Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold.
In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clinical studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compounds. In addition, by introducing a hydroxyl group, our compounds have significantly improved solubility and may target specific polar residues Arg57, Glu69 and Arg134 of Plk1. Moreover, most of our compounds exhibited antitum...
Source: European Journal of Medicinal Chemistry - October 11, 2019 Category: Chemistry Authors: Lv X, Yang X, Zhan MM, Cao P, Zheng S, Peng R, Han J, Xie Z, Tu Z, Liao C Tags: Eur J Med Chem Source Type: research

Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity.
Abstract Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 μM) value which is significantly lower than the activity of trimethoprim (IC50 39.23 μM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88-83.49 μM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalia...
Source: European Journal of Medicinal Chemistry - October 10, 2019 Category: Chemistry Authors: Rosada B, Bekier A, Cytarska J, Płaziński W, Zavyalova O, Sikora A, Dzitko K, Łączkowski KZ Tags: Eur J Med Chem Source Type: research

Discovery of coumarin-derived imino sulfonates as a novel class of potential cardioprotective agents.
Abstract The burst of reactive oxygen species (ROS) contributes to and exacerbates cardiac injury. Exogenous supplementation of antioxidants or upregulation of endogenous antioxidant defense genes should be the potential therapies for cardiovascular disease. Sixteen coumarin-derived imino sulfonates compounds were synthesized with the ability of attenuating oxidative stress directly by reducing intracellular ROS level via promoting Nrf2 pathway. The cell-based assays showed that most of the compounds had significant protective activity against H2O2-induced oxidative injury in H9c2 cells. Compound 5h with the highe...
Source: European Journal of Medicinal Chemistry - October 10, 2019 Category: Chemistry Authors: Wei B, Zhou J, Xu JJ, Cui J, Ping FF, Ling JJ, Chen YJ Tags: Eur J Med Chem Source Type: research

Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors.
Abstract Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 va...
Source: European Journal of Medicinal Chemistry - October 9, 2019 Category: Chemistry Authors: Lu W, Wang J, Li Y, Tao H, Xiong H, Lian F, Gao J, Ma H, Lu T, Zhang D, Ye X, Ding H, Yue L, Zhang Y, Tang H, Zhang N, Yang Y, Jiang H, Chen K, Zhou B, Luo C Tags: Eur J Med Chem Source Type: research

Molecular and clinical insights into protein misfolding and associated amyloidosis.
Abstract The misfolding of normally soluble proteins causes their aggregation and deposition in the tissues which disrupts the normal structure and function of the corresponding organs. The proteins with high β-sheet contents are more prone to form amyloids as they exhibit high propensity of self-aggregation. The self aggregated misfolded proteins act as template for further aggregation that leads to formation of protofilaments and eventually amyloid fibrils. More than 30 different types of proteins are known to be associated with amyloidosis related diseases. Several aspects of the amyloidogenic behavior of ...
Source: European Journal of Medicinal Chemistry - October 7, 2019 Category: Chemistry Authors: Pande M, Srivastava R Tags: Eur J Med Chem Source Type: research

Novel thiosemicarbazone derivatives containing indole fragment as potent and selective anticancer agent.
In this report, a series of novel thiosemicarbazone derivatives containing indole fragment were designed and synthesized. Most compounds exhibited excellent antiproliferative activity against PC3, MGC803 and EC109 cell lines with low micromolar IC50 (0.14-12μM). Especially, compound 5j can selectively inhibit PC3 cells in three tested tumor cells with IC50 value of 0.14 μM, which may be attributed to a synergistic effect after introducing indole fragment into the TSC structure. Meanwhile, compound 5j displayed more selectivity in PC3 cells toward two normal WPMY-1 and GES-1 cell lines, compared to those of 3-AP...
Source: European Journal of Medicinal Chemistry - October 7, 2019 Category: Chemistry Authors: He Z, Qiao H, Yang F, Zhou W, Gong Y, Zhang X, Wang H, Zhao B, Ma L, Liu HM, Zhao W Tags: Eur J Med Chem Source Type: research

Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases.
In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies. Our modelling experiments and the chemical structures of the compounds predict the possibility of covalent inhibition. The most effective compounds triggered apoptosis in FLT3-ITD AML cells but had either weak or no effect in FLT3-independent leukemic and non-leukemic cell lines. Our results strongly suggest that our compounds may become therapeut...
Source: European Journal of Medicinal Chemistry - October 5, 2019 Category: Chemistry Authors: Baska F, Sipos A, Őrfi Z, Nemes Z, Dobos J, Szántai-Kis C, Szabó E, Szénási G, Dézsi L, Hamar P, Cserepes MT, Tóvári J, Garamvölgyi R, Krekó M, Őrfi L Tags: Eur J Med Chem Source Type: research

Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl- β-phosphate scaffold.
Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-β-phosphate scaffold. Eur J Med Chem. 2019 Oct 04;184:111754 Authors: Nassir M, Pelletier J, Arad U, Arguin G, Khazanov N, Gendron FP, Sévigny J, Senderowitz H, Fischer B Abstract Overexpression of ecto-nucleotide pyrophosphatase-1 (NPP1) is associated with diseases such as calcium pyrophosphate dihydrate deposition disease, calcific aortic valve disease, and type 2 diabetes. In this context, NPP1 inhibitors are potential drug candidates for the treatment of these diseases. The present study focuses ...
Source: European Journal of Medicinal Chemistry - October 4, 2019 Category: Chemistry Authors: Nassir M, Pelletier J, Arad U, Arguin G, Khazanov N, Gendron FP, Sévigny J, Senderowitz H, Fischer B Tags: Eur J Med Chem Source Type: research

Chalcone derivatives targeting mitosis: synthesis, evaluation of antitumor activity and lipophilicity.
This study describes the synthesis of a series of chalcones, including pyrazole and α,β-epoxide derivatives, and evaluation of their cell growth inhibitory activity in three human tumor cell lines, as well as their lipophilicity using liposomes as a biomimetic membrane model. Structure-activity and structure-lipophilicity relationships were established for the synthetized chalcones. From this work, nine chalcones (3, 5, 9, 11, 15-19) showing suitable drug-like lipophilicity with potent growth inhibitory activity were identified, being the growth inhibitory effect of compounds 15-17 associated with a pronounced a...
Source: European Journal of Medicinal Chemistry - October 3, 2019 Category: Chemistry Authors: Pinto P, Machado CM, Moreira J, Almeida JDP, Silva PMA, Henriques AC, Soares JX, Salvador JAR, Afonso C, Pinto M, Bousbaa H, Cidade H Tags: Eur J Med Chem Source Type: research

Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors.
Abstract Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit...
Source: European Journal of Medicinal Chemistry - October 3, 2019 Category: Chemistry Authors: Zou Y, Hu Y, Ge S, Zheng Y, Li Y, Liu W, Guo W, Zhang Y, Xu Q, Lai Y Tags: Eur J Med Chem Source Type: research

Strong in  vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives.
Strong in vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives. Eur J Med Chem. 2019 Oct 02;184:111751 Authors: Qin QP, Wang ZF, Huang XL, Tan MX, Zou BQ, Liang H Abstract A series of novel organoplatinum(II) complexes, [PtII(QC1)(H-QC1)Cl] (Pt1), [PtII(QC2)(H-QC2)Cl] (Pt2), [PtII(QC3)(H-QC3)Cl] (Pt3), [PtII(QC4)(H-QC4)Cl]⋅CH3OH (Pt4), [PtII(QC5)(H-QC5)Cl] (Pt5), [PtII(H-QC6)(DMSO)Cl2] (Pt6), [PtII(H-QC7)(DMSO)Cl2]⋅H2O (Pt7), [PtII(H-QC8)(DMSO)Cl2] (Pt8), [PtII(H-QC9)(DMSO)Cl2]⋅CH3OH (Pt9), [PtII(H-QC10)(DMSO)Cl2] (Pt10) and [PtII(H-...
Source: European Journal of Medicinal Chemistry - October 2, 2019 Category: Chemistry Authors: Qin QP, Wang ZF, Huang XL, Tan MX, Zou BQ, Liang H Tags: Eur J Med Chem Source Type: research

Discovery of novel allosteric site and covalent inhibitors of FBPase with potent hypoglycemic effects.
Abstract Fructose-1,6-bisphosphatase (FBPase) is an essential enzyme of GNG pathway. Significant advances demonstrate the FBPase plays a critical role in treatment of diabetes. Numerous FBPase inhibitors were developed by targeting AMP site, nevertheless, none of these inhibitors has exhibited suitable potency and druggability. Herein, a new allosteric site (C128) on FBPase was discovered, and several nitrostyrene compounds exhibiting potent FBPase inhibitions were found covalently bind to C128 site on FBPase. Mutagenesis suggest that C128 is the only cysteine that can influence FBPase inhibition, the N125-S124-S1...
Source: European Journal of Medicinal Chemistry - September 30, 2019 Category: Chemistry Authors: Huang Y, Wei L, Han X, Chen H, Ren Y, Xu Y, Song R, Rao L, Su C, Peng C, Feng L, Wan J Tags: Eur J Med Chem Source Type: research

Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives.
Abstract Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted f...
Source: European Journal of Medicinal Chemistry - September 28, 2019 Category: Chemistry Authors: Macan AM, Harej A, Cazin I, Klobučar M, Stepanić V, Pavelić K, Pavelić SK, Schols D, Snoeck R, Andrei G, Raić-Malić S Tags: Eur J Med Chem Source Type: research

Recent development of membrane-active molecules as antibacterial agents.
Abstract The continuous emergence of drug-resistant bacteria has become a severe threat to the public health. Therefore, the discovery of novel antibacterial mechanisms to combat this jeopardized problem is urgently needed. In the past decades, plenty of new antibacterial modes of action have been discovered continuously, based on which many promising scaffolds have been designed and synthesized. In particular, cationic amphiphilic small-molecules open a door to the new mode of action of bactericidal agents by depolarizing and disturbing the bacteria membrane. The cationic amphiphilic are characterized by high eff...
Source: European Journal of Medicinal Chemistry - September 27, 2019 Category: Chemistry Authors: Zhang N, Ma S Tags: Eur J Med Chem Source Type: research

Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease.
Abstract A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50 = 1.3 ± 0.01 μM) and butyrylcholinesterase (IC50 = 1.2 ± 0.09 μM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57 ± 0.01 μM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Aβ1-42 a...
Source: European Journal of Medicinal Chemistry - September 27, 2019 Category: Chemistry Authors: Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J, Lu X, Sang Z Tags: Eur J Med Chem Source Type: research

Design and synthesis of H2S-donor hybrids: A new treatment for Alzheimer's disease?
Abstract Hydrogen sulphide (H2S) is an endogenous gasotransmitter, largely known as a pleiotropic mediator endowed with antioxidant, anti-inflammatory, pro-autophagic, and neuroprotective properties. Moreover, a strong relationship between H2S and aging has been recently identified and consistently, a significant decline of H2S levels has been observed in patients affected by Alzheimer's disease (AD). On this basis, the use of H2S-donors could represent an exciting and intriguing strategy to be pursued for the treatment of neurodegenerative diseases (NDDs). In this work, we designed a small series of multitarget m...
Source: European Journal of Medicinal Chemistry - September 27, 2019 Category: Chemistry Authors: Sestito S, Pruccoli L, Runfola M, Citi V, Martelli A, Saccomanni G, Calderone V, Tarozzi A, Rapposelli S Tags: Eur J Med Chem Source Type: research

Novel tertiary sulfonamide derivatives containing benzimidazole moiety as potent anti-gastric cancer agents: Design, synthesis and SAR studies.
Abstract With the expectation to find out new anti-gastric cancer agents with high efficacy and selectivity, a series of novel tertiary sulfonamide derivatives were synthesized and the anti-cancer activity was studied in three selected cancer cell lines (MGC-803, PC-3, MCF-7) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells and were more potent than the positive control (5-Fu). The structure-activity relationship of tertiary sulfonamide derivatives was explored in this report. Among the tested compounds, compound 13g containing benzimidazol...
Source: European Journal of Medicinal Chemistry - September 25, 2019 Category: Chemistry Authors: Jian-Song, Gao QL, Wu BW, Li D, Shi L, Zhu T, Lou JF, Jin CY, Zhang YB, Zhang SY, Liu HM Tags: Eur J Med Chem Source Type: research

Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants.
Abstract Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited exc...
Source: European Journal of Medicinal Chemistry - September 24, 2019 Category: Chemistry Authors: Chen W, Guo X, Zhang C, Ke D, Zhang G, Yu Y Tags: Eur J Med Chem Source Type: research

Synthesis and biological evaluation of [18F](2S,4S)4-(3-fluoropropyl) arginine as a tumor imaging agent.
Abstract Designing novel 18F-labeled amino acid derivatives for targeted amino acid transporters is an attractive strategy for the development of therapeutic and diagnostic agents for cancer therapy. In this work, we have developed a novel 3-fluoropropyl analog of arginine, namely, (2S,4S)4-[18F]FPArg, [18F]1, to be used as a probe for studying arginine metabolism. Optically pure and labeled with 18F and 19F, (2S,4S)4-(3-fluoropropyl)arginine was synthesized and isolated in high radiochemical purity (>95%). In vitro uptake assays in human MCF-7 cells revealed that [18F]1 enters cells mainly via sodium-in...
Source: European Journal of Medicinal Chemistry - September 22, 2019 Category: Chemistry Authors: Wu R, Liu S, Liu Y, Sun Y, Cheng X, Huang Y, Yang Z, Wu Z Tags: Eur J Med Chem Source Type: research

Ellagic acid a multi-target bioactive compound for drug discovery in CNS? A narrative review.
Abstract It is well-known that the health properties attributed to several fruits, herbs, seeds and their processed foods/beverages are due to an important group of natural polyphenols classified as hydrolysable tannins (HT) named ellagitannins (ETs), that encompass both one or more gallic acid (GA) units and one or more hexahydroxydiphenoic acid (HHDP) units, ester-connected with a sugar residue. In vivo, ETs are rather not absorbed and in gastrointestinal tract (GIT), they are hydrolysed providing mainly ellagic acid (EA). Due to its trivial water-solubility, first pass effect, metabolism in GIT, or irrever...
Source: European Journal of Medicinal Chemistry - September 20, 2019 Category: Chemistry Authors: Alfei S, Turrini F, Catena S, Zunin P, Grilli M, Pittaluga AM, Boggia R Tags: Eur J Med Chem Source Type: research

Structural isomers of cinnamic hydroxamic acids block HCV replication via different mechanisms.
Abstract A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correla...
Source: European Journal of Medicinal Chemistry - September 20, 2019 Category: Chemistry Authors: Kozlov MV, Konduktorov KA, Malikova AZ, Kamarova KA, Shcherbakova AS, Solyev PN, Kochetkov SN Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives as novel xanthine oxidase inhibitors.
Abstract In our previous study, we reported a series of N-phenylisonicotinamide derivatives as novel xanthine oxidase (XO) inhibitors and identified N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (compound 1) as the most potent one with an IC50 value of 0.312 μM. To further optimize the structure and improve the potency, a structure-based drug design (SBDD) strategy was performed to construct the missing H-bond between the small molecule and the Asn768 residue of XO. We introduced a tetrazole moiety at the 3'-position of the phenyl to serve as an H-bond acceptor and obtained a series of N-(3-(1H-tetr...
Source: European Journal of Medicinal Chemistry - September 18, 2019 Category: Chemistry Authors: Zhang TJ, Zhang Y, Tu S, Wu YH, Zhang ZH, Meng FH Tags: Eur J Med Chem Source Type: research

Structure based design, synthesis and in  vitro antitumour activity of tiazofurin stereoisomers with nitrogen functions at the C-2' or C-3' positions.
Structure based design, synthesis and in vitro antitumour activity of tiazofurin stereoisomers with nitrogen functions at the C-2' or C-3' positions. Eur J Med Chem. 2019 Sep 18;183:111712 Authors: Kojić V, Popsavin M, Spaić S, Jakimov D, Kovačević I, Svirčev M, Aleksić L, Zelenović BS, Popsavin V Abstract Three novel tiazofurin analogues having d-arabino stereochemistry and nitrogen functionalities at the C-2' position (5-7) have been designed and synthesized in multistep sequences, starting from d-glucose. The known d-xylo stereoisomer of 1 (compound 2) along with two new analogues beari...
Source: European Journal of Medicinal Chemistry - September 18, 2019 Category: Chemistry Authors: Kojić V, Popsavin M, Spaić S, Jakimov D, Kovačević I, Svirčev M, Aleksić L, Zelenović BS, Popsavin V Tags: Eur J Med Chem Source Type: research

Dual-targeting liposomes with active recognition of GLUT5 and αvβ3 for triple-negative breast cancer.
Dual-targeting liposomes with active recognition of GLUT5 and αvβ3 for triple-negative breast cancer. Eur J Med Chem. 2019 Sep 18;183:111720 Authors: Pu Y, Zhang H, Peng Y, Fu Q, Yue Q, Zhao Y, Guo L, Wu Y Abstract At present, chemo- and radiotherapies remain to be the mainstream methods for treating triple-negative breast cancer (TNBC), which is known for poor prognosis and high rate of mortality. Two types of novel dual-targeting TNBC liposomes (Fru-RGD-Lip and Fru+RGD-Lip) that actively recognize both fructose transporter GLUT5 and integrin αvβ3 were designed and prepared in t...
Source: European Journal of Medicinal Chemistry - September 18, 2019 Category: Chemistry Authors: Pu Y, Zhang H, Peng Y, Fu Q, Yue Q, Zhao Y, Guo L, Wu Y Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents.
Abstract A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC50 values in the 10-8-10-9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC5...
Source: European Journal of Medicinal Chemistry - September 18, 2019 Category: Chemistry Authors: Wang R, Chen Y, Zhao X, Yu S, Yang B, Wu T, Guo J, Hao C, Zhao D, Cheng M Tags: Eur J Med Chem Source Type: research

Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines.
Abstract A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo- and 6-chloro-indole analogues which also exhibited modest activity (MIC 34-50 μM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Ps...
Source: European Journal of Medicinal Chemistry - September 17, 2019 Category: Chemistry Authors: Cadelis MM, Pike EIW, Kang W, Wu Z, Bourguet-Kondracki ML, Blanchet M, Vidal N, Brunel JM, Copp BR Tags: Eur J Med Chem Source Type: research

Heme Oxygenase-2 (HO-2) as a therapeutic target: Activators and inhibitors.
meo G Abstract Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activ...
Source: European Journal of Medicinal Chemistry - September 17, 2019 Category: Chemistry Authors: Intagliata S, Salerno L, Ciaffaglione V, Leonardi C, Fallica AN, Carota G, Amata E, Marrazzo A, Pittalà V, Romeo G Tags: Eur J Med Chem Source Type: research

A drug repurposing screening reveals a novel epigenetic activity of hydroxychloroquine.
Abstract Multiple myeloma (MM) is an incurable hematological malignancy driven by several genetic and epigenetic alterations. The hyperactivation of the Polycomb repressive complex 2 (PRC2), a multi-subunit oncogenic histone methyltransferase, has been implicated in the pathogenesis of this malignancy. Upon protein-protein interaction (PPI) between the catalytic subunit EZH2 and EED, PRC2 primarily methylates lysine 27 of histone H3 (H3K27me3), thus modulating the chromatin structure and inducing transcriptional repression. Herein, we highlight a new mechanism of action that can contribute to explain the anti-tumo...
Source: European Journal of Medicinal Chemistry - September 17, 2019 Category: Chemistry Authors: Catalano R, Rocca R, Juli G, Costa G, Maruca A, Artese A, Caracciolo D, Tagliaferri P, Alcaro S, Tassone P, Amodio N Tags: Eur J Med Chem Source Type: research

1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships.
Abstract Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable...
Source: European Journal of Medicinal Chemistry - September 16, 2019 Category: Chemistry Authors: Xu Z, Zhao SJ, Liu Y Tags: Eur J Med Chem Source Type: research

Progress in the development of more effective and safer analgesics for pain management.
cci L Abstract Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics ...
Source: European Journal of Medicinal Chemistry - September 16, 2019 Category: Chemistry Authors: Turnaturi R, Chiechio S, Salerno L, Rescifina A, Pittalà V, Cantarella G, Tomarchio E, Parenti C, Pasquinucci L Tags: Eur J Med Chem Source Type: research

Synthesis of coumarin-sulfonamide derivatives and determination of their cytotoxicity, carbonic anhydrase inhibitory and molecular docking studies.
Abstract Carbonic anhydrases isoforms CA IX, and XII are known to be highly expressed in various human tissues and malignancies. CA IX is a prominent target for especially colorectal cancers, because it is overexpressed in colorectal cancer and this overexpression leads poor prognosis. Inhibition of CA IX activity by small molecule CA inhibitors like sulfonamides, sulfonamide derivative or coumarins leads to inhibition of tumorigenesis. Novel twenty-seven compounds in three series (sulfonamide-based imines (6a-6i), coumarin-based aldehydes (7a-7i), and coumarin-sulfonamide-based target molecules (8a-8i)) were synt...
Source: European Journal of Medicinal Chemistry - September 14, 2019 Category: Chemistry Authors: Zengin Kurt B, Sonmez F, Ozturk D, Akdemir A, Angeli A, Supuran CT Tags: Eur J Med Chem Source Type: research

Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries.
In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cd...
Source: European Journal of Medicinal Chemistry - September 14, 2019 Category: Chemistry Authors: Jing L, Wu G, Hao X, Olotu FA, Kang D, Chen CH, Lee KH, Soliman MES, Liu X, Song Y, Zhan P Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of cinnamic acid derivatives with synergetic neuroprotection and angiogenesis effect.
Abstract As for complex brain diseases involved with multiple pathogenic factors, it is extremely difficult to achieve curative effect by acting on a single target. Multi-approach drugs provide a promising prospect in the treatment of complex brain diseases and have been attracting more and more interest. Enlightened by synergetic effect of combination in traditional herb medicines, forty-two novel cinnamic acid derivatives were designed and synthesized by introducing capsaicin and/or ligustrazine moieties to enhance biological activities in both neurological function and neurovascular protection. Elevated levels ...
Source: European Journal of Medicinal Chemistry - September 13, 2019 Category: Chemistry Authors: Zhang WX, Wang H, Cui HR, Guo WB, Zhou F, Cai DS, Xu B, Jia XH, Huang XM, Yang YQ, Chen HS, Qi JC, Wang PL, Lei HM Tags: Eur J Med Chem Source Type: research

Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives.
Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives. Eur J Med Chem. 2019 Sep 13;183:111689 Authors: Zhao L, Sun N, Tian L, Sun Y, Chen Y, Wang X, Zhao S, Su X, Zhao D, Cheng M Abstract A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that ...
Source: European Journal of Medicinal Chemistry - September 13, 2019 Category: Chemistry Authors: Zhao L, Sun N, Tian L, Sun Y, Chen Y, Wang X, Zhao S, Su X, Zhao D, Cheng M Tags: Eur J Med Chem Source Type: research

Potent combretastatin A-4 analogs containing 1,2,4-triazole: Synthesis, antiproliferative, anti-tubulin activity, and docking study.
Abstract A series of cis restricted 1,2,4-triazole analogs of combretastatin A-4 (CA-4) were designed and synthesized. The antiproliferative activity of these compounds was measured on hepatocellular carcinoma HepG2, leukemia HL-60, and breast cancer MCF-7 cell lines. The obtained results showed a substantial ability of the synthesized anilides to inhibit tumor growth. On HepG2 cells, 5o and 5r showed potent IC50 values of 0.10 and 0.04 μM, respectively. While on HL-60 cells, the IC50 values were 0.004 and 0.01 μM for 5b and 5i, respectively. The inhibitory activity of tubulin polymerization was eval...
Source: European Journal of Medicinal Chemistry - September 12, 2019 Category: Chemistry Authors: Mustafa M, Anwar S, Elgamal F, Ahmed ER, Aly OM Tags: Eur J Med Chem Source Type: research

Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors.
Abstract A library of twenty two novel 1,2,3-triazole benzenesulfonamides incorporating thiosemicarbazide, 5(4H)-thione-1,2,4-triazole and variously substituted phenacyl appended 1,2,4-triazole as tail were designed, synthesized and assessed for their efficacy as inhibitors against carbonic anhydrase human (h) isoforms hCA I, II, IV and IX. The physiologically important and off-target cytosolic isoform hCA I was weakly inhibited by most of the newly synthesized sulfonamides while the glaucoma associated isoform hCA II was moderately inhibited with KIs spanning in low nanomolar range (KI = 8.0 nM-0.903 μ...
Source: European Journal of Medicinal Chemistry - September 12, 2019 Category: Chemistry Authors: Vats L, Kumar R, Bua S, Nocentini A, Gratteri P, Supuran CT, Sharma PK Tags: Eur J Med Chem Source Type: research

Indole: A privileged scaffold for the design of anti-cancer agents.
Abstract In general, heterocyclic compounds are a significant source of pharmacologically active compounds. Among them, the indole scaffold widely distributes in natural products and bioactive molecules including anti-cancer agents. In view of its unique physic-chemical and biological properties, it has been used as a privileged scaffold in the anti-cancer agents design. So far, many natural and synthetic indole derivatives have been discovered as promising anti-cancer agents used in clinic or clinical evaluations, suggesting its prominent place in anti-cancer drugs development. This review aimed to provide a clea...
Source: European Journal of Medicinal Chemistry - September 11, 2019 Category: Chemistry Authors: Wan Y, Li Y, Yan C, Yan M, Tang Z Tags: Eur J Med Chem Source Type: research

Corrigendum to"An insight into the medicinal perspective of synthetic analogs of indole: A review" [Eur. J. Med. Chem. 180 (2019) 562-612 11516].
Corrigendum to"An insight into the medicinal perspective of synthetic analogs of indole: A review" [Eur. J. Med. Chem. 180 (2019) 562-612 11516]. Eur J Med Chem. 2019 Sep 11;183:111680 Authors: Thanikachalam PV, Maurya RK, Garg V, Monga V PMID: 31520927 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - September 11, 2019 Category: Chemistry Authors: Thanikachalam PV, Maurya RK, Garg V, Monga V Tags: Eur J Med Chem Source Type: research

Discovery of a potent p38 α/MAPK14 kinase inhibitor: Synthesis, in vitro/in vivo biological evaluation, and docking studies.
This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38α/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38α/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 μM, comparable to the potency of dasatinib. Compound 2b inhibited TNF-&alpha...
Source: European Journal of Medicinal Chemistry - September 8, 2019 Category: Chemistry Authors: El-Gamal MI, Anbar HS, Tarazi H, Oh CH Tags: Eur J Med Chem Source Type: research

Two optimized antimicrobial peptides with therapeutic potential for clinical antibiotic-resistant Staphylococcus aureus.
In this study, novel peptides were designed based on antimicrobial peptide fragments derived from Aristicluthys nobilia interferon-I to promote anti-MRSA activity and decrease adverse effects. Design strategies included substitutions of charged or hydrophobic amino acid residues for noncharged polar residues to promote amphipathicity. Two designed peptides, P5 (YIRKIRRFFKKLKKILKK-NH2) and P9 (SYERKINRHFKTLKKNLKKK-NH2), showed potent antimicrobial activities against both sensitive Staphylococcus aureus clinical isolates and MRSA strains without significant hemolysis or cytotoxicity to human hemocytes and renal epithelial ce...
Source: European Journal of Medicinal Chemistry - September 7, 2019 Category: Chemistry Authors: Li C, Zhu C, Ren B, Yin X, Shim SH, Gao Y, Zhu J, Zhao P, Liu C, Yu R, Xia X, Zhang L Tags: Eur J Med Chem Source Type: research

Single-molecule chemiluminescent photosensitizer for a self-activating and tumor-selective photodynamic therapy of cancer.
N, Esteves da Silva JCG Abstract While photodynamic therapy is known for significant advantages over conventional cancer therapies, its dependence on light has limited it to treating tumors on or just under the skin or on the outer lining of organs/cavities. Herein, we have developed a single-molecule photosensitizer capable of intracellular self-activation and with potential tumor-selectivity due to a chemiluminescent reaction involving only a cancer marker. Thus, the photosensitizer is directly chemiexcited to a triplet excited state capable of generating singlet oxygen, without requiring either a light source o...
Source: European Journal of Medicinal Chemistry - September 6, 2019 Category: Chemistry Authors: Pinto da Silva L, Núnez-Montenegro A, Magalhães CM, Ferreira PJO, Duarte D, González-Berdullas P, Rodríguez-Borges JE, Vale N, Esteves da Silva JCG Tags: Eur J Med Chem Source Type: research

Synthesis of benzotriazoles derivatives and their dual potential as α-amylase and α-glucosidase inhibitors in vitro: Structure-activity relationship, molecular docking, and kinetic studies.
Synthesis of benzotriazoles derivatives and their dual potential as α-amylase and α-glucosidase inhibitors in vitro: Structure-activity relationship, molecular docking, and kinetic studies. Eur J Med Chem. 2019 Sep 05;183:111677 Authors: Hameed S, Kanwal, Seraj F, Rafique R, Chigurupati S, Wadood A, Rehman AU, Venugopal V, Salar U, Taha M, Khan KM Abstract Benzotriazoles (4-6) were synthesized which were further reacted with different substituted benzoic acids and phenacyl bromides to synthesize benzotriazole derivatives (7-40). The synthetic compounds (7-40) were characterized via di...
Source: European Journal of Medicinal Chemistry - September 5, 2019 Category: Chemistry Authors: Hameed S, Kanwal, Seraj F, Rafique R, Chigurupati S, Wadood A, Rehman AU, Venugopal V, Salar U, Taha M, Khan KM Tags: Eur J Med Chem Source Type: research

A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling.
Abstract Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a "fluorine scan" strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs. Unlike other modifications which often led to ...
Source: European Journal of Medicinal Chemistry - September 4, 2019 Category: Chemistry Authors: Zhang B, Liu J, Gao D, Yu X, Wang J, Lei X Tags: Eur J Med Chem Source Type: research

Synthesis and in  vitro biological evaluation of novel derivatives of Flexicaulin A condensation with amino acid trifluoroacetate.
Synthesis and in vitro biological evaluation of novel derivatives of Flexicaulin A condensation with amino acid trifluoroacetate. Eur J Med Chem. 2019 Sep 03;182:111645 Authors: Ke Y, Hu TX, Huo JF, Yan JK, Wang JY, Yang RH, Xie H, Liu Y, Wang N, Zheng ZJ, Sun YX, Wang C, Du J, Liu HM Abstract As our research focus on anticancer drugs, two series of novel derivatives of Flexicaulin A (FA), an ent-kaurene diterpene, condensation with amino acid trifluoroacetate were synthesized, and their anti-proliferative activity against four human cancer cell lines (TE-1, MCF-7, A549 and MGC-803) were evaluate...
Source: European Journal of Medicinal Chemistry - September 3, 2019 Category: Chemistry Authors: Ke Y, Hu TX, Huo JF, Yan JK, Wang JY, Yang RH, Xie H, Liu Y, Wang N, Zheng ZJ, Sun YX, Wang C, Du J, Liu HM Tags: Eur J Med Chem Source Type: research

Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL.
This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism. PMID: 31494467 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - August 31, 2019 Category: Chemistry Authors: Yang L, Liu Y, Fan M, Zhu G, Jin H, Liang J, Liu Z, Huang Z, Zhang L Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of novel diazaspiro[4.5]decan-1-one derivatives as potential chitin synthase inhibitors and antifungal agents.
Abstract A series of 2,8-diazaspiro[4.5]decan-1-one derivatives were designed, synthesized and screened for their inhibition activities against chitin synthase (CHS) and antimicrobial activities in vitro. The biological assays revealed that compounds 4a, 4e, 4h, 4j, 4o, 4q and 4r exhibited moderated to excellent potency against CHS with IC50 values ranging from 0.12 to 0.29 mM. Compounds 4e, 4j with IC50 value of 0.13 mM, 0.12 mM respectively, showed excellent inhibition potency among these compounds, which were similar to that of polyoxin B whose IC50 value was 0.08 mM. Meanwhile, the screening of th...
Source: European Journal of Medicinal Chemistry - August 31, 2019 Category: Chemistry Authors: Li B, Wang K, Zhang R, Li B, Shen Y, Ji Q Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of stereo- and regioisomers of amino aryl esters as multidrug resistance (MDR) reversers.
Abstract Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell lin...
Source: European Journal of Medicinal Chemistry - August 30, 2019 Category: Chemistry Authors: Teodori E, Contino M, Riganti C, Bartolucci G, Braconi L, Manetti D, Romanelli MN, Trezza A, Athanasios A, Spiga O, Perrone MG, Giampietro R, Gazzano E, Salerno M, Colabufo NA, Dei S Tags: Eur J Med Chem Source Type: research

Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in  vitro and in vivo.
Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in vitro and in vivo. Eur J Med Chem. 2019 Aug 30;182:111665 Authors: Wang LL, Kong L, Liu H, Zhang Y, Zhang L, Liu X, Yuan F, Li Y, Zuo Z Abstract A series of novel derivatives of artemisinin-4-(arylamino)quinazoline have been designed and synthesized, and most of them showing potent in vitro cytotoxic activity against HCT116 and WM-266-4 cell lines. Compound 32 was the most active derivative against HCT116 cell line with an IC50 of 110 nM, and significantly improved the antitum...
Source: European Journal of Medicinal Chemistry - August 30, 2019 Category: Chemistry Authors: Wang LL, Kong L, Liu H, Zhang Y, Zhang L, Liu X, Yuan F, Li Y, Zuo Z Tags: Eur J Med Chem Source Type: research

Natural products as important tyrosine kinase inhibitors.
Abstract As an important source of drugs, natural products play an important role in the discovery and development of new drugs. More than 60% of anti-tumor drugs are closely related to natural products. At the same time, as the main cause of tumors, the abnormal activity of tyrosine kinase has become an important target for clinical treatment. Although, small molecule targeted drugs dominate the cancer treatment. Natural active products are driving the development of new tyrosine kinase inhibitors with their unique mode of action and molecular structure diversity. Obtaining new chemical entities with tyrosine kin...
Source: European Journal of Medicinal Chemistry - August 30, 2019 Category: Chemistry Authors: Yin B, Fang DM, Zhou XL, Gao F Tags: Eur J Med Chem Source Type: research

ROS-responsive fluorinated polycations as non-viral gene vectors.
In this report, a series of fluorobenzene substituted and thioacetal contained polycations (TAEA-S-xF) were prepared to explore novel alternatives for safe and efficient non-viral polymeric gene vectors. The reactive oxygen species (ROS)-responsive property of thioacetal moieties together with the fluorine effect were hope to bring the vector better performance in gene delivery process. These materials could efficiently condense DNA into nanoparticles with proper size and surface potential. The structure-activity relationship of these materials was systematically investigated, and the In vitro transfection results rev...
Source: European Journal of Medicinal Chemistry - August 30, 2019 Category: Chemistry Authors: Zhang JH, Wang WJ, Zhang J, Xiao YP, Liu YH, Yu XQ Tags: Eur J Med Chem Source Type: research