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European Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28535470/pharmacophore-guided-discovery-of-small-molecule-interleukin-15-inhibitors
#1
Barbara Żyżyńska-Granica, Bartosz Trzaskowski, Szymon Niewieczerzał, Sławomir Filipek, Oliwia Zegrocka-Stendel, Małgorzata Dutkiewicz, Piotr Krzeczyński, Magdalena Kowalewska, Katarzyna Koziak
Upregulation of interleukin 15 (IL-15) contributes directly i.a. to the development of inflammatory and autoimmune diseases. Selective blockade of IL-15 aimed to treat rheumatoid arthritis, psoriasis and other IL-15-related disorders has been recognized as an efficient therapeutic method. The aim of the study was to identify small molecules which would interact with IL-15 or its receptor IL-15Rα and inhibit the cytokine's activity. Based on the crystal structure of IL-15Rα·IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Rα inhibitors...
May 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28535469/novel-propanamides-as-fatty-acid-amide-hydrolase-inhibitors
#2
Alessandro Deplano, Carmine Marco Morgillo, Monica Demurtas, Emmelie Björklund, Mariateresa Cipriano, Mona Svensson, Sanaz Hashemian, Giovanni Smaldone, Emilia Pedone, F Javier Luque, Maria G Cabiddu, Ettore Novellino, Christopher J Fowler, Bruno Catalanotti, Valentina Onnis
Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroaryl)-2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)phenyl)propanamides, as FAAH inhibitors...
May 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28528302/nanomolar-anti-sickling-compounds-identified-by-ligand-based-pharmacophore-approach
#3
Odailson Santos Paz, Milena de Jesus Pinheiro, Renan Fernandes do Espirito Santo, Cristiane Flora Villarreal, Marcelo Santos Castilho
Adenosine receptors are considered as potential targets for drug development against several diseases. The discovery of subtype 2B adenosine receptors role in erythrocyte sickling process proved its importance to neglected diseases such as sickle cell anemia, which affects approximately 29.000 people around the world, but whose treatment is restricted to just one FDA approved drug (hydroxyurea). In order to widen the therapeutic arsenal available to treat sickle cell anemia patients, it is imperative to identify new lead compounds that modify the sickling course and not just its symptoms...
May 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28526474/recent-updates-on-third-generation-egfr-inhibitors-and-emergence-of-fourth-generation-egfr-inhibitors-to-combat-c797s-resistance
#4
REVIEW
Harun Patel, Rahul Pawara, Azim Ansari, Sanjay Surana
EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525842/indole-coumarin-thiadiazole-hybrids-an-appraisal-of-their-mcf-7%C3%A2-cell-growth-inhibition-apoptotic-antimetastatic-and-computational-bcl-2-binding-potential
#5
Pooja R Kamath, Dhanya Sunil, Manu M Joseph, Abdul Ajees Abdul Salam, Sreelekha T T
Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525841/ll-37-derived-short-antimicrobial-peptide-kr-12-a5-and-its-d-amino-acid-substituted-analogs-with-cell-selectivity-anti-biofilm-activity-synergistic-effect-with-conventional-antibiotics-and-anti-inflammatory-activity
#6
Eun Young Kim, Ganesan Rajasekaran, Song Yub Shin
KR-12-a5 is a 12-meric α-helical antimicrobial peptide (AMP) with dual antimicrobial and anti-inflammatory activities designed from human cathelicidin LL-37. We designed and synthesized a series of d-amino acid-substituted analogs of KR-12-a5 with the aim of developing novel α-helical AMPs that possess higher cell selectivity than KR-12-a5, while maintaining the anti-inflammatory activity. d-amino acid incorporation into KR-12-a5 induced a significant improvement in the cell selectivity by 2.6- to 13.6-fold as compared to KR-12-a5, while maintaining the anti-inflammatory activity...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525840/indole-carboxylic-acid-esters-of-melampomagnolide-b-are-potent-anticancer-agents-against-both-hematological-and-solid-tumor-cells
#7
Shobanbabu Bommagani, Jessica Ponder, Narsimha R Penthala, Venumadhav Janganati, Craig T Jordan, Michael J Borrelli, Peter A Crooks
A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03-0.30 μM and 0.04-0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525838/design-synthesis-and-evaluation-of-azaacridine-derivatives-as-dual-target-egfr-and-src-kinase-inhibitors-for-antitumor-treatment
#8
Zhishan Cui, Shaopeng Chen, Yanwei Wang, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Overexpression of EGFR is often associated with advanced stage disease and poor prognosis. In certain cancers, Src works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and Src is of therapeutic advantage against these cancers. Based on molecular docking and our previous studies, we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors. Most of the synthesized azaacridines displayed good antiproliferative activity against K562 and A549 cells...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28527405/synthesis-and-structure-activity-relationships-of-novel-fused-ring-analogues-of-q203-as-antitubercular-agents
#9
Sunhee Kang, Young Mi Kim, Heekyung Jeon, Sejin Park, Min Jung Seo, Saeyeon Lee, Dongsik Park, Jiyeon Nam, Seokwoo Lee, Kiyean Nam, Sanghee Kim, Jaeseung Kim
A set of fused ring analogues of a new antitubercular agent, Q203, was designed and synthesized. To reduce the lipophilicity of Q203 caused by linearly extended side chains, shorter and heteroatoms containing fused rings were introduced into the side chain region. Antitubercular activity was tested against H37Rv-GFP replicating in liquid broth culture medium (extracellular) and within macrophages (intracellular). Many analogues showed potent extracellular activities as well as intracellular activities without cytotoxicity...
May 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525839/discovery-of-efficient-stimulators-for-adult-hippocampal-neurogenesis-based-on-scaffolds-in-dragon-s-blood
#10
Jian-Hua Liang, Liang Yang, Si Wu, Si-Si Liu, Mark Cushman, Jing Tian, Nuo-Min Li, Qing-Hu Yang, He-Ao Zhang, Yun-Jie Qiu, Lin Xiang, Cong-Xuan Ma, Xue-Meng Li, Hong Qing
Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring...
May 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28521261/novel-anti-inflammatory-agents-targeting-cxcr4-design-synthesis-biological-evaluation-and-preliminary-pharmacokinetic-study
#11
Renren Bai, Zhongxing Liang, Younghyoun Yoon, Eric Salgado, Amber Feng, Saumya Gurbani, Hyunsuk Shim
CXCR4 plays a crucial role in the inflammatory disease process, providing an attractive means for drug targeting. A series of novel amide-sulfamide derivatives were designed, synthesized and comprehensively evaluated. This new scaffold exhibited much more potent CXCR4 inhibitory activity, with more than 70% of the compounds showed notably better binding affinity than the reference drug AMD3100 in the binding assay. Additionally, in the Matrigel invasion assay, most of our compounds significantly blocked the tumor cell invasion, demonstrating superior efficacy compared to AMD3100...
May 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28505535/thiosemicarbazones-and-4-thiazolidinones-indole-based-derivatives-synthesis-evaluation-of-antiproliferative-activity-cell-death-mechanisms-and-topoisomerase-inhibition-assay
#12
Jamerson Ferreira de Oliveira, Talitha Santos Lima, Débora Barbosa Vendramini-Costa, Sybelle Christianne Batista de Lacerda Pedrosa, Elizabeth Almeida Lafayette, Rosali Maria Ferreira da Silva, Sinara Monica Vitalino de Almeida, Ricardo Olímpio de Moura, Ana Lúcia Tasca Gois Ruiz, João Ernesto de Carvalho, Maria do Carmo Alves de Lima
In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI50 values ranging between 1...
May 8, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525843/formation-of-platinum-ii-as-a-six-member-ring-for-sustained-polymeric-delivery
#13
Sanjeewa N Senadheera, Ti Zhang, Chad E Groer, M Laird Forrest
A new pH-activated polymer chelate of cisplatin was synthesized using a scalable and green aqueous technique. Synthesis of the chelate was based on formation of a 6-member ring of platinum(II) with acetyl-homo-Lysine (Ac-homo-Lys), which was accomplished under completely aqueous conditions using a traceless photocleavable protection chemistry. Synthesis preceded by, first, amidation of a photocaged homo-Ac-Lys with hyaluronic acid (HA) in water using a p-hydroxyphenacyl (pHP) group as the photoremovable protecting group, followed by reaction of cisplatin (diaqua form) in water to form the reversible chelate...
May 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28505534/discorhabdin-alkaloids-from-antarctic-latrunculia-spp-sponges-as-a-new-class-of-cholinesterase-inhibitors
#14
Tanja Botić, Andrea Defant, Pietro Zanini, Monika Cecilija Žužek, Robert Frangež, Dorte Janussen, Daniel Kersken, Željko Knez, Ines Mancini, Kristina Sepčić
The brominated pyrroloiminoquinone alkaloids discorhabdins B, L and G and 3-dihydro-7,8- dehydrodiscorhabdin C, isolated from methanol extracts of two specimens of Latrunculia sp. sponges collected near the Antarctic Peninsula, are here demonstrated for the first time to be reversible competitive inhibitors of cholinesterases. They showed Ki for electric eel acetylcholinesterase of 1.6-15.0 μM, for recombinant human acetylcholinesterase of 22.8-98.0 μM, and for horse serum butyrylcholinesterase of 5.0-76...
May 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28527406/the-relevance-of-ki-calculation-for-bi-substrate-enzymes-illustrated-by-kinetic-evaluation-of-a-novel-lysine-k-acetyltransferase-8-inhibitor
#15
Hannah Wapenaar, Thea van den Bosch, Niek G J Leus, Petra E van der Wouden, Nikolaos Eleftheriadis, Jos Hermans, Gebremedhin Solomon Hailu, Dante Rotili, Antonello Mai, Alexander Dömling, Rainer Bischoff, Hidde J Haisma, Frank J Dekker
Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28502586/novel-zinc-complexes-of-a-non-steroidal-anti-inflammatory-drug-niflumic-acid-structural-characterization-human-dna-and-albumin-binding-properties
#16
Romana Smolková, Vladimír Zeleňák, Lukáš Smolko, Juraj Kuchár, Miroslava Rabajdová, Michaela Ferenčáková, Mária Mareková
Three novel Zn(II) complexes of NSAID niflumic acid (Hnif) were prepared and studied, namely; [Zn(MeOH)4(nif)2] (1), [Zn(cyclam)(nif)2] (2) and [Zn(nif)2(tmen)] (3), where nif is deprotonated niflumic acid, cyclam is 1,4,8,11-Tetraazacyclotetradecane and tmen is N,N,N',N'-Tetramethylethylenediamine. The complexes have been characterized by infrared spectroscopy, elemental and thermal analysis and single-crystal X-ray structure analysis. All three complexes contain two deprotonated niflumato anions monodentately coordinated via carboxylato groups...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28494257/novel-1-7-ethoxy-1-benzofuran-2-yl-substituted-chalcone-derivatives-synthesis-characterization-and-anticancer-activity
#17
Demet Coskun, Merve Erkisa, Engin Ulukaya, Mehmet Fatih Coskun, Ferda Ari
Cancer treatment still requires new compounds to be discovered. Chalcone and its derivatives exhibit anticancer potential in different cancer cells. A new series of benzofuran substituted chalcone derivatives was synthesized by the base-catalyzed Claisen-Schmidt reaction of the 1-(7-ethoxy-1-benzofuran-2-yl) ethanone with different aromatic aldehydes to yield 1-(7-ethoxy-1-benzofuran-2-yl) substituted chalcone derivatives 3a-j. The derivatives were characterized by elemental analysis, FT-IR, (1)H NMR and (13)C NMR spectroscopy techniques...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28494256/designing-multi-targeted-agents-an-emerging-anticancer-drug-discovery-paradigm
#18
REVIEW
Rong-Geng Fu, Yuan Sun, Wen-Bing Sheng, Duan-Fang Liao
The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28494251/nitric-oxide-releasing-derivatives-of-brefeldin-a-as-potent-and-highly-selective-anticancer-agents
#19
Kangtao Tian, Fanxing Xu, Xiang Gao, Tong Han, Jia Li, Huaqi Pan, Linghe Zang, Dahong Li, Zhanlin Li, Takahiro Uchita, Ming Gao, Huiming Hua
A series of NO-donating mono- or diester derivatives of brefeldin A were designed, synthesized and biologically evaluated. Some derivatives exhibited potent antiproliferative activity with low IC50 values. The most potent NO-donating hybrid 13b exhibited stronger cytotoxicity against human prostate cancer PC-3 cells, human colon carcinoma HT-29 cells and human liver cancer HepG-2 cells than BFA with IC50 values of 25 nM, 160 nM and 180 nM, respectively. More importantly, compound 13b showed good selectivity between human normal and tumor liver cells with selectivity index of 33...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28531811/synthesis-of-novel-indole-derivatives-as-promising-dna-binding-agents-and-evaluation-of-antitumor-and-antitopoisomerase-i-activities
#20
Elizabeth Almeida Lafayette, Sinara Mônica Vitalino de Almeida, Renata Virginia Cavalcanti Santos, Jamerson Ferreira de Oliveira, Cezar Augusto da Cruz Amorim, Rosali Maria Ferreira da Silva, Maira Galdino da Rocha Pitta, Ivan da Rocha Pitta, Ricardo Olimpio de Moura, Luiz Bezerra de Carvalho Júnior, Moacyr Jesus Barreto de Melo Rêgo, Maria do Carmo Alves de Lima
Molecules bearing indole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated both to DNA and protein interactions. This study focused on the synthesis of new indole derivatives with thiazolidines and imidazolidine rings condensed as side chains as well as the evaluation of their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized and their structures were elucidated by mass spectrometry (MS), infrared (IR), spectroscopy (1)H NMR, (13)C NMR, COSY (1)H-(1)H and HSQC (1)H-(13)C...
May 4, 2017: European Journal of Medicinal Chemistry
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