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European Journal of Medicinal Chemistry

Qiang Wang, Feiyang Liu, Shuang Qi, Ziping Qi, Xiao-E Yan, Beilei Wang, Aoli Wang, Wei Wang, Cheng Chen, Xiaochuan Liu, Zongru Jiang, Zhenquan Hu, Li Wang, Wenchao Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Qingsong Liu, Jing Liu
Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong potency against purified PDGFRα (IC50 : 132 nM) but not structurally similar PDGFRβ, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling...
March 12, 2018: European Journal of Medicinal Chemistry
Asmaa E Kassab, Ehab M Gedawy
As we are interested in synthetizing biologically active leads with dual anticancer and antibacterial activity, we adopted biology oriented drug synthesis (BIODS) strategy to synthesize a series of novel ciprofloxacin (CP) hybrids. The National Cancer Institute (USA) selected seventeen newly synthesized compounds for anticancer evaluation against 59 different human tumor cell lines. Five compounds 3e, 3f, 3h, 3o and 3p were further studied through determination of IC50 values against the most sensitive cancer cell lines...
March 9, 2018: European Journal of Medicinal Chemistry
Silvia Salerno, Aída Nelly García-Argáez, Elisabetta Barresi, Sabrina Taliani, Francesca Simorini, Concettina La Motta, Giorgio Amendola, Stefano Tomassi, Sandro Cosconati, Ettore Novellino, Federico Da Settimo, Anna Maria Marini, Lisa Dalla Via
Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in anticancer therapy. So far, many monoclonal antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1-21 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH3 , or Cl at 8-position...
March 7, 2018: European Journal of Medicinal Chemistry
Mousumi Pal, Utpal Nandi, Debaraj Mukherjee
Ruthenium (Ru) complexes are known for their promising anticancer activity presumably due to octahedral coordination geometry, slow ligand exchange rate, the range of different oxidation states and target specificity. This review article summarizes the physicochemical processes which are responsible for the selectivity of Ru complexes toward cancer cells over the normal cells. Emphasis has been given on the activation mechanism of Ru(III) complex administered as a prodrug and then the release of active species in an acidic environment of cancer cell through normal or photo induced hydrolysis or ligand oxidation...
March 7, 2018: European Journal of Medicinal Chemistry
Yi-Lei Fan, Xiao-Hong Jin, Zhong-Ping Huang, Hai-Feng Yu, Zhi-Gang Zeng, Tao Gao, Lian-Shun Feng
Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity...
March 7, 2018: European Journal of Medicinal Chemistry
Anushka C Galasiti Kankanamalage, Yunjeong Kim, Vishnu C Damalanka, Athri D Rathnayake, Anthony R Fehr, Nurjahan Mehzabeen, Kevin P Battaile, Scott Lovell, Gerald H Lushington, Stanley Perlman, Kyeong-Ok Chang, William C Groutas
There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties...
March 6, 2018: European Journal of Medicinal Chemistry
Chunlong Zhao, Jie Zang, Qin'ge Ding, Elizabeth S Inks, Wenfang Xu, C James Chou, Yingjie Zhang
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (∼30-fold) which was confirmed by western blot analysis...
March 6, 2018: European Journal of Medicinal Chemistry
Akande Akinsola Adegboye, Khalid Mohammed Khan, Uzma Salar, Sherifat Adeyinka Aboaba, Kanwal, Sridevi Chigurupati, Itrat Fatima, Mohammad Taha, Abdul Wadood, Jahidul Isalm Mohammad, Huma Khan, Shahnaz Perveen
Despite of many diverse biological activities exhibited by benzimidazole scaffold, it is rarely explored for the α-amylase inhibitory activity. For that purpose, 2-aryl benzimidazole derivatives 1-45 were synthesized and screened for in vitro α-amylase inhibitory activity. Structures of all synthetic compounds were deduced by various spectroscopic techniques. All compounds revealed inhibition potential with IC50 values of 1.48 ± 0.38-2.99 ± 0.14 μM, when compared to the standard acarbose (IC50  = 1...
March 6, 2018: European Journal of Medicinal Chemistry
Marco Betti, Daniela Catarzi, Flavia Varano, Matteo Falsini, Katia Varani, Fabrizio Vincenzi, Diego Dal Ben, Catia Lambertucci, Vittoria Colotta
A new series of amino-3,5-dicyanopyridines (3-28) as analogues of the adenosine hA2B receptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA2B adenosine receptor display EC50 values in the range 9-350 nM behaving as partial agonists, with the only exception being the 2-{[4-(4-acetamidophenyl)-6-amino-3,5-dicyanopyridin-2-yl]thio}acetamide (8) which shows a full agonist profile. Moreover, the 2-[(1H-imidazol-2-yl)methylthio)]-6-amino-4-(4-cyclopropylmethoxy-phenyl)pyridine-3,5-dicarbonitrile (15) turns out to be 3-fold more active than 1 although less selective...
March 6, 2018: European Journal of Medicinal Chemistry
Marcin D Tomala, Katarzyna Magiera-Mularz, Katarzyna Kubica, Sylwia Krzanik, Bartosz Zieba, Bogdan Musielak, Marcin Pustula, Grzegorz M Popowicz, Michael Sattler, Grzegorz Dubin, Lukasz Skalniak, Tad A Holak
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a...
March 5, 2018: European Journal of Medicinal Chemistry
Sonia de Castro, María-José Camarasa
HIV infection still has a serious health and socio-economical impact and is one of the primary causes of morbidity and mortality all over the world. HIV infection and the AIDS pandemic are still matters of great concern, especially in less developed countries where the access to highly active antiretroviral therapy (HAART) is limited. Patient compliance is another serious drawback. Nowadays, HAART is the treatment of choice although it is not the panacea. Despite the fact that it suppresses viral replication at undetectable viral loads and prevents progression of HIV infection into AIDS HAART has several pitfalls, namely, long-term side-effects, drug resistance development, emergence of drug-resistant viruses, low compliance and the intolerance of some patients to these drugs...
March 5, 2018: European Journal of Medicinal Chemistry
Claudia Bello, Jianfei Bai, Bartosz K Zambron, Pilar Elías-Rodríguez, Consuelo Gajate, Inmaculada Robina, Irene Caffa, Michele Cea, Fabrizio Montecucco, Alessio Nencioni, Aimable Nahimana, Dominique Aubry, Caroline Breton, Michel A Duchosal, Faustino Mollinedo, Pierre Vogel
We have synthesized a wide array of structurally related amphiphilic compounds, containing a functionalized pyrrolidine polar group coupled to different ether-linked hydrocarbon chains, to generate novel structures with antitumor activity. These newly synthesized amphiphilic pyrrolidine-derived compounds were classified in three different sub-libraries regarding the number of hydroxyl groups substituting the pyrrolidine moiety at C3 and C4. Pyrrolidine compounds with one or none hydroxyl groups showed a potent cell killing activity against pancreatic cancer cells, but they lacked selectivity for tumor cells...
March 2, 2018: European Journal of Medicinal Chemistry
V Hepnarova, J Korabecny, L Matouskova, P Jost, L Muckova, M Hrabinova, N Vykoukalova, M Kerhartova, T Kucera, R Dolezal, E Nepovimova, K Spilovska, E Mezeiova, N L Pham, D Jun, F Staud, D Kaping, K Kuca, O Soukup
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line...
March 2, 2018: European Journal of Medicinal Chemistry
Renren Bai, Jian Sun, Zhongxing Liang, Younghyoun Yoon, Eric Salgado, Amber Feng, Yoonhyeun Oum, Yuanyuan Xie, Hyunsuk Shim
The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells...
March 2, 2018: European Journal of Medicinal Chemistry
Cosimo Walter D'Acunto, Robert Kaplánek, Helena Gbelcová, Zdeněk Kejík, Tomáš Bříza, Liudmila Vasina, Martin Havlík, Tomáš Ruml, Vladimír Král
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting tens of million people. Currently marketed drugs have limited therapeutic efficacy and only slowing down the neurodegenerative process. Interestingly, it has been suggested that biometal cations in the amyloid beta (Aβ) aggregate deposits contribute to neurotoxicity and degenerative changes in AD. Thus, chelation therapy could represent novel mode of therapeutic intervention. Here we describe the features of chelators with therapeutically relevant mechanism of action...
March 2, 2018: European Journal of Medicinal Chemistry
Tong Han, Kangtao Tian, Huaqi Pan, Yongxiang Liu, Fanxing Xu, Zhanlin Li, Takahiro Uchita, Ming Gao, Huiming Hua, Dahong Li
A series of novel conjugates of brefeldin A (11a-c, 12a-c and 13a-c) were obtained by introducing a variety of nitrogen mustards at 4-OH or 7-OH position to explore more efficacious and less toxic antitumor agents. The antiproliferative activities were tested against three cancer cell lines (HL-60, PC-3 and Bel-7402) and one multidrug resistant cell line Bel-7402/5-FU. Among them, compound 11a was the strongest derivative with IC50 values of 4.48, 9.37, 0.2 and 0.84 μM, respectively, and more potent than nitrogen mustards...
March 1, 2018: European Journal of Medicinal Chemistry
Paweł Borowiecki, Patrycja Wińska, Maria Bretner, Małgorzata Gizińska, Mirosława Koronkiewicz, Monika Staniszewska
Three out of 16 newly synthesized 1,3-dimethylxanthine derivatives (proxyphylline analogues) exhibited consistencies between antifungal and anticancer properties. Proxyphylline possessing 1-(10H-phenothiazin-10-yl)propan-2-yl (6) and polybrominated benzimidazole (41) or benzotriazole moiety (42) remained selectively cidal against Candida albicans (lg R ≥ 3 at conc. of 31, 36 and 20 μM, respectively) however not against normal mammalian Vero cell line in vitro (IC50  ≥ 280 μM) and Galleria mellonella in vivo...
February 27, 2018: European Journal of Medicinal Chemistry
Smriti Srivastava, Devla Bimal, Kapil Bohra, Balram Singh, Prija Ponnan, Ruchi Jain, Mandira Varma-Basil, Jyotirmoy Maity, M Thirumal, Ashok K Prasad
A series of β-d-ribofuranosyl coumarinyl-1,2,3-triazoles have been synthesized by Cu-catalyzed cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62-70% overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in nature and some of them were found to be more active than one of the first line antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420 times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin, ethambutol and streptomycin) against multidrug resistant clinical isolate 591...
February 27, 2018: European Journal of Medicinal Chemistry
Devendra Kumar, Sukesh K Gupta, Ankit Ganeshpurkar, Gopichand Gutti, Sairam Krishnamurthy, Gyan Modi, Sushil K Singh
Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50  = 32.45 ± 0.044, 28.65 ± 0.029, BuChE, IC50  = 157.95 ± 0.264, 160.58 ± 0.082 and MMP-2, IC50  = 36...
February 27, 2018: European Journal of Medicinal Chemistry
Miriam Palacios, Ricardo Tampe, Miguel Del Campo, Ta-Ying Zhong, Mercedes N López, Flavio Salazar-Onfray, María Inés Becker
Conjugation to carrier proteins is a way to improve the immunogenicity of peptides. Such is the case for peptides mimicking carbohydrate tumor-associated antigens in cancer vaccine development. The most used protein for this purpose is the keyhole limpet hemocyanin (KLH) from Megathura crenulata. Its limited bioavailability has prompted interest in finding new candidates; nevertheless, it is not known whether other hemocyanins might be equally efficient as carrier of carbohydrate peptide mimotopes to promotes anti-tumor responses...
February 27, 2018: European Journal of Medicinal Chemistry
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