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European Journal of Medicinal Chemistry

Piyoosh Sharma, Avanish Tripathi, Prabhash Nath Tripathi, Santosh Kumar Prajapati, Ankit Seth, Manish Kumar Tripathi, Pavan Srivastava, Vinod Tiwari, Sairam Krishnamurthy, Sushant Kumar Shrivastava
The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets...
February 14, 2019: European Journal of Medicinal Chemistry
Ren-Jun Wu, Kai-Xuan Zhou, Haijin Yang, Guo-Qing Song, Yong-Hong Li, Jia-Xin Fu, Xiao Zhang, Shu-Jing Yu, Li-Zhong Wang, Li-Xia Xiong, Cong-Wei Niu, Fu-Hang Song, Haitao Yang, Jian-Guo Wang
Since pyrithiobac (PTB) is a successful commercial herbicide with very low toxicity against mammals, it is worth exploring its derivatives for an extensive study. Herein, a total of 35 novel compounds were chemically synthesized and single crystal of 6-6 was obtained to confirm the molecular structure of this family of compounds. The novel PTB derivatives were fully evaluated against various biological platforms. From the bioassay results, the best AHAS inhibitor 6-22 displayed weaker herbicidal activity but stronger anti-Candida activity than PTB did...
February 14, 2019: European Journal of Medicinal Chemistry
Rong Yang, Zhiwei Wang, Ying Yuan, Ting Qian, Qibing Zhou
Conventional chemotherapeutic and photodynamic therapy have recently been shown to also elicit immune response against cancer through the immunogenic cell death mechanism, which can be potentially translated into effective cancer vaccines. However, there are few studies on the potential of nanodelivery system to promote the immunogenic cell death as a cancer vaccine. We reported here that cRGD target liposome delivery system was capable to promote the immunogenic cell death through enhanced potency of a thymidine conjugate post UVA activation as a cancer vaccine...
February 13, 2019: European Journal of Medicinal Chemistry
Xue-Qing Song, Zhong-Ying Ma, Yi-Gang Wu, Miao-Liang Dai, Dong-Bo Wang, Jing-Yuan Xu, Yangzhong Liu
The great interest in epithelial-to-mesenchymal transition (EMT) programme lies in its association with process of metastasis and invasion, which is a crucial cause of cancer-related death. Herein, we designed and reported three new NSAID-Pt(IV) prodrugs, taking Non-Steroid Anti-Inflammatory Drugs (NSAIDs) to disrupt EMT programme and assist genotoxic platinum-based drugs as a cytotoxicity booster, to offer a class of potential anticarcinogens with a multi-functional action mechanism. The NSAID-Pt(IV) prodrugs, especially Eto-Pt(IV), highly enhanced cellular uptake with amount up to 42-fold at 3 h compared with CDDP, and greatly increased DNA damage and cell apoptosis, showing much higher cytotoxicity than cisplatin in the tested cancer cells even in A549/cis cells...
February 13, 2019: European Journal of Medicinal Chemistry
Shuai Wang, Zhong-Rui Li, Feng-Zhi Suo, Xiao-Han Yuan, Bin Yu, Hong-Min Liu
The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC50  = 1.72 μM) and showed selectivity to LSD1 over MAO-A/B...
February 13, 2019: European Journal of Medicinal Chemistry
Hong Yao, Feijie Xu, Guangyu Wang, Shaowen Xie, Wenlong Li, Hequan Yao, Cong Ma, Zheying Zhu, Jinyi Xu, Shengtao Xu
A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system...
February 12, 2019: European Journal of Medicinal Chemistry
Loredana Salerno, Giuseppe Floresta, Valeria Ciaffaglione, Davide Gentile, Fatima Margani, Rita Turnaturi, Antonio Rescifina, Valeria Pittalà
Heme oxygenases (HOs) are a family of enzymes involved in the selective catabolism of free circulating heme. While HO-2 is constitutively expressed, HO-1 is strongly overexpressed under stressful stimuli (e.g., oxidative stress). Under these conditions, HO-1 exerts its strong cytoprotective activities and plays a crucial role in stimulating cell survival by removing the pro-oxidant heme and by producing carbon monoxide and biliverdin (promptly reduced to bilirubin). Unfortunately, the broad spectrum of HO-1 cytoprotective effects has been well experimentally documented both in normal and tumor cells, where the enzyme can be overexpressed, making it an exciting target in the management of some type of tumors...
February 12, 2019: European Journal of Medicinal Chemistry
José C Espinoza-Hicks, Karla Fabiola Chacón-Vargas, Jessica L Hernández-Rivera, Benjamín Nogueda-Torres, Joaquín Tamariz, Luvia Enid Sánchez-Torres, Alejandro Camacho-Dávila
The available drugs for treating Leishmaniasis and American trypanosomiasis have high toxicity and multiple side effects, among other problems. More effective and less toxic treatments are urgently needed. A series of chalcones that contained a prenyloxy or geranyloxy substituent was synthesized and characterized. Each substituent was attached to the A ring in some compounds and to the B ring in others, with additional substituents placed on the chalcone moiety. The present aim was to evaluate the effect of the substitution pattern on leishmanicidal and trypanocidal activity...
February 12, 2019: European Journal of Medicinal Chemistry
Jianchang Qian, Xianxin Chen, Sheng Shu, Wenxin Zhang, Bo Fang, Xiaojing Chen, Yunjie Zhao, Zhiguo Liu, Guang Liang
A novel series of di-carbonyl analogs of curcumin (DACs) were prepared and evaluated for their anti-inflammatory properties. Preliminary results showed that a vast majority of compounds tested in this study could effectively suppress LPS-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Structure-activity relationships of the compounds were discussed. Compounds 5a27 and 5a28 showed the most potent anti-inflammatory activities and had higher structural stability and orally bioavailability than curcumin in vitro...
February 12, 2019: European Journal of Medicinal Chemistry
Hugues Prevet, Martin Moune, Abdalkarim Tanina, Christian Kemmer, Adrien Herledan, Rosangela Frita, Alexandre Wohlkönig, Marilyne Bourotte, Baptiste Villemagne, Florence Leroux, Marc Gitzinger, Alain R Baulard, Benoit Déprez, René Wintjens, Nicolas Willand, Marion Flipo
Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis, represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis...
February 10, 2019: European Journal of Medicinal Chemistry
Davide Benedetto Tiz, Žiga Skok, Martina Durcik, Tihomir Tomašič, Lucija Peterlin Mašič, Janez Ilaš, Anamarija Zega, Gábor Draskovits, Tamás Révész, Ákos Nyerges, Csaba Pál, Cristina D Cruz, Päivi Tammela, Dušan Žigon, Danijel Kikelj, Nace Zidar
ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6...
February 10, 2019: European Journal of Medicinal Chemistry
Stella Cascioferro, Barbara Parrino, Giovanna Li Petri, Maria Grazia Cusimano, Domenico Schillaci, Veronica Di Sarno, Simona Musella, Elisa Giovannetti, Girolamo Cirrincione, Patrizia Diana
A class of 36 new 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-negative strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compounds, were able to inhibit biofilm formation of the tested staphylococcal strains showing BIC50 lower than 10 μg/ml...
February 10, 2019: European Journal of Medicinal Chemistry
Nguyen Dinh Thanh, Do Son Hai, Vu Thi Ngoc Bich, Pham Thi Thu Hien, Nguyen Thi Ky Duyen, Nguyen Thi Mai, Tran Thi Dung, Vu Ngoc Toan, Hoàng Thi Kim Van, Le Hai Dang, Duong Ngoc Toan, Tran Thi Thanh Van
The series of 2-amino-7-propargyloxy-4H-chromene-3-carbonitriles 5a-t were synthesized from corresponding 2-amino-7-phydroxy-4H-chromene-3-carbonitriles 4a-t and propargyl bromide. Two procedures were used in these syntheses: K2 CO3 /acetone and NaH/DMF procedures with yields of 65-89% and 80-96%, respectively. 1H-1,2,3-Triazole-tethered 4H-chromene-d-glucose conjugates 7a-t were synthesized using click chemistry of propargyl ethers 5a-t and tetra-O-acetyl-β-d-glucopyranosyl azide. Cu@MOF-5 was the optimal catalyst for this chemistry...
February 8, 2019: European Journal of Medicinal Chemistry
Felipe A Calil, Juliana S David, Estela R C Chiappetta, Fernando Fumagalli, Rodrigo B Mello, Franco H A Leite, Marcelo S Castilho, Flavio S Emery, M Cristina Nonato
Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH...
February 8, 2019: European Journal of Medicinal Chemistry
Fatima Arshad, Mohemmed Faraz Khan, Wasim Akhtar, Mohammad Mumtaz Alam, Lalit Mohan Nainwal, Sumit Kumar Kaushik, Mymoona Akhter, Suhel Parvez, Syed Misbahul Hasan, Mohammad Shaquiquzzaman
Morpholine, a six-membered heterocycle containing one nitrogen and one oxygen atom, is a moiety of great significance. It forms an important intermediate in many industrial and organic syntheses. Morpholine containing drugs are of high therapeutic value. Its wide array of pharmacological activity includes anti-diabetic, anti-emetic, growth stimulant, anti-depressant, bronchodilator and anticancer. Multi-drug resistance in cancer cases have emerged in the last few years and have led to the failure of many chemotherapeutic drugs...
February 8, 2019: European Journal of Medicinal Chemistry
Xiao-Long Shi, Jing-De Wu, Ping Liu, Zhao-Peng Liu
To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu2+ , Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3β inhibitors and selective Cu2+ and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3β inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+ -induced Aβ aggregation inhibition, Cu2+ -Aβ complex disaggregation, ROS formation inhibition, and antioxidant activities...
February 8, 2019: European Journal of Medicinal Chemistry
Ehab D AlFadly, Perihan A Elzahhar, Anna Tramarin, Salwa Elkazaz, Hossam Shaltout, Marwa M Abu-Serie, Jana Janockova, Ondrej Soukup, Doaa A Ghareeb, Ahmed F El-Yazbi, Rim W Rafeh, Nour-Mounira Z Bakkar, Firas Kobeissy, Isabel Iriepa, Ignacio Moraleda, Manal N S Saudi, Manuela Bartolini, Ahmed S F Belal
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition)...
February 8, 2019: European Journal of Medicinal Chemistry
Om P S Patel, Ashutosh Arun, Pankaj K Singh, Deepika Saini, Sharanbasappa Shrimant Karade, Manish K Chourasia, Rituraj Konwar, Prem P Yadav
A series of new pyranocarbazole derivatives were synthesized via semi-synthetic modification of koenimbine (1a) and koenidine (1b) isolated from the leaves of Murraya koenigii. Among all, compound 3bg displayed significant anti-cancer activity against MDA-MB-231, DU145 and PC3 cell lines with the IC50 values of 3.8, 7.6 and 5.8 μM, respectively. It was also observed that the halogenated-benzyl substitution at N-9 position, C-3 Methyl and C-7 methoxy group on carbazole motif are favoured for anti-cancer activity...
February 7, 2019: European Journal of Medicinal Chemistry
Bin-Rong Yao, Yue Sun, Shuang-Long Chen, Hao-Dong Suo, Yu-Long Zhang, Hao Wei, Chun-Hua Wang, Feng Zhao, Wei Cong, Wen-Yu Xin, Gui-Ge Hou
To get new anti-hepatoma agents with anti-inflammatory activity and hypotoxicity, a series of dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs, 25-82) were designed and synthesized. Many of them exhibited potential anti-hepatoma properties against human hepatocellular carcinoma cell lines (HepG2, QGY-7703, SMMC-7721) and hypotoxicity for human normal heptical cell line (HHL-5, LO2), and prominently inhibited lipopolysaccharides (LPS) induced IL-6, TNF-α secretion to exert its anti-inflammatory effect...
February 7, 2019: European Journal of Medicinal Chemistry
Takeshi Yokoyama, Ryota Kitakami, Mineyuki Mizuguchi
MutT homologue 1 (MTH1) protects the nucleotide pool from oxidative stress by hydrolyzing oxidized nucleoside triphosphates and prevents their incorporation into DNA. Cancer cells are dependent on the MTH1 activity for survival due to the high-level of reactive oxygen species in cancer cells; therefore, MTH1 is considered to be a novel target for treatment of various cancers. Here, we show by X-ray crystallographic screening using an in-house cocktail library that α-mangostin, a natural xanthone from mangosteen pericarp, binds to the active site of MTH1...
February 7, 2019: European Journal of Medicinal Chemistry
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