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European Journal of Medicinal Chemistry

Mohamed A Abdelrahman, Ismail Salama, Mohamed S Gomaa, Mahmoud M Elaasser, Marwa M Abdel-Aziz, Dalia H Soliman
The increased development of highly resistant bacterial strains and tuberculosis, constitute a serious public health threat, highlighting the urgent need of novel antibacterial agents. In this work, two novel series of nicotinic acid hydrazone derivatives (6a-r) and quinolone hydrazide derivatives (12a-l) were synthesized and evaluated as antimicrobial and antitubercular agents. The synthesized compounds were evaluated in vitro for their antibacterial, antifungal and antimycobacterial activities. Compounds 6f and 6p bearing the 3,4,5- (OCH3)3 and 2,5-(OCH3)2 benzylidene motifs were the most potent and as antibacterial, antifungal (MIC: 0...
July 4, 2017: European Journal of Medicinal Chemistry
Jin Chang, Hongyu Ren, Mingxia Zhao, Yan Chong, Wenwen Zhao, Yong He, Yunling Zhao, Huabei Zhang, Chuanmin Qi
4-anilinoquinazoline-based derivatives represent an attractive scaffold for small molecular EGFR-TKIs in the field of medicinal chemistry. A series of novel heterocyclic substituted derivatives have been designed, synthesized and evaluated their antitumor bioactivities as potential EGFR-TKIs. Most of the new compounds exhibited certain efficient inhibition potency for proliferation of a panel of five human cancer cells with IC50 values at the low micromolar level, and some of them possessed good broad-spectrum inhibition activities, compared to Gefitinib...
July 4, 2017: European Journal of Medicinal Chemistry
Chao Tian, Meng Wang, Zifei Han, Fang Fang, Zhili Zhang, Xiaowei Wang, Junyi Liu
A series of novel 6-substituted pyrrolo[3,2-d]pyrimidine analogues (10a, 11a-13a, 15a, 17a, 18a, 27a and 28a) have been designed and synthesized as antifolate antitumor agents. The anti-proliferative activities of these compounds against HL60, A549, H1299, Hela, HCT116 and HT29 tumor cells were evaluated. Most of the compounds exhibited micromolar anti-proliferative potencies. Compound 15a, the most potent one, has GI50 value of 0.73, 1.72, and 8.92 μM against A549, H1299 and HL60 cells, respectively. The cell cycle distribution assay displayed that 15a could increase the accumulation of G2/M-phase cells...
July 4, 2017: European Journal of Medicinal Chemistry
Ghaneya S Hassan, Doaa E Abdel Rahman, Yassin M Nissan, Esraa A Abdelmajeed, Tamer M Abdelghany
A series of novel pyrazolo[3,4-d]pyrimidines bearing benzenesulfonamide moiety 5a-f, 6 and 7 were synthesized. Cytotoxic screening was conducted against MCF-7 and HepG2. 6-(4-Methoxyphenyl)-4-oxopyrazolopyrimidine derivative 5e and 4-imino-6-oxopyrazolopyrimidine derivative 6 revealed potent cytotoxic activity with IC50 1.4 μM (MCF-7) and 0.4 μM (HepG2), respectively compared to that of doxorubicin, (IC50 = 1.02 μM and 0.9 μM, respectively). Compounds 5e and 6 were subjected to cell cycle analysis and apoptosis assay after 24 h and 48 h treatment...
July 3, 2017: European Journal of Medicinal Chemistry
Zheng Li, Chunxia Liu, Xue Xu, Qianqian Qiu, Xin Su, Yuxuan Dai, Jianyong Yang, Huilan Li, Wei Shi, Chen Liao, Miaobo Pan, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFA1) has emerged as an attractive anti-diabetic target that mediates glucose-stimulated insulin secretion. Several FFA1 agonists have been reported, but many of them possessed somewhat high lipophilicity and/or molecular weight. Herein, we describe the identification of sulfone-carboxylic acid moiety with the multiple advantages of reducing lipophilicity, cytotoxicity and β-oxidation associated with compound 2. Further structure-activity relationship study based on the previleged scaffolds led to the discovery of 2-{(4-[(2'-chloro-[1,1'-biphenyl]-3-yl)methoxy]phenyl)sulfonyl}acetic acid (compound 20), which showed a better balance than compound 2 in terms of physicochemical properties, cytotoxicity profiles and pharmacokinetic properties...
July 3, 2017: European Journal of Medicinal Chemistry
Sougata Dey, Louisa Temme, Julian A Schreiber, Dirk Schepmann, Bastian Frehland, Kirstin Lehmkuhl, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities...
July 1, 2017: European Journal of Medicinal Chemistry
Yang Liu, Yanzhen Yin, Zhen Zhang, Carrie J Li, Hui Zhang, Daoguang Zhang, Changying Jiang, Krystle Nomie, Liang Zhang, Michael L Wang, Guisen Zhao
Targeting of Akt has been validated as a well rationalized approach to cancer treatment, and represents a promising therapeutic strategy for aggressive hematologic malignancies. We describe herein an exploration of novel Akt inhibitors for cancer therapy through structural optimization of previously described 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives. Our studies yielded a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides capable of potent inhibition of Akt1. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells...
June 30, 2017: European Journal of Medicinal Chemistry
Mehr-Un Nisa, Munawar A Munawar, Amber Iqbal, Asrar Ahmed, Muhammad Ashraf, Qurra-Tul-Ann A Gardener, Misbahul A Khan
A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2...
June 30, 2017: European Journal of Medicinal Chemistry
Y Gilad, H Tuchinsky, G Ben-David, R Minnes, A Gancz, H Senderowitz, G Luboshits, M A Firer, G Gellerman
The resistance of cancer cells to chemotherapeutic agents, whether through intrinsic mechanisms or developed resistance, motivates the search for new chemotherapeutic strategies. In the present report, we demonstrate a facile synthetic strategy towards the discovery of new anti-cancer substances. This strategy is based on simple covalent coupling between known anti-cancer drugs, which results in novel 'chimeric' small molecules. One of these novel compounds, CM358, is the product of an amide bond formation between the known Topoisomerase II (Topo II) inhibitor amonafide (AM) and the known DNA mustard alkylator chlorambucil (CLB)...
June 29, 2017: European Journal of Medicinal Chemistry
Anum Khalid Khan, Ayaz Ahmed, Mustafa Hussain, Ishtiaq Ahmad Khan, Syed Abid Ali, Ahsana Dar Farooq, Shaheen Faizi
The clerodane diterpenoids 16-oxo-cleroda-3, 13(14) E-diene-15 oic acid (1) and kolavenic acid (2) isolated from Polyalthia longifolia var. pendula (Linn.) were previously reported for their antimicrobial activity. Thus present study was designed to investigate the biofilm inhibiting potential of these diterpenoids (1-2) and five new lactone derivatives (3-7) of 1 against methicillin resistant Staphylococcus aureus (MRSA), Streptococcus mutans, Klebsiella pneumoniae and Proteus mirabilis. Compounds 1 and 3 at 10-20 μg/mL were found to be bacteriostatic and significantly reduced the biofilm formation and metabolically active cells of MRSA and S...
June 29, 2017: European Journal of Medicinal Chemistry
Maíra Bidart de Macedo, Roman Kimmel, Damijana Urankar, Martin Gazvoda, Antonio Peixoto, Freya Cools, Eveline Torfs, Luc Verschaeve, Emerson Silva Lima, Antonín Lyčka, David Milićević, Antonín Klásek, Paul Cos, Stanislav Kafka, Janez Košmrlj, Davie Cappoen
In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 μM and against Mycobacterium bovis AN5A below 15 μM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range...
June 29, 2017: European Journal of Medicinal Chemistry
Ozkan Sari, Sebastien Boucle, Bryan D Cox, Tugba Ozturk, Olivia Ollinger Russell, Leda Bassit, Franck Amblard, Raymond F Schinazi
The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion...
June 29, 2017: European Journal of Medicinal Chemistry
Aneta Pogorzelska, Jarosław Sławiński, Beata Żołnowska, Krzysztof Szafrański, Anna Kawiak, Jarosław Chojnacki, Szymon Ulenberg, Joanna Zielińska, Tomasz Bączek
A series of new 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The obtained results indicated that these compounds display prominent cytotoxic effect. The best anticancer properties have been observed for derivatives 44 (IC50 = 6-18 μM) and 45 (IC50 = 8-14 μM). Very good results of antiproliferative assays have been also shown for compounds 26, 36, and 46 and noticeable anticancer profile has been found for set of derivatives 34-39...
June 29, 2017: European Journal of Medicinal Chemistry
Wenxuan Zhang, Jun Wu, Bo Li, Xu Lian, Jie Xia, Qi Zhou, Song Wu
Two conformationally restricted salinomycin derivatives by tethering the hydroxyl groups at C1 and C20 with different chain length were designed and synthesized. The cyclic derivatives showed better biological activities than C1/C20 modified derivatives, indicating the importance of the compact conformation for the ion binding capacity. In addition, the length of the connective chain plays critical role in the biological activities, thus cyclic the derivative 7 preserved some pharmacological activity but derivative 5 with two carbon atom shorter chain showed significantly reduced activity...
June 29, 2017: European Journal of Medicinal Chemistry
Xianling Ning, Hailong Qi, Ridong Li, Yunqiao Li, Yan Jin, Michael A McNutt, Junyi Liu, Yuxin Yin
Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme of the glycolytic pathway which is highly expressed in cancer cells. Cancer cells rely heavily on PKM2 for anabolic and energy requirements, and specific targeting of PKM2 therefore has potential as strategy for cancer therapy. Here, we report the synthesis and biologic evaluation of novel naphthoquinone derivatives as selective small molecule inhibitors of PKM2. Some target compounds, such as compound 3k, displayed more potent PKM2 inhibitory activity than the reported optimal PKM2 inhibitor shikonin...
June 29, 2017: European Journal of Medicinal Chemistry
Irene G Salado, Josefa Zaldivar-Diez, Víctor Sebastián-Pérez, Lingling Li, Larissa Geiger, Silvia González, Nuria E Campillo, Carmen Gil, Aixa V Morales, Daniel I Perez, Ana Martinez
Leucine-rich repeat kinase 2 (LRRK2) is one of the most pursued targets for Parkinson's disease (PD) therapy. Moreover, it has recently described its role in regulating Wnt signaling and thus, it may be involved in adult neurogenesis. This new hypothesis could give rise to double disease-modifying agents firstly by the benefits of inhibiting LRRK2 and secondly by promoting adult neurogenesis. Herein we report, the design, synthesis, biological evaluation, SAR and potential binding mode of indoline-like LRRK2 inhibitors and their preliminary neurogenic effect in neural precursor cells isolated from adult mice ventricular-subventricular zone...
June 29, 2017: European Journal of Medicinal Chemistry
Rocío Recio, Empar Vengut-Climent, Bernard Mouillac, Hélène Orcel, Miguel López-Lázaro, José Manuel Calderón-Montaño, Eleuterio Álvarez, Noureddine Khiar, Inmaculada Fernández
A library of 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyrans has been synthesized as a new family of non-peptide NK1 receptor ligands by a one-pot cascade process. Their biological effects via interaction with the NK1 receptor were experimentally determined as percentage of inhibition (for antagonists) and percentage of activation (for agonists), compared to the substance P (SP) effect, in IPone assay. A set of these amino compounds was found to inhibit the action of SP, and therefore can be considered as a new family of SP-antagonists...
June 28, 2017: European Journal of Medicinal Chemistry
Anthony D Verderosa, César de la Fuente-Núñez, Sarah C Mansour, Jicong Cao, Timothy K Lu, Robert E W Hancock, Kathryn E Fairfull-Smith
As bacterial biofilms display extreme tolerance to conventional antibiotic treatments, it has become imperative to develop new antibacterial strategies with alternative mechanisms of action. Herein, we report the synthesis of a series of ciprofloxacin-nitroxide conjugates and their corresponding methoxyamine derivatives in high yield. This was achieved by linking various nitroxides or methoxyamines to the secondary amine of the piperazine ring of ciprofloxacin using amide bond coupling. Biological evaluation of the prepared compounds on preformed P...
June 28, 2017: European Journal of Medicinal Chemistry
Guojun Pan, Xuehui Li, Long Zhao, Meng Wu, Chao Su, Xuzhe Li, Yongmin Zhang, Peng Yu, Yuou Teng, Kui Lu
Two novel flavonoids (±)-Anastatins A and B as well as 14 analogs, which containing a benzofuran moiety, were synthesized by using halogenation, Suzuki coupling reaction and an oxidation/Oxa-Michael reaction cascade as the key steps. The structures of the new flavonoids were confirmed by (1)H NMR, (13)C NMR and HRMS. The antioxidant activities of them as well as the key intermediates were evaluated by ferric reducing antioxidant power (FRAP) assay and the active compounds were evaluated in the PC12 cell model of hydrogen peroxide (H2O2)-induced oxidative damage...
June 27, 2017: European Journal of Medicinal Chemistry
Macarena Martínez-Bailén, Ana T Carmona, Elena Moreno-Clavijo, Inmaculada Robina, Daisuke Ide, Atsushi Kato, Antonio J Moreno-Vargas
The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two β-glucosidase (almond) inhibitors (14b,f) in the low μM range. The additional biological analysis of 14b,f towards β-glucocerebrosidase (human lysosomal β-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme...
June 27, 2017: European Journal of Medicinal Chemistry
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