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European Journal of Medicinal Chemistry

Marta Rui, Giacomo Rossino, Stefania Coniglio, Stefania Monteleone, Arianna Scuteri, Alessio Malacrida, Daniela Rossi, Laura Catenacci, Milena Sorrenti, Mayra Paolillo, Daniela Curti, Letizia Venturini, Dirk Schepmann, Bernhard Wünsch, Klaus R Liedl, Guido Cavaletti, Vittorio Pace, Ernst Urban, Simona Collina
In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed...
September 8, 2018: European Journal of Medicinal Chemistry
Chetan P Shah, Prashant S Kharkar
The enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, and thus regulates the guanine nucleotide pool required for cell proliferation. Of the two isoforms, human IMPDH type 2 (hIMPDH2) is a validated molecular target for potential immunosuppressive, antiviral and anticancer chemotherapy. In search of newer hIMPDH2 inhibitors as potential anticancer agents, three novel series (A: 5-aminoisobenzofuran-1(3H)-one, B: 3,4-dimethoxyaniline and C: benzo[d]-[1,3]dioxol-5-ylmethanamine) were synthesized and evaluated for in vitro and cell-based activities...
September 7, 2018: European Journal of Medicinal Chemistry
Barbara Parrino, Salviana Ullo, Alessandro Attanzio, Stella Cascioferro, Virginia Spanò, Anna Carbone, Alessandra Montalbano, Paola Barraja, Girolamo Cirrincione, Luisa Tesoriere, Patrizia Diana
Pyrrolizinones represent an interesting class of compounds with varied degrees of structural complexity and pharmacological activity. Among these, 9H-pyrido[2,3-b]pyrrolizin-9-one, tripentone analogs, recently reported by us, showed significant antiproliferative activity against human tumor cell lines, inducing apoptosis and not affecting viability of Caco-2 differentiated in normal intestinal-like cells. Considering their interesting biological activity, their 5H-pyrido[3,2-b]pyrrolizin-5-one analogs were efficiently synthesized in good to excellent yields (61-91%)...
September 7, 2018: European Journal of Medicinal Chemistry
Shuang-Xi Gu, Huan-Huan Lu, Gen-Yan Liu, Xiu-Lian Ju, Yuan-Yuan Zhu
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges...
September 6, 2018: European Journal of Medicinal Chemistry
Ming Guo, Daiying Zuo, Junlong Zhang, Lingyun Xing, Wenfeng Gou, Feng Jiang, Nan Jiang, Dajun Zhang, Xin Zhai
To identify ALK and ROS1 dual inhibitors conferring resistance to ALK secondary mutations, especially 'gatekeeper' L1196 M and the most predominant ceritinib-resistant G1202R mutations, a series of novel 2,4-diarylaminopyrimidine analogues were designed and synthesized by incorporating 2-alkoxy-6-alicyclic aminopyridinyl motifs. The biological evaluations on cellular and enzymatic assays led to identification of compound F-1, which turned out to be effective against ALKWT , ROS1WT , ALKL1196M and ALKG1202R kinases with IC50 of 2...
September 6, 2018: European Journal of Medicinal Chemistry
Jingjing Peng, Lifen Zhao, Lanlan Wang, Hui Chen, Yunguang Qiu, Jiang Wang, Huaiyu Yang, Jun Liu, Hong Liu
A novel series of 2-(phenoxyaryl)-3-urea derivatives were designed, synthesized, and biologically evaluated for their anti-thrombotic activity. Most of compounds exhibited good inhibition against P2Y1 receptor. Among them, three compounds 11, 12, and 13 demonstrated good P2Y1 receptor antagonistic potency in vitro (IC50  = 0.62 μM, 0.82 μM, and 0.21 μM, respectively). In antiplatelet aggregation study, four compounds 2, 3, 9, and 13 showed good antiplatelet activity. The possible binding modes of compounds with P2Y1 receptor were also explored by molecular docking simulation...
September 6, 2018: European Journal of Medicinal Chemistry
Julian A Schreiber, Sebastian L Müller, Stefanie E Westphälinger, Dirk Schepmann, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
GluN2A containing N-methyl-D-aspartate receptors (NMDARs) are important ion channels in the central nervous system and highly involved in several different neurophysiological but also neuropathophysiological processes. However, current understanding of the contribution of GluN2A containing NMDARs in these processes is incomplete. Therefore, highly selective compounds are required to further investigate these ion channels. In 2010, TCN-201 (2), one of the first selective negative allosteric modulators was reported...
September 6, 2018: European Journal of Medicinal Chemistry
Usama M Ammar, Mohammed S Abdel-Maksoud, Chang-Hyun Oh
Frequent oncogenic mutations have been identified in MAPK (mitogen-activated protein kinase) signaling pathway components. As a result, MAPK pathway is associated with human cancer initiation, in particular RAF (rapidly accelerated fibrosarcoma) component. The mutation in RAF component leads to auto-activation of MAPK signaling pathway, stimulating the uncontrolled cell growth and proliferation. In last few years, diverse chemical scaffolds have been identified as RAF inhibitors. Most of these scaffolds show potent anti-cancer activity...
September 6, 2018: European Journal of Medicinal Chemistry
Qi-Pin Qin, Shu-Long Wang, Ming-Xiong Tan, Zhen-Feng Wang, Dong-Mei Luo, Bi-Qun Zou, Yan-Cheng Liu, Peng-Fei Yao, Hong Liang
In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH3 OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4'-dimethyl-2,2'-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1Pt7 exhibited cytotoxic activity against the tested NCIH460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity...
September 6, 2018: European Journal of Medicinal Chemistry
Ling-Hsien Tu, Ning-Hsuan Tseng, Ya-Ru Tsai, Tien-Wei Lin, Yi-Wei Lo, Jien-Lin Charng, Hua-Ting Hsu, Yu-Sheng Chen, Rong-Jie Chen, Ying-Ta Wu, Yi-Tsu Chan, Chang-Shi Chen, Jim-Min Fang, Yun-Ru Chen
One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-β (Aβ) fibrils. Blocking Aβ self-assembly or disassembling Aβ aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aβ fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ∼5.0 Å in length, which is close to the distance of adjacent β sheets in Aβ fibrils, showed good potency to inhibit Aβ(1-42) fibrillization...
September 5, 2018: European Journal of Medicinal Chemistry
Alessandro Giraudo, Jacob Krall, Birgitte Nielsen, Troels E Sørensen, Kenneth T Kongstad, Barbara Rolando, Donatella Boschi, Bente Frølund, Marco L Lolli
The correct application of bio(iso)steric replacement, a potent tool for the design of optimized compounds, requires the continuous development of new isosters able to respond to specific target requirements. Among carboxylic acid isosters, as the hydroxylated pentatomic heterocyclic systems, the hydroxy-1,2,3-triazole represents one of the most versatile but less investigated. With the purpose to enlarge its bioisosteric application, we report the results of a study devoted to obtain potential biomimetics of the γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS)...
September 5, 2018: European Journal of Medicinal Chemistry
Yachuang Wu, Xiudong Ding, Liang Ding, Yongsheng Zhang, Lei Cui, Lu Sun, Wei Li, Di Wang, Yanfang Zhao
A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome...
September 5, 2018: European Journal of Medicinal Chemistry
Walaa M El-Husseiny, Magda A-A El-Sayed, Naglaa I Abdel-Aziz, Adel S El-Azab, Yousif A Asiri, Alaa A-M Abdel-Aziz
A new series of non-carboxylic naproxen analogues, bearing a variety of ring systems, such as oxadiazoles 3a-c and 6a-c, cycloalkanes 4a-d, cyclic imides 5a-c, and triazoles 7-9 and 10a-c, was synthesized. In addition, in vitro antitumor activity and cyclooxygenase isozymes (COX-1/COX-2) inhibition assay of the target compounds 3-10 was studied. The results of the antitumor activity assays indicated that compounds 4b, 6c, 10b, and 10c exhibited the greatest antitumor activities against the tested cell lines MCF-7, MDA-231, HeLa, and HCT-116, with an IC50 range of 4...
September 5, 2018: European Journal of Medicinal Chemistry
Giulia Martelli, Daria Giacomini
Antimicrobial resistance is widely recognized as a grave threat to global health in the 21st century, since the past decades have seen a dramatic increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. New antimicrobial agents are urgently required, particularly in the treatment of chronic infections such as cystic fibrosis, often associated with persistent colonization by drug-resistant pathogens and epithelial damage by pulmonary oxidative stress. In such events, it would be favourable to find agents that could have antioxidant and antibacterial activities combined in one molecule...
September 5, 2018: European Journal of Medicinal Chemistry
Sarfaraj Niazi, Madhusudan Purohit, Javed H Niazi
Maintenance of genome integrity under the stressed condition is paramount for normal functioning of cells in the multicellular organisms. Cells are programmed to protect their genome through specialized adaptive mechanisms which will help decide their fate under stressed conditions. These mechanisms are the outcome of activation of the intricate circuitries that are regulated by the p53 master protein. In this paper, we provided a comprehensive review on p53, p53 homologues and their isoforms, including a description about the ubiquitin-proteasome system emphasizing its role in p53 regulation...
September 4, 2018: European Journal of Medicinal Chemistry
Sarah S Darwish, Mohammad Abdel-Halim, Ahmed K ElHady, Mohamed Salah, Ashraf H Abadi, Walter Becker, Matthias Engel
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a potential target in Alzheimer's disease (AD) because of the established correlation between its over-expression and generation of neurofibrillary tangles (NFT) as well as the accumulation of amyloid plaques. However, the use of Dyrk1A inhibitors requires a high degree of selectivity over closely related kinases. In addition, the physicochemical properties of the Dyrk1A inhibitors need to be controlled to enable CNS permeability. In the present study, we optimized our previously published 2,4-bispyridyl thiophene class of Dyrk1A inhibitors by the synthesis of a small library of amide derivatives, carrying alkyl, cycloalkyl, as well as acidic and basic residues...
September 3, 2018: European Journal of Medicinal Chemistry
Shweta Sinha, Mukesh Doble, S L Manju
Human 5-Lipoxygenase (5-LOX) is a key enzyme targeted for asthma and inflammation. Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems. In the present study, the performance of rationally designed conjugates of thiazole (2) and thiourea (3) scaffolds from our previously reported 2-amino-4-aryl thiazole (1) is reported. They are synthesized (total 31 derivatives), characterized, and tested against the 5-LOX enzyme in vitro and the mode of action of the most active ones are determined...
September 3, 2018: European Journal of Medicinal Chemistry
Guillaume Compain, Nassima Oumata, Jonathan Clarhaut, Elodie Péraudeau, Brigitte Renoux, Hervé Galons, Sébastien Papot
We report on the synthesis and in vitro biological evaluations of a nanomolar protein kinase inhibitor (PKI) and its β-glucuronidase-responsive albumin-binding prodrug. The highly potent PKI is 400-3400 times more cytotoxic than the well-known PKI Roscovitine. The prodrug is able to bind covalently to human serum albumin through Michael addition and release the cytotoxic PKI in the presence of β-glucuronidase, an enzyme over-expressed in the microenvironment of solid tumours.
September 3, 2018: European Journal of Medicinal Chemistry
Andrea Angeli, Elena Trallori, Marta Ferraroni, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Claudiu T Supuran
A series of disubstituted selenazole derivatives was synthetized and evaluated as carbonic anhydrase (CA, EC inhibitors against the human (h) isoforms hCA I, II, IV, VA, VB and IX, involved in a variety of diseases including glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors. The investigated compounds showed potent inhibition against the tumor-associated transmembrane hCA IX, with KI s in the subnanomolar - low nanomolar range, and were evaluated for their effects on cell viability against the human prostate (PC3) and breast (MDA-MB-231) cancer cell lines, showing effective anti-tumor activity...
September 3, 2018: European Journal of Medicinal Chemistry
Carlotta Granchi
ATP citrate lyase (ACLY) is a cytosolic homotetrameric enzyme that catalyzes the conversion of citrate and coenzyme A (CoA) to acetyl-CoA and oxaloacetate, with the simultaneous hydrolysis of ATP to ADP and phosphate. Interestingly, ACLY is a strategic enzyme linking both the glycolytic and lipidic metabolism. In tumour cells characterized by an altered energetic metabolism, an increased glucose uptake and an accelerated glycolytic flux lead to an intensified production of mitochondrial citrate. Once transported to the cytosol, citrate is here converted by ACLY to acetyl-CoA, an essential biosynthetic precursor for fatty acid synthesis and mevalonate pathway...
September 1, 2018: European Journal of Medicinal Chemistry
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