derivatives could interact with HSP90, in which HCP1 exhibited the best binding ability and inhibited the activity of HSP90...
January 10, 2018: European Journal of Medicinal Chemistry
Xiaoke Gu, Yanfei Jiang, Yingying Qu, Jing Chen, Dingding Feng, Chenglin Li, Xiaoxing Yin
As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells...
January 9, 2018: European Journal of Medicinal Chemistry
Nicolas Richy, Daad Sarraf, Xavier Maréchal, Naëla Janmamode, Rémy Le Guével, Emilie Genin, Michèle Reboud-Ravaux, Joëlle Vidal
Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive proteasome and immunoproteasome acting at the nanomolar level (IC50 = 7...
January 8, 2018: European Journal of Medicinal Chemistry
Nidhi Gupta, Arem Qayum, Arun Raina, Ravi Shankar, Sumeet Gairola, Shashank Singh, Payare L Sangwan
A library of 28 analogs of bavachinin including aliphatic and aromatic ethers, epoxide, chalcone, oxime, semicarbazide, oxime ether and triazole derivatives have been synthesized and evaluated for cytotoxicity against four different human cancer cell lines. Bio-evaluation studies exhibited better cytotoxic profile for many analogs compare to bavachinin. Best results were observed for a 1,2,3-triazole analog (17i) with IC50 values 7.72, 16.08, 7.13 and 11.67 μM against lung (A549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines respectively...
January 8, 2018: European Journal of Medicinal Chemistry
Xuxing Chen, Xiajuan Huan, Qiufeng Liu, Yuqin Wang, Qian He, Cun Tan, Yi Chen, Jian Ding, Yechun Xu, Zehong Miao, Chunhao Yang
The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively...
January 8, 2018: European Journal of Medicinal Chemistry
Peng-Hui Li, Hong Jiang, Wen-Jin Zhang, Yong-Lian Li, Min-Cong Zhao, Wei Zhou, Lan-Yue Zhang, Ya-Dong Tang, Chang-Zhi Dong, Zhi-Shu Huang, Hui-Xiong Chen, Zhi-Yun Du
Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity...
January 6, 2018: European Journal of Medicinal Chemistry
Adileh Ayati, Rezvan Esmaeili, Setareh Moghimi, Tayebeh Oghabi Bakhshaiesh, Zahra Eslami-S, Keivan Majidzadeh-A, Maliheh Safavi, Saeed Emami, Alireza Foroumadi
A series of 4-amino-5-cinnamoylthiazoles 3a-p were designed and synthesized as chalcone-like anticancer agents. The synthesized derivatives 3a-p were evaluated for their in vitro antiproliferative activities against three different human cancer cell lines including MCF-7, HepG2 and SW480. Most of compounds could significantly prevent proliferation of tested cell lines. In particular, the pyrrolidine derivative 3e namely (E)-1-(4-amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one showed promising activity, especially against HepG2 cells (IC50 = 10...
January 6, 2018: European Journal of Medicinal Chemistry
Ahmed M Gouda, Hoda A El-Ghamry, Tahani M Bawazeer, Thoraya A Farghaly, Ashraf N Abdalla, Akhmed Aslam
Two novel series including Schiff bases of the pyrrolizine-5-carboxamides and their Cu(II) complexes were designed, synthesized and analysed using spectral and analytical techniques. The analytical results indicated the formation of the complexes in 1:1 or 1:2 (Metal:Ligand) ratio. The geometry around the Cu centers was confirmed to be tetrahedral or octahedral. The cytotoxic activity of the new compounds was evaluated using MCF-7 (human breast adenocarcinoma), A2780 (human ovary adenocarcinoma) and HT29 (human colon adenocarcinoma), in addition to MRC5 (normal human fetal lung fibroblast) cells using the MTT cytotoxicity assay...
January 6, 2018: European Journal of Medicinal Chemistry
Talita P C Chierrito, Susimaire Pedersoli-Mantoani, Carlos Roca, Victor Sebastian-Pérez, Loreto Martínez-Gonzalez, Daniel I Pérez, Concepción Perez, Angeles Canales, F Javier Cañada, Nuria E Campillo, Ivone Carvalho, Ana Martinez
Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and β-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil...
January 5, 2018: European Journal of Medicinal Chemistry
Valeria Romanucci, Armando Zarrelli, Sandra Liekens, Sam Noppen, Christophe Pannecouque, Giovanni Di Fabio
The biological relevance of tetramolecular G-quadruplexes especially as anti-HIV agents has been extensively reported in the literature over the last years. In the light of our recent results regarding the slow G-quadruplex folding kinetics of ODNs based on d(TGGGAG) sequence, here we report a systematic anti-HIV screening to investigate the impact of the G-quadruplex folding on their anti-HIV activity. In particular, varying the single stranded concentrations of ODNs, it has been tested a pool of ODN sample solutions with different G-quadruplex concentrations...
January 5, 2018: European Journal of Medicinal Chemistry
Dong Lu, Jianan Liu, Yunzhe Zhang, Feifei Liu, Limin Zeng, Runze Peng, Li Yang, Huazhou Ying, Wei Tang, Wuhong Chen, Jianping Zuo, Xiankun Tong, Tao Liu, Youhong Hu
Using a dengue replicon cell line-based screening, we identified 3-(dimethylamino)propyl(3-((4-(4-fluorophenyl)-1-oxophthalazin-2(1H)-yl)methyl)phenyl)carbamate (10a) as a potent DENV-2 inhibitor, with an IC50 value of 0.64 μM. A series of novel phthalazinone derivatives based on hit 10a were synthesized and evaluated for their in vitro anti-DENV activity and cytotoxicity. The subsequent SAR study and optimization led to the discovery of the most promising compound 14l, which displayed potent anti-DENV-2 activity, with low IC50 value against DENV-2 RNA replication of 0...
January 5, 2018: European Journal of Medicinal Chemistry
Avinash C Tripathi, Savita Upadhyay, Sarvesh Paliwal, Shailendra K Saraf
This review aims to be a comprehensive, authoritative, critical, and readable review of general interest to the medicinal chemistry community because it focuses on the pharmacological, chemical, structural and computational aspects of diverse chemical categories as monoamine oxidase inhibitors (MAOIs). Monoamine oxidases (MAOs), namely MAO-A and MAO-B represent an enormously valuable class of neuronal enzymes embodying neurobiological origin and functions, serving as potential therapeutic target in neuronal pharmacotherapy, and hence we have coined the term "Neurozymes" which is being introduced for the first time ever...
January 4, 2018: European Journal of Medicinal Chemistry
Zu-Zhuang Wei, Qi-Pin Qin, Ting Meng, Cai-Xing Deng, Hong Liang, Zhen-Feng Chen
Two platinum(II) complexes [Pt(L)(DMSO)Cl] (1) and [Pt(L)(pn)]Cl (2) with 5-bromo-oxoisoaporphine (H-L) were synthesized. We found that the two new platinum(II) complexes were more selective for Hep-G2 tumor cells than for normal cells (HL-7702, WI-38 and L-o2 cell lines). 5-Bromine-oxoisoaporphine platinum(II) complex 2 was a telomerase inhibitor targeting c-myc G4, and it triggered Hep-G2 cell apoptosis more potently than complex 1. Moreover, they induced cell apoptosis via disruption of mitochondrial functions...
January 4, 2018: European Journal of Medicinal Chemistry
Mingshuo Xu, Yu Wang, Feipu Yang, Chunhui Wu, Zhen Wang, Bin Ye, Xiangrui Jiang, Qingjie Zhao, Jianfeng Li, Yongjian Liu, Junchi Zhang, Guanghui Tian, Yang He, Jingshan Shen, Hualiang Jiang
In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation...
January 4, 2018: European Journal of Medicinal Chemistry
Uladzimir Bildziukevich, Lucie Rárová, David Šaman, Zdeněk Wimmer
A series of picolyl amides of betulinic acid (3a-3c and 6a-6c) was prepared and subjected to the cytotoxicity screening tests. Structure-activity relationships studies resulted in finding differences in biological activity in dependence on o-, m- and p-substitution of the pyridine ring in the target amides, when cytotoxicity data of 3a-3c and 6a-6c were obtained and compared. The amides 3b and 3a displayed cytotoxicity (given in the IC50 values) in G-361 (0.5 ± 0.1 μM and 2.4 ± 0.0 μM, respectively), MCF7 (1...
January 4, 2018: European Journal of Medicinal Chemistry
A Sergi Capilla, Richard Soucek, Laura Grau, Manel Romero, Jaime Rubio-Martínez, Daniel H Caignard, Maria Dolors Pujol
This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4]dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties...
January 3, 2018: European Journal of Medicinal Chemistry
Guanglong Sun, Junwei Wang, Xiaodan Guo, Min Lei, Yinan Zhang, Xiachang Wang, Xu Shen, Lihong Hu
A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC50 value of 0.22 μM. Further investigation demonstrated that compound A6 can significantly reduce Aβ production and increase Aβ clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice...
January 2, 2018: European Journal of Medicinal Chemistry
Seon-Mi Kim, Minhee Lee, So Young Lee, Soo-Min Lee, Eun Jeong Kim, Jae Sun Kim, Jihyae Ann, Jiyoun Lee, Jeewoo Lee
We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue...
January 2, 2018: European Journal of Medicinal Chemistry
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