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European Journal of Medicinal Chemistry

Wang Wang, Yanli Wu, Xinxin Chen, Peng Zhang, Hua Li, Lixia Chen
Two series of andrographolide derivatives with nitrogen-containing heterocycles, phenols and aromatic acids as bioisostere moiety of lactone ring were synthesized. 8 from 18 tested compounds showed stronger inhibitory effect on LPS-induced NO production in RAW264.7 macrophage than hydrocortisone. Among them, compound 8m exhibited the most potent inhibition with IC50 of 3.38 ± 1.03 μM. The structure-activity relationships (SARs) suggested that the replacement of lactone ring with small-molecule phenols could improve the anti-inflammatory efficacy...
November 3, 2018: European Journal of Medicinal Chemistry
Xiaoke Gu, Yanfei Jiang, Jing Chen, Yinpeng Zhang, Mingyu Guan, Xin Li, Qingqing Zhou, Qian Lu, Jingying Qiu, Xiaoxing Yin
Oxidative stress plays a significant role in the pathogenesis of various human diseases. In this study, a series of bifendate derivatives bearing acrylamide moiety were synthesized and evaluated as anti-oxidant agents. Biological evaluation indicated that compounds 6a and 6e displayed more potent cytoprotective effect against H2 O2 -induced HBZY-1 mesangial cells death than lead compound bifendate and positive control resveratrol and sulforaphane. Preliminary anti-oxidant mechanism studies showed that compound 6e could diminish the ROS accumulation by dose- and time-dependently activating Nrf2 and increasing the expression of downstream detoxification enzymes NQO-1, HO-1, GCLM and GCLC at protein and mRNA levels, thus displaying potent anti-oxidant activity...
November 3, 2018: European Journal of Medicinal Chemistry
Života Selaković, Julie P Tran, Krishna P Kota, Marija Lazić, Cary Retterer, Robert Besh, Rekha G Panchal, Veronica Soloveva, Vantongreen A Sean, Wells B Jay, Aleksandar Pavić, Tatjana Verbić, Branka Vasiljević, Kathleen Kuehl, Allen J Duplantier, Sina Bavari, Rajini Mudhasani, Bogdan A Šolaja
Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group...
October 31, 2018: European Journal of Medicinal Chemistry
Ana Tejería, Yolanda Pérez-Pertejo, Rosa M Reguera, Rubén Carbajo-Andrés, Rafael Balaña-Fouce, Concepción Alonso, Endika Martin-Encinas, Asier Selas, Gloria Rubiales, Francisco Palacios
Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L...
October 31, 2018: European Journal of Medicinal Chemistry
R Ramajayam
The privileged structures have been widely used as a valuable template in new drug discovery. 1,2-Diaryl or vicinal diaryl is a simple scaffold found in many drugs and naturally occurring compounds. From synthetic point of view, the vicinal diaryl derivatives are easily accessible due to their facile and expedient syntheses. These scaffolds have shown numerous interesting pharmacological activities against various diseases with lot of clinical potentials. This review aims to highlight the evidence of vicinal diaryl motif as a privileged scaffold in COX-2 inhibitors and CA-4 analogs...
October 31, 2018: European Journal of Medicinal Chemistry
Ahmed H E Hassan, Eunwoo Choi, Yoon Mi Yoon, Kun Won Lee, Sung Yeun Yoo, Min Chang Cho, Ji Seul Yang, Hye In Kim, Joo Young Hong, Ji-Sun Shin, Kyung-Sook Chung, Jeong-Hun Lee, Kyung-Tae Lee, Yong Sup Lee
Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4'-trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases...
October 29, 2018: European Journal of Medicinal Chemistry
Dmitry Dar'in, Vladimir Zarubaev, Anastasia Galochkina, Maxim Gureev, Mikhail Krasavin
A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion...
October 29, 2018: European Journal of Medicinal Chemistry
A L Zakharenko, O A Luzina, D N Sokolov, V I Kaledin, V P Nikolin, N A Popova, J Patel, O D Zakharova, A A Chepanova, A Zafar, J Reynisson, E Leung, I K H Leung, K P Volcho, N F Salakhutdinov, O I Lavrik
The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling...
October 28, 2018: European Journal of Medicinal Chemistry
Jianjun Yu, Lei Xu, Duidui Hong, Xiaotuan Zhang, Jieyu Liu, Daqiang Li, Jia Li, Yubo Zhou, Tao Liu
A series of novel phenol ether derivatives were designed, synthesized, and evaluated as non-covalent proteasome inhibitors. Most compounds exhibited moderate to excellent proteasome inhibitory activity. In particular, compound 18x proved to be the most potent compound (chymotrypsin-like: IC50  = 49 nM), exhibiting a 2-fold higher potency compared to the reported PI-1840. Besides, compound 18x exhibited excellent metabolic stability and selective anti-proliferative activity against solid cancer cell lines including HepG2 and HGC27, providing incentive for the further development as a potential anticancer agent against solid cancers...
October 26, 2018: European Journal of Medicinal Chemistry
Tao-Qian Zhao, Yuan-Di Zhao, Xin-Yang Liu, Zhong-Hua Li, Bo Wang, Xin-Hui Zhang, Ya-Quan Cao, Li-Ying Ma, Hong-Min Liu
To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC50 value of 0...
October 25, 2018: European Journal of Medicinal Chemistry
Carmen Terán, Pedro Besada, Noemí Vila, Ma Carmen Costas-Lago
Phthalazin-1(2H)-one is a diazaheterobicycle found in a wide variety of synthetic molecules relevant to several branches of chemistry, including medicinal chemistry. The versatility of phthalazinone core in drug discovery has promoted the search for new synthetic methods to get access to differently substituted and functionalized derivatives. This review highlights the latest advances in synthesis of phthalazinone derivatives that have relevance to drug discovery processes, analyzing modifications of classical methodologies based on [4 + 2] two-component cyclocondensations as well as novel multicomponent approaches, mostly based on a [3 + 2+1] three-component strategy and very attractive not only because of its synthetic efficiency but also in the matter of environmental compatibility...
October 25, 2018: European Journal of Medicinal Chemistry
Abdulkarim Najjar, Charlott Platzer, Anton Luft, Chris Alexander Aßmann, Nehal H Elghazawy, Frank Erdmann, Wolfgang Sippl, Matthias Schmidt
In the current work, we applied computational methods to analyze the membrane-associated inhibitory kinase PKMYT1 and small molecule inhibitors. PKMYT1 regulates the cell cycle at G2/M transition and phosphorylates Thr14 and Tyr15 in the Cdk1-cyclin B complex. A combination of in silico and in vitro screening was applied to identify novel PKMYT1 inhibitors. The computational approach combined structural analysis, molecular docking, binding free energy calculations, and quantitative structure-activity relationship (QSAR) models...
October 24, 2018: European Journal of Medicinal Chemistry
Monica de Gaetano, Eibhlín Butler, Kevin Gahan, Andrea Zanetti, Mariam Marai, Jianmin Chen, Antonino Cacace, Emily Hams, Catherine Maingot, Alisha McLoughlin, Eoin Brennan, Xavier Leroy, Christine E Loscher, Padraic Fallon, Mauro Perretti, Catherine Godson, Patrick J Guiry
Lipoxins (LXs) are endogenously generated eicosanoids with potent bio-actions consistent with attenuation of inflammation. The costly synthesis and metabolic instability of LXs may limit their therapeutic potential. Here we report the synthesis and characterization of novel imidazole-/oxazole-containing synthetic-LX-mimetics (sLXms). The key steps of asymmetric synthesis of putative sLXms include a Suzuki reaction and an asymmetric ketone reduction. The effect of the novel compounds on inflammatory responses was assessed using a human monocyte cell line stably expressing a Nuclear Factor Kappa B (NFkB) reporter gene, by investigating downstream cytokine secretion...
October 23, 2018: European Journal of Medicinal Chemistry
Gemma L Howse, Richard A Bovill, Peter J Stephens, Helen M I Osborn
There is an ongoing urgent need for new targeted antibacterial compounds with novel mechanisms of action for the treatment of infections caused by bacteria that are resistant to currently available materials. Since the expression of glycosidase enzymes within bacteria is unequally distributed, glycoside derivatives of antibacterial agents offer potential as targeted prodrugs for bacterial infections. Herein we report the synthesis and characterisation of four α-D-glycopyranosides and three β-D-glycopyranosides of the broad antibacterial agent triclosan, in generally good synthetic yields, and with excellent purities...
October 23, 2018: European Journal of Medicinal Chemistry
Shaban Darwish, Neda Sadeghiani, Shirley Fong, Saghar Mozaffari, Parinaz Hamidi, Thimanthi Withana, Sun Yang, Rakesh Kumar Tiwari, Keykavous Parang
Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4 K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH...
October 23, 2018: European Journal of Medicinal Chemistry
Guangyan Zhou, Shidong Chu, Ariana Nemati, Chunsheng Huang, Beth A Snyder, Roger G Ptak, Miriam Gochin
In previous work, we described 6-6'-bisindole compounds targeting a hydrophobic pocket on the N-heptad repeat region of viral glycoprotein-41 as effective inhibitors of HIV-1 fusion. Two promising compounds with sub-micromolar IC50 's contained a benzoic acid group and a benzoic acid ester attached at the two indole nitrogens. Here we have conducted a thorough structure-activity relationship (SAR) study evaluating the contribution of each of the ring systems and various substituents to compound potency. Hydrophobicity, polarity and charge were varied to produce 35 new compounds that were evaluated in binding, cell-cell fusion and viral infectivity assays...
October 23, 2018: European Journal of Medicinal Chemistry
Satya Narayan, Srinivasa Ramisetti, Aruna S Jaiswal, Brian K Law, Ashona Singh-Pillay, Parvesh Singh, Shantu Amin, Arun K Sharma
Despite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical...
October 23, 2018: European Journal of Medicinal Chemistry
Qi-Pin Qin, Shu-Long Wang, Ming-Xiong Tan, Yan-Cheng Liu, Ting Meng, Bi-Qun Zou, Hong Liang
Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other spectroscopic and analytical studies of ClQ-Pt and BrQ-Pt revealed that the coordination geometry of Pt(II) can be described as a four-coordinated square planar geometry. By MTT assay, ClQ-Pt displayed the most potent activity, with IC50 values of 5...
October 23, 2018: European Journal of Medicinal Chemistry
Jessica Hernandez, Laurent Hoffer, Bruno Coutard, Gilles Querat, Philippe Roche, Xavier Morelli, Etienne Decroly, Karine Barral
No antiviral drugs to treat or prevent life-threatening flavivirus infections such as those caused by mosquito-borne Dengue (DENV) and more recently Zika (ZIKV) viruses are yet available. We aim to develop, through a structure-based drug design approach, novel inhibitors targeting the NS5 AdoMet-dependent mRNA methyltransferase (MTase), a viral protein involved in the RNA capping process essential for flaviviruses replication. Herein, we describe the optimization of a hit (5) identified using fragment-based and structure-guided linking techniques, which binds to a proximal site of the AdoMet binding pocket...
October 23, 2018: European Journal of Medicinal Chemistry
Xinyu Li, Chengzhe Wu, Xin Lin, Xuerong Cai, Linyi Liu, Guoshun Luo, Qidong You, Hua Xiang
SERMs are a series of important small molecular compounds to modulate estrogen receptor, such as tamoxifen. Although these drugs have showed great benefits in the treatment of breast cancer, the risk of endometrial cancer and endocrine resistance restrict their use. The reasonable designing of multi-target drugs can decrease the side effects and improve the tolerance of antineoplastic agents Studies have identified that VEGFR-2 plays a pivotal role in tumor angiogenesis and drug resistance. Besides, a combination of Tamoxifen and low dose of a VEGFR-2 inhibitor was reported to maximize therapeutic efficacy as well as to retard SERM resistant tumor growth...
October 19, 2018: European Journal of Medicinal Chemistry
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