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European Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28088086/design-and-synthesis-of-new-raf-kinase-inhibiting-antiproliferative-quinoline-derivatives-part-2-diarylurea-derivatives
#1
Mohammed I El-Gamal, Mohammad Ashrafuddin Khan, Hamadeh Tarazi, Mohammed S Abdel-Maksoud, Mahmoud M Gamal El-Din, Kyung Ho Yoo, Chang-Hyun Oh
This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 cancer cell lines of nine cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC50 and total growth inhibition (TGI) values against the cell lines...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28088085/new-pyridazinone-4-carboxamides-as-new-cannabinoid-receptor-type-2-inverse-agonists-synthesis-pharmacological-data-and-molecular-docking
#2
Giulio Ragusa, María Gómez-Cañas, Paula Morales, Carmen Rodríguez-Cueto, María R Pazos, Battistina Asproni, Elena Cichero, Paola Fossa, Gerard A Pinna, Nadine Jagerovic, Javier Fernández-Ruiz, Gabriele Murineddu
In the last few years, cannabinoid type-2 receptor (CB2R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCB1R and hCB2R. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB2-affinity (KiCB2 = 2...
January 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28076825/polar-aromatic-periphery-increases-agonist-potency-of-spirocyclic-free-fatty-acid-receptor-gpr40-agonists-inspired-by-ly2881835
#3
Mikhail Krasavin, Alexey Lukin, Daria Bagnyukova, Nikolay Zhurilo, Aleksei Golovanov, Sergey Zozulya, Ihor Zahanich, Daniel Moore, Irina G Tikhonova
A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC50 = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study...
January 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068602/synthesis-of-2-3-6-7-tetramethoxyphenanthren-9-amine-an-efficient-precursor-to-access-new-4-aza-2-3-dihydropyridophenanthrenes-as-apoptosis-inducing-agents
#4
Niggula Praveen Kumar, Pankaj Sharma, T Srinivasa Reddy, Shalini Nekkanti, Nagula Shankaraiah, Guntuku Lalita, S Sujanakumari, Suresh K Bhargava, V G M Naidu, Ahmed Kamal
A new route for the synthesis of novel 2,3,6,7-tetramethoxy phenanthrene amine precursor has been successfully accomplished. Subsequently, this amine precursor has been directly utilized for the synthesis of a new series of 4-aza-2,3-dihydropyridophenanthrene derivatives via a three component reaction with tetronic acid and substituted aldehydes. These compounds were evaluated for their cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MDA-MB-231 and 4T1), gastric (HGC-27), colon (Caco-2) and cervical (HeLa) cancer cell lines...
January 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068600/design-synthesis-and-antibacterial-evaluation-of-novel-pleuromutilin-derivatives-possessing-piperazine-linker
#5
Mei-Ling Gao, Jie Zeng, Xi Fang, Jian Luo, Zhen Jin, Ya-Hong Liu, You-Zhi Tang
A series of pleuromutilin derivatives bearing piperazine ring have been reported. The in vitro antibacterial activities of the synthetic derivatives against MRSA (ATCC 43300), Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212), Enterococcus faecium (ATCC35667) and Escherichia coli (ATCC25922) were evaluated by the broth dilution method. Most of the synthesized derivatives displayed potent activities. Compounds 11c, 12a and 12c were found to be the most active antibacterial derivatives against MRSA (minimum inhibitory concentration = 0...
January 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068603/rational-design-synthesis-and-evaluation-of-novel-2-4-chloro-and-hydroxy-substituted-diphenyl-benzofuro-3-2-b-pyridines-non-intercalative-catalytic-topoisomerase-i-and-ii-dual-inhibitor
#6
Seojeong Park, Til Bahadur Thapa Magar, Tara Man Kadayat, Hwa Jong Lee, Ganesh Bist, Aarajana Shrestha, Eung-Seok Lee, Youngjoo Kwon
Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-b]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4-position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range...
January 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068599/discovery-of-novel-anti-angiogenesis-agents-part-6-multi-targeted-rtk-inhibitors
#7
Lin Zhang, Yuanyuan Shan, Chuansheng Li, Ying Sun, Ping Su, Jinfeng Wang, Lisha Li, Xiaoyan Pan, Jie Zhang
Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4...
January 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28063354/diaryltriazenes-as-antibacterial-agents-against-methicillin-resistant-staphylococcus-aureus-mrsa-and-mycobacterium-smegmatis
#8
Jure Vajs, Conor Proud, Anamaria Brozovic, Martin Gazvoda, Adrian Lloyd, David I Roper, Maja Osmak, Janez Košmrlj, Christopher G Dowson
Diaryltriazene derivatives were synthesized and evaluated for their antimicrobial properties. Initial experiments showed some of these compounds to have activity against both methicillin-resistant strains of Staphylococus aureus (MRSA) and Mycobacterium smegmatis, with MICs of 0.02 and 0.03 μg/mL respectively. Those compounds with potent anti-staphylococcal and anti-mycobacterial activity were not found to act as growth inhibitors of mammalian cell lines or yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at <10(-9)...
December 31, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068604/2-8-bis-trifluoromethyl-quinoline-analogs-show-improved-anti-zika-virus-activity-compared-to-mefloquine
#9
Giselle Barbosa-Lima, Adriana M Moraes, Adriele da S Araújo, Emerson T da Silva, Caroline S de Freitas, Yasmine R Vieira, Andressa Marttorelli, José Cerbino Neto, Patrícia T Bozza, Marcus V N de Souza, Thiago Moreno L Souza
Zika virus (ZIKV), an arthropod-born Flavivirus, has been associated with a wide range of neurological diseases in adults, foetuses and neonates. Since no vaccine is available, repurposing of antiviral drugs currently in medical use is necessary. Mefloquine has confirmed anti-ZIKV activity. We used medicinal chemistry-driven approaches to synthesize and evaluate the ability of a series of new 2,8-bis(trifluoromethyl)quinoline derivatives to inhibit ZIKV replication in vitro, in order to improve the potency of mefloquine...
December 30, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28063352/a-tumor-targeted-activatable-phthalocyanine-tetrapeptide-doxorubicin-conjugate-for-synergistic-chemo-photodynamic-therapy
#10
Mei-Rong Ke, Shao-Fang Chen, Xiao-Hui Peng, Qiao-Feng Zheng, Bi-Yuan Zheng, Chih-Kuang Yeh, Jian-Dong Huang
Chemo-photodynamic therapy is a promising strategy for cancer treatments. However, it remains a challenge to develop a chemo-photodynamic therapeutic agent with little side effect, high tumor-targeting, and efficient synergistic effect simultaneously. Herein, we report a zinc(II) phthalocyanine (ZnPc)-doxorubicin (DOX) prodrug linked with a fibroblast activation protein (FAP)-responsive short peptide with the sequence of Thr-Ser-Gly-Pro for chemo-photodynamic therapy. In the conjugate, both photosensitizing activity of ZnPc and cytotoxicity of DOX are inhibited obviously...
December 29, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28063353/rationally-designed-benzopyran-fused-isoxazolidines-and-derived-%C3%AE-2-3-3-amino-alcohols-as-potent-analgesics-synthesis-biological-evaluation-and-molecular-docking-analysis
#11
Gagandeep Singh, Gurjit Singh, Rajbir Bhatti, Vivek Gupta, Ajay Mahajan, Palwinder Singh, Mohan Paul Singh Ishar
Based on structure activity analysis of morphine related opiates, we have synthesized some novel benzopyran fused isoxazolidines (2a-e) and derived conformationally constrained β(2,3,3)-amino alcohols (3a-e), which were evaluated in vivo for their anti-nociceptive activity through acetic acid induced writhing test (peripheral) and formalin induced algesia (central). Results showed that, compound 2a possesses significant opioid agonist activity. Further, molecular docking analysis reveals that compound 2a binds to δ-opioid receptor (DOR) with comparatively better D-score than to μ (MOR) and κ (KOR) receptors...
December 28, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28061346/syntheses-and-antibacterial-activity-of-soluble-9-bromo-substituted-indolizinoquinoline-5-12-dione-derivatives
#12
Hui Yang, Hao-Wen Wang, Teng-Wei Zhu, Le-Mao Yu, Jian-Wen Chen, Lu-Xia Wang, Lei Shi, Ding Li, Lian-Quan Gu, Zhi-Shu Huang, Lin-Kun An
In our previous research, 9-bromo indolizinoquinoline-5,12-dione 1 has been found to be a good anti-MRSA agent. However, it had very low bioavailability in vivo possibly due to its low solubility in water. In order to obtain the derivatives with higher anti-MRSA activity and good water solubility, twenty eight bromo-substituted indolizinoquinoline-5,12-dione derivatives were synthesized in the present study. The antibacterial activity of the synthesized compounds was evaluated against one gram-negative and some gram-positive bacterial strains including 100 clinical MRSA strains...
December 27, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28039774/design-synthesis-and-antimicrobial-activities-of-thiouracil-derivatives-containing-triazolo-thiadiazole-as-seca-inhibitors
#13
Penglei Cui, Xiaoliu Li, Mengyuan Zhu, Binghe Wang, Jing Liu, Hua Chen
A series of novel thiouracil derivatives containing a triazolo-thiadiazole moiety (7a-7l) have been synthesized by structural modifications on a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7d and 7g were also tested for their inhibitory activities against SecA ATPase due to their promising antimicrobial activities. The inhibitory activity of compound 7d was found to be higher than that of 2...
December 27, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28076824/discovery-of-new-nanomolar-inhibitors-of-gpa-extension-of-2-oxo-1-2-dihydropyridinyl-3-yl-amide-based-gpa-inhibitors
#14
Wendy A Loughlin, Ian D Jenkins, N David Karis, Peter C Healy
Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold...
December 26, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068598/novel-flavonolignan-hybrid-antioxidants-from-enzymatic-preparation-to-molecular-rationalization
#15
Eva Vavříková, Vladimír Křen, Lubica Jezova-Kalachova, Michal Biler, Benjamin Chantemargue, Michaela Pyszková, Sergio Riva, Marek Kuzma, Kateřina Valentová, Jitka Ulrichová, Jiří Vrba, Patrick Trouillas, Jan Vacek
A series of antioxidants was designed and synthesized based on conjugation of the hepatoprotective flavonolignan silybin with l-ascorbic acid, trolox alcohol or tyrosol via a C12 aliphatic linker. These hybrid molecules were prepared from 12-vinyl dodecanedioate-23-O-silybin using the enzymatic regioselective acylation procedure with Novozym 435 (lipase B) or with lipase PS. Voltammetric analyses showed that the silybin-ascorbic acid conjugate exhibited excellent electron donating ability, in comparison to the other conjugates...
December 26, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28064079/tacrine-resveratrol-fused-hybrids-as-multi-target-directed-ligands-against-alzheimer-s-disease
#16
Jakub Jeřábek, Elisa Uliassi, Laura Guidotti, Jan Korábečný, Ondřej Soukup, Vendula Sepsova, Martina Hrabinova, Kamil Kuča, Manuela Bartolini, Luis Emiliano Peña-Altamira, Sabrina Petralla, Barbara Monti, Marinella Roberti, Maria Laura Bolognesi
Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities...
December 26, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28061347/synthesis-and-biological-evaluation-of-deferiprone-resveratrol-hybrids-as-antioxidants-a%C3%AE-1-42-aggregation-inhibitors-and-metal-chelating-agents-for-alzheimer-s-disease
#17
Ping Xu, Minkui Zhang, Rong Sheng, Yongmin Ma
A series of deferiprone-resveratrol hybrids have been designed and synthesized as multitarget-directed ligands (MTDLs) through merging the chelating moiety 3-hydroxypyridin-4-one into the structure of resveratrol, a natural antioxidant agent and β-amyloid peptide (Aβ) aggregation inhibitor. The in vitro biological evaluation revealed that most of these newly synthesized compounds exhibited good inhibitory activity against self-induced Aβ1-42 aggregation, excellent antioxidant activity and potent metal chelating capability...
December 26, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28039772/synthesis-crystal-structures-and-antitumor-activity-of-two-platinum-ii-complexes-with-methyl-hydrazinecarbodithioate-derivatives-of-indolin-2-one
#18
You-Shan Li, Bin Peng, Li Ma, Sheng-Li Cao, Lu-Lu Bai, Chao-Rui Yang, Chong-Qing Wan, Hao-Jie Yan, Pan-Pan Ding, Zhong-Feng Li, Ji Liao, Ying-Ying Meng, Hai-Long Wang, Jing Li, Xingzhi Xu
Two new platinum(II) complexes 7a and 7b with methyl hydrazinecarbodithioate derivatives of indolin-2-one have been prepared and characterized by single-crystal X-ray diffraction, NMR spectroscopy and mass spectrometry. Antiproliferative activity of the two complexes and their ligands 6a and 6b against HCT-116, MCF-7 and MDA-MB-231 cell lines was determined by the MTS assay. Complexes 7a and 7b exhibited stronger antiproliferative activity against three cell lines than compounds 6a and 6b (IC50, 1.89-5.60 versus 6...
December 26, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28076827/new-diphenylmethane-derivatives-as-peroxisome-proliferator-activated-receptor-alpha-gamma-dual-agonists-endowed-with-anti-proliferative-effects-and-mitochondrial-activity
#19
Luca Piemontese, Carmen Cerchia, Antonio Laghezza, Pamela Ziccardi, Sabina Sblano, Paolo Tortorella, Vito Iacobazzi, Vittoria Infantino, Paolo Convertini, Fabrizio Dal Piaz, Angelo Lupo, Vittorio Colantuoni, Antonio Lavecchia, Fulvio Loiodice
We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers...
December 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28064078/novel-indolizino-8-7-b-indole-hybrids-as-anti-small-cell-lung-cancer-agents-regioselective-modulation-of-topoisomerase-ii-inhibitory-and-dna-crosslinking-activities
#20
Sue-Ming Chang, Wilson Christian, Ming-Hsi Wu, Tai-Lin Chen, Yi-Wen Lin, Ching-Shu Suen, Hima Bindu Pidugu, Dilip Detroja, Anamik Shah, Ming-Jing Hwang, Tsann-Long Su, Te-Chang Lee
A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking...
December 24, 2016: European Journal of Medicinal Chemistry
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