European Journal of Medicinal Chemistry

Identification and optimization of novel 6-acylamino-2-aminoquinolines as potent Hsp90 C-terminal inhibitors ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Fen Jiang, An-ping Guo, Jia-cheng Xu, Hui-Jie Wang, Xiao-fei Mo, Qi-Dong You, Xiao-Li Xu In order to discover novel Hsp90 inhibitors targeting the C-terminal ATP binding pocket, a novobiocin derivative based ROCS model was constructed for virtual screening. Compound 13 was identified as the lead compound and then systematical structure activity relationship (SAR) study was conducted. These efforts led to compound 69, which exhibited potent anti-proliferative activities against MCF7 and SKBr3 breast cancer cell lines. In 4T1 mice breast cancer models, 69 exhibited potent tumor growth inhibition and anti-metastasis effect. Compound 69 as a potent antitumor agent targeting the Hsp90 C-terminal is worthy of further pre-clinical study. Graphical abstract image
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An insight into the biological activities of heterocyclic–fatty acid hybrid molecules ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Vijayendar Venepally, Ram Chandra Reddy Jala Heterocyclic compounds are the interesting core structures for the development of new bioactive compounds. Fatty acids are derived from renewable raw materials and exhibit various biological activities. Several researchers are amalgamating these two bioactive components to yield bioactive hybrid molecules with some desirable features. Heterocyclic–fatty acid hybrid derivatives are a new class of heterocyclic compounds with a broad range of biological activities and significance in the field of medicinal chemistry. Over the last few years, many research articles emphasized the significance of heterocyclic–fatty acid hybrid derivatives. The present review article focuses the developments in designing and biological evaluation of heterocyclic-fatty acid hybrid molecules. Graphical abstract image
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Inhibitors of Yellow Fever Virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Rossella Fioravanti, Nicoletta Desideri, Antonio Carta, Elena Maria Atzori, Ilenia Delogu, Gabriella Collu, Roberta Loddo By the antiviral screening of an in house library of pyrazoline compounds, 4-(3-(4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (5a) was identified as a promising hit compound for the development of anti- Yellow Fever Virus (YFV) agents. Structural optimization studies were focused on the development of 5a analogues which retain the potency as YFV inhibitors and show a reduced cytotoxicity. The synthesized 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) were evaluated in cell based assays for cytotoxicity and antiviral activity against representative viruses of two of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV) and Flavivirus (YFV). These compounds were also tested against a large panel of different pathogenic RNA and DNA viruses. Most of the new 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) exhibited a specific activity against YFV, showing EC50 values in the low micromolar range with almost a 10-fold improvement in potency compared to the reference inhibitor 6-azauridine. However, the selectivity indexes of the unsubstituted (4a-j) and the phenoxy (5a-j) analogues were generally modest due to the pronounced cytotoxicity against BHK-21 cells. Otherwise, the benzyloxy derivatives (6a-j) generally coupled high potency and selectivity. On the basis of both anti-YFV activity and selectivity index, pyrazolines 6a and 6b were chosen for time of addition experiments. The selected pyrazolines and the reference inhibitor 6-azauridine displayed maximal inhibition when added in the pretreatment or during the infection. Graphical abstract image
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Recent advances in discovery and development of natural products as source for anti-Parkinson's disease lead compounds ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Hongjia Zhang, Lan Bai, Jun He, Lei Zhong, Xingmei Duan, Liang Ouyang, Yuxuan Zhu, Ting Wang, Yiwen Zhang, Jianyou Shi Parkinson's disease (PD) is a common chronic degenerative disease of the central nervous system. Although the cause remains unknown, several pathological processes and central factors such as oxidative stress, mitochondrial injury, inflammatory reactions, abnormal deposition of α-synuclein, and cell apoptosis have been reported. Currently, anti-PD drugs are classified into two major groups: drugs that affect dopaminergic neurons and anti-cholinergic drugs. Unfortunately, the existing conventional strategies against PD are with numerous side effects, and cannot fundamentally improve the degenerative process of dopaminergic neurons. Therefore, novel therapeutic approaches which have a novel structure, high efficiency, and fewer side effects are needed. For many years, natural products have provided an efficient resource for the discovery of potential therapeutic agents. Among them, many natural products possess anti-PD properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding protein misfolding and the regulatory effects of PD related pathways. Indeed, with the steady improvement in the technologies for the isolation and purification of natural products and the in-depth studies on the pathogenic mechanisms of PD, many monomer components of natural products that have anti-PD effects have been gradually discovered. In this article, we reviewed the research status of 37 natural products that have been discovered to have significant anti-PD effects as well as their mode of action. Overall, this review may guide the design of novel therapeutic drugs in PD. Graphical abstract image
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Design, synthesis and immunological evaluation of novel amphiphilic desmuramyl peptides ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Farooq-Ahmad Khan, Marina Ulanova, Bing Bai, Damayanthi Yalamati, Zi-Hua Jiang Muramyl dipeptide (MDP) – an essential bacterial cell wall component – is recognized by our immune system as pathogen-associated molecular pattern (PAMP) which results in immune responses with adverse toxic effects. In order to harness the beneficial properties from the pro-inflammatory characteristics of the bacterial cell wall motif, MDP was strategically re-designed while conserving the L-D configurations of the dipeptide moiety. The muramic acid was replaced with a hydrophilic arene and lipophilic chain was introduced at peptide end to give the amphiphilic desmuramyl peptides (DMPs). The novel DMPs were found to modulate the immune response by amplifying the LPS-induced surface glycoprotein (ICAM-1) expression in THP-1 cells without showing significant toxicity. Furthermore, these compounds were able to trigger the secretion of higher levels of pro-inflammatory cytokine (TNF-α) than the well-studied NOD2 agonist, Murabutide. Graphical abstract image
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4-Quinolone hybrids and their antibacterial activities ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Yuan-Qiang Hu, Shu Zhang, Zhi Xu, Zao-Sheng Lv, Ming-Liang Liu, Lian-Shun Feng The emergence and wide-spread of drug-resistant bacteria including multi-drug resistant and pan-drug resistant pathogens which are associated with considerable mortality, represent a significant global health threat. 4-Quinolones which are exemplified by fluoroquinolones are the second largest chemotherapy agents used in clinical practice for the treatment of various bacterial infections. However, the resistance of bacteria to 4-quinolones develops rapidly and spreads widely throughout the world due to the long-term, inappropriate use and even abuse. To overcome the resistance and improve the potency, several strategies have been developed. Amongst them, molecular hybridization, which is based on the incorporation of two or more pharmacophores into a single molecule with a flexible linker, is one of the most practical approaches. This review aims to summarize the recent advances made towards the discovery of 4-quinolone hybrids as potential antibacterial agents as well as their structure-activity relationship (SAR). The enriched SAR may pave the way for the further rational development of 4-quinolone hybrids with excellent potency against both drug-susceptible and drug-resistant bacteria. Graphical abstract image
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A pentanoic acid derivative targeting matrix metalloproteinase-2 (MMP-2) induces apoptosis in a chronic myeloid leukemia cell line ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Avinaba Mukherjee, Nilanjan Adhikari, Tarun Jha Depending on our previous observations, some compounds of pentanoic acid were designed and synthesized. Characterization of the synthesized compounds was done by mass, NMR and IR spectroscopy as well as elemental analysis. Among the synthesized molecules, (2S)-5-oxo-2-[(nitrobenzene-4-yl sulfonyl) amino]-5-(pentylamino) pentanoic acid (Cpd 11) was found as a lead and potent inhibitor of matrix metalloproteinase-2 (MMP-2). Molecular modeling and enzyme inhibition studies were done to confirm the interaction or inhibitory potential of this compound. Thereafter, the biological screening was done through cytotoxicity, anti-invasion and apoptosis-related assays. Docking analysis revealed that Cpd 11 interacted with the target molecule MMP-2 and with MMP-9. However, enzyme inhibition assay showed 3-fold MMP-2 inhibition compared to MMP-9. Cytotoxicity assay showed the inhibitory potential of Cpd 11 against K562 cell line having IC50 value of 17.9 ± 0.01 μM after 48 h of incubation. The cell death was apoptotic in nature as revealed from the annexin V and sub-G1 cell cycle arrest assay. Besides this, Cpd 11 also exhibited dose dependent anti-invasive activity into K562 cell line. On the other hand, flow cytometry and western blot data revealed Cpd 11 induced downregulation of MMP-2 in K562 cell line after 48 h of incubation that might be linked with the anti-invasive and apoptotic activity furthermore. Therefore, the overall results validated each method and make this molecule as a potent MMP-2 inhibitor that blocked the invasion and could bring apoptosis at later stages in K562 cells sparing the normal ones. Graphical abstract image
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Enzyme inhibitory activities an insight into the structure–Activity relationship of biscoumarin derivatives ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Muhammad Faisal, Aamer Saeed, Danish Shahzad, Tanzeela Abdul Fattah, Bhajan Lal, Pervaiz Ali Channar, Jamaluddin Mahar, Shomaila Saeed, Parvez Ali Mahesar, Fayaz Ali Larik Biscoumarin derivatives, a dimeric form of coumarin, are well known derivatives of coumarin, occurred in the bioactive metabolites of marine and terrestrial organisms. On account of pharmacological and biological applications, biscoumarins have long been the subject of innumerable enzyme inhibition studies. In this review the pros and cons of enzyme inhibition studies of biscoumarins as urease inhibitors, aromatase inhibitors, NPPs, α-glucosidase inhibitors, α-amylase inhibitors, HIV-1 integrase inhibition, steroid sulfatase inhibitors and c-Met inhibitors are discussed in a systematic way. Moreover, the review discusses the structure activity relationship of biscoumarin scaffold with enzyme inhibitory potency which would unleash new avenues for further development. The purpose of the current review is to disclose the value of biscoumarins as potent and efficient enzyme inhibitor. This review provides a guideline to elaborate the diversity of biscoumarin inhibitors by exploring the effects of electronic groups linked with biscoumarin nucleus. Graphical abstract image
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Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Ekaterina S. Shchegravina, Alexander A. Maleev, Stanislav K. Ignatov, Iuliia A. Gracheva, Andreas Stein, Hans-Günther Schmalz, Andrey E. Gavryushin, Anastasiya A. Zubareva, Elena V. Svirshchevskaya, Alexey Yu. Fedorov Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC50 < 1 nM, cell cycle arrest in the G2/M phase, 25% apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out. Graphical abstract image
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New dimeric cGMP analogues reduce proliferation in three colon cancer cell lines ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Dorit Hoffmann, Andreas Rentsch, Eleonora Vighi, Evelina Bertolotti, Antonella Comitato, Frank Schwede, Hans-Gottfried Genieser, Valeria Marigo Activation of the cGMP-dependent protein kinase G (PKG) can inhibit growth and/or induce apoptosis in colon cancer. In this study we evaluated the effects on cell viability, cell death and proliferation of novel dimeric cGMP analogues, compared to a monomeric compound. Three colon cancer cell lines, which only express isoform 2 of PKG, were treated with these novel cGMP analogues and responded with increased PKG activity. cGMP analogues reduced cell viability in the three cell lines and this was due to a cytostatic rather than cytotoxic effect. These findings suggest that activation of PKG2 can be a therapeutic target in the treatment of colon cancer and, most importantly, that dimeric cGMP analogues can further improve the beneficial effects previously observed with monomeric cGMP analogues. Graphical abstract image
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Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Elver Otero, Elisa García, Genesis Palacios, Lina M. Yepes, Miguel Carda, Raúl Agut, Iván D. Vélez, Wilson I. Cardona, Sara M. Robledo The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18–23, 26 and 30) and eight of them against T. cruzi (19–22, 24 and 28–30) with EC50 values lower than 40 μM. Compounds 19–22, 24 and 28–30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 μM and 8.25 and 8.69 μM, respectively. Compounds 19–22, 24 and 28–30 showed higher activities than benznidazole (BNZ). Most of the compounds showed antiprotozoal activity and with exception of 18, 26 and 28, the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19, bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity. Graphical abstract image
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Discovery of Benzo[g]quinazolin benzenesulfonamide derivatives as dual EGFR/HER2 inhibitors ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Mansour S. Alsaid, Abdullah A. Al-Mishari, Aiten M. Soliman, Fatma A. Ragab, Mostafa M. Ghorab An array of some new N-(substituted)-2-((4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)acetamide 5–19 were synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl)benzenesulfonamide 4, to be assessed for their cytotoxic activity against A549 lung cancer cell line and to determine their inhibitory effect on EGFR tyrosine kinase enzyme. Compounds 5–19 showed high activity towards A549 cell line with IC50 values of 0.12–8.70 μM. Compounds 6, 12 and 18 were the most potent in this series. These compounds were further screened as dual inhibitors for EGFR/HER2 enzymes in comparison with erlotinib and were found to possess very potent activity. Compound 12 showed the highest activity with IC50 values of 0.06 μM and 0.30 μM towards EGFR and HER2, respectively. Accordingly, the apoptotic effect of the most potent compounds 6, 12 and 18 was investigated and showed a marked increase in the level of caspases-3 by 6, 9 and 8 folds, respectively, compared to the control cells. Moreover, Molecular modeling was performed inside the active site of EGFR, keeping in mind their binding possibilities, bond lengths, angles and energy scores. It was found that the most active compounds demonstrated the best binding scores in the active site of EGFR, which may clarify their high inhibition profile. Graphical abstract image
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Baicalin and its metabolites suppresses gluconeogenesis through activation of AMPK or AKT in insulin resistant HepG-2 cells ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Tao Wang, Hongmei Jiang, Shijie Cao, Qian Chen, Mingyuan Cui, Zhijie Wang, Dandan Li, Jing Zhou, Tao Wang, Feng Qiu, Ning Kang Scutellaria baicalensis Georgi (S. baicalensis), as a traditional Chinese herbal medicine, is an important component of several famous Chinese medicinal formulas for treating patients with diabetes mellitus. Baicalin (BG), a main bioactive component of S. baicalensis, has been reported to have antidiabetic effects. However, pharmacokinetic studies have indicated that BG has poor oral bioavailability. Therefore, it is hard to explain the pharmacological effects of BG in vivo. Interestingly, several reports show that BG is extensively metabolized in rats and humans. Therefore, we speculate that the BG metabolites might be responsible for the pharmacological effects. In this study, BG and its three metabolites (M1-M3) were examined their effects on glucose consumption in insulin resistant HepG-2 cells with a commercial glucose assay kit. Real-time PCR and western blot assay were used to confirm genes and proteins of interest, respectively. The results demonstrate that BG and its metabolites (except for M3) enhanced the glucose consumption which might be associated with inhibiting the expression of the key gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolypyruvate carboxykinase (PEPCK) and glucose transporter 2 (GLUT2). Further study found that BG and M1 could suppress hepatic gluconeogenesis via activation of the AMPK pathway, while M2 could suppress hepatic gluconeogenesis via activation of the PI3K/AKT signaling pathway. Taken together, our findings suggest that both BG and its metabolites have antihyperglycemic activities, and might be the active forms of oral doses of BG in vivo. Graphical abstract image
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Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Yue-Yang Ji, Sen-Dong Lin, Yu-Jie Wang, Ming-Bo Su, Wei Zhang, Hendra Gunosewoyo, Fan Yang, Jia Li, Jie Tang, Yu-Bo Zhou, Li-Fang Yu Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials. However, thus far the majority of structure-activity relationship studies reported on these TCP derivatives have been mostly limited to the racemates. In this study, we present the SAR data for a novel series of conformationally-restricted TCP-based LSD1 inhibitors, both in their racemic and enantiomerically pure forms. Compounds 18b and 19b were identified as the most potent LSD1 inhibitors within this series, possessing excellent selectivity (>10,000-fold) against MAO-A and MAO-B. These compounds activated CD86 expression on the human MV4-11 AML cells following 10 days of exposure, accompanied with the apparent cytotoxicity. Taken together, these findings are consistent with the pharmacological inhibition of LSD1 and further provide structural insights on the binding modes of these TCP derivatives and their enantiomers at the LSD1. Graphical abstract image
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Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Elisa Uliassi, Giulia Fiorani, R. Luise Krauth-Siegel, Christian Bergamini, Romana Fato, Giulia Bianchini, J. Carlos Menéndez, Maria Teresa Molina, Eulogio López-Montero, Federico Falchi, Andrea Cavalli, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Gesa Witt, Carolina B. Moraes, Lucio H. Freitas-Junior, Chiara Borsari, Maria Paola Costi, Maria Laura Bolognesi Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 μM (% inhibition TbGAPDH = 64% and % inhibition TcTR = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 μM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 μM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed. Graphical abstract image
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Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Jayakanth Kankanala, Karen A. Kirby, Andrew D. Huber, Mary C. Casey, Daniel J. Wilson, Stefan G. Sarafianos, Zhengqiang Wang Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC50 = 0.04 μM) with decent antiviral potency (EC50 = 7.4 μM) and no cytotoxicity (CC50 > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC50 = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode. Graphical abstract image
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Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ) ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Konrad A. Szychowski, Marcin L. Leja, Danylo V. Kaminskyy, Anna P. Kryshchyshyn, Urszula E. Binduga, Oleh R. Pinyazhko, Roman B. Lesyk, Jakub Tobiasz, Jan Gmiński Peroxisome proliferator-activated receptors (PPARs) play an important role in numerous chronic diseases such as diabetes, obesity, atherosclerosis and cancer, and PPAR modulators are among the approved drugs and drug-candidates for their treatment. The aim of this study was to elucidate the involvement of PPARs in the mechanism of cytotoxic and pro-apoptotic action of novel anticancer 4-thiazolidinone derivatives (Les-2194, Les-3377, Les-3640) and approved 4-thiazolidinones (Rosiglitazone, Pioglitazone) towards the human squamous carcinoma (SCC-15) cell line. Experiments with 4-thiazaolidinone derivatives and PPAR-specific siRNA were conducted and PPARα, PPARβ and PPARγ mRNA expression was studied. Moreover, after PPARα, PPARβ and PPARγ siRNA gene silencing, cell viability, cell metabolism and caspase-3 activity were measured. The results showed a decrease of mRNA expression of the studied PPARs in SCC-15 cells treated with 10 and 50 μM Les-2194, Les-3377 and Les-3640. PPARγ knockdown protected the cells from the cytotoxic effect of the tested compounds (50 μM). It was established that novel anticancer 4-thiazolidinone derivatives act mainly through the PPARγ pathway in SCC-15 cells. Our results suggest that all studied compounds act as PPARs agonists. Interestingly, silencing of PPARγ gene increases the expression of PPARα, PPARβ mRNA in SCC-15 cells. The anticancer potential of new studied compounds was more expressed as compared to Rosiglitazone and Pioglitazone. Graphical abstract image
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Fragment-based approach to identify IDO1 inhibitor building blocks ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Alice Coletti, Francesca Camponeschi, Elisa Albini, Francesco Antonio Greco, Vincenzo Maione, Chiara Custodi, Federica Ianni, Ursula Grohmann, Ciriana Orabona, Francesca Cantini, Antonio Macchiarulo Indoleamine 2,3-dioxygenase 1 (IDO1) is attracting a great deal of interest as drug target in immune-oncology being highly expressed in cancer cells and participating to the tumor immune-editing process. Although several classes of IDO1 inhibitors have been reported in literature and patent applications, only few compounds have proved optimal pharmacological profile in preclinical studies to be advanced in clinical trials. Accordingly, the quest for novel structural classes of IDO1 inhibitors is still open. In this paper, we report a fragment-based screening campaign that combines Water-LOGSY NMR experiments and microscale thermophoresis approach to identify fragments that may be helpful for the development of novel IDO1 inhibitors as therapeutic agents in immune-oncology disorders. Graphical abstract image
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Synthesis and antibacterial activity of new symmetric polyoxygenated dibenzofurans ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Sandra Oramas-Royo, Kriss Dayana Pantoja, Ángel Amesty, Carmen Romero, Isabel Lorenzo-Castrillejo, Félix Machín, Ana Estévez-Braun A series of symmetric polyoxygenated dibenzofurans with 2-methylbutyril moieties at C-4 and C-6 were obtained from commercial phloroglucinol through a sequence of reactions that include monoacylation, iodination, Suzuki-Miyaura coupling, oxidative dimerization and cyclization. Some of the compounds obtained were active against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical isolates. The dibenzofuran 28 with propyl chains at C-2 and C-8 exhibited the best antibacterial activity with values comparable to those of the natural dibenzofuran achyrofuran. From the obtained results some structure-activity relationships were outlined. Graphical abstract image
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Serendipitous discovery of potent human head and neck squamous cell carcinoma anti-cancer molecules: A fortunate failure of a rational molecular design ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Chiara Zagni, Venerando Pistarà, Luciana A. Oliveira, Rogerio M. Castilho, Giovanni Romeo, Ugo Chiacchio, Antonio Rescifina Histone deacetylase inhibitors (HDACis) play an important role as valuable drugs targeted to cancer therapy: several HDACis are currently being tested in clinical trials. Two new potential HDACis 1a and 1d, characterized by the presence of a biphenyl-4-sulfonamide group as a connection unit between the N-{4-[(E)-(2-formylhydrazinylidene)methyl]-3-hydroxyphenyl} and the 2-hydroxy-N-(trifluoroacetyl)benzamide moiety, respectively, as two zinc-binding group (ZBG), have been designed, synthesized and tested for their biological activity. Surprisingly, compounds 1a and 12, this last exclusively obtained in place of 1d, exhibited a very low HDAC inhibitory activity. A serendipitous assay of these two compounds, conducted on three chemoresistant cell lines of head and neck squamous cell carcinoma (HNSCC), showed their antiproliferative activity at low nanomolar concentrations, better than cisplatin. In vitro, biological assays indicated that compounds 1a and 12 are able to increase acetylation of histone H3 and to interfere with the PI3K/Akt/mTOR pathway by inducing the accumulation of PTEN protein. Graphical abstract image
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New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Fabiana Pandolfi, Daniela De Vita, Martina Bortolami, Antonio Coluccia, Roberto Di Santo, Roberta Costi, Vincenza Andrisano, Francesco Alabiso, Christian Bergamini, Romana Fato, Manuela Bartolini, Luigi Scipione A new series of pyridine derivatives with carbamic or amidic function has been designed and synthesized to act as cholinesterase inhibitors. The synthesized compounds were tested toward EeAChE and hAChE and toward eqBChE and hBChE. The carbamate 8 was the most potent hAChE inhibitor (IC50 = 0.153 ± 0.016 μM) while the carbamate 11 was the most potent inhibitor of hBChE (IC50 = 0.828 ± 0.067 μM). A molecular docking study indicated that the carbamate 8 was able to bind AChE by interacting with both CAS and PAS, in agreement with the mixed inhibition mechanism. Furthermore, the carbamates 8, 9 and 11 were able to inhibit Aβ42 self-aggregation and possessed quite low toxicity against human astrocytoma T67 and HeLa cell lines, being the carbamate 8 the less toxic compound on both cell lines. Graphical abstract image
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Platinum(IV) prodrugs multiply targeting genomic DNA, histone deacetylases and PARP-1 ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Zichen Xu, Weiwei Hu, Zhimei Wang, Shaohua Gou Several Pt(IV) prodrugs containing SAA, a histone deacetylases inhibitor, were designed and prepared for multiply targeting genomic DNA, histone deacetylases and PARP-1. The resulting Pt(IV) prodrug had significantly strong antiproliferative activity against the tested cancer cell lines, especially SAA1, derived from the conjugation of cisplatin and SAA, had potent ability to overcome cisplatin resistance. Under the combined action of DNA platination and inhibition of HDACs and PARP-1 activity, the cytotoxic activity of SAA1 was 174-fold higher than cisplatin against cisplatin-resistant SGC7901/CDDP cancer cells. The mechanism of action of SAA1 was preliminarily investigated, in which cellular uptake, cell apoptosis and cell cycle arrest as well as western blot analysis were made by treating SAA1 with SGC7901/CDDP cells. Besides, HDACs inhibition activity and PARP-1 enzyme inhibition of SAA1 were also studied. Graphical abstract image
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Synthesis and biological evaluation of a Platinum(II)-c(RGDyK) conjugate for integrin-targeted photodynamic therapy ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): T. Chatzisideri, S. Thysiadis, S. Katsamakas, P. Dalezis, I. Sigala, T. Lazarides, E. Nikolakaki, D. Trafalis, O.A. Gederaas, M. Lindgren, V. Sarli A cancer-targeting conjugate 4 of a cyclometalated [N,C,N-Pt(II)] complex bearing a NˆCˆN 1,3-di(2-pyridyl)-benzene with c(RGDyK) peptide as guiding molecule was designed and synthesized for real-time drug delivery monitoring in cancer cells and photodynamic therapy (PDT). This conjugate demonstrates a mild cytostatic effect to six cancer cell lines expressing integrins at different extent, while possessing promising features for PDT. Conjugate 4 demonstrated rapid cell uptake by receptor-mediated endocytosis and efficient generation of 1O2 upon irradiation. Incubation of rat bladder cancer cells AY27 with conjugate 4 (50 μΜ) prior to blue light exposure (5 min) resulted in significant reduction (50%) of cell survival compared to control cells as measured by MTT assay post 24 h after treatment. Graphical abstract image
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Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Aβ-induced neurotoxicity ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): TaeHun Kim, Woo Seung Son, Mohammad Neaz Morshed, Ashwini M. Londhe, Seo Yun Jung, Jong-Hyun Park, Woo-Kyu Park, Sang Min Lim, Ki Duk Park, Sung Jin Cho, Kyu-Sung Jeong, Jiyoun Lee, Ae Nim Pae Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[2′,3’:4,5]pyrrolo[1,2-d][1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Aβ-induced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD. Graphical abstract image
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Discovery of novel diarylpyrazolylquinoline derivatives as potent anti-dengue virus agents ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Jin-Ching Lee, Chin-Kai Tseng, Chun-Kuang Lin, Chih-Hua Tseng A number of diarylpyrazolylquinoline derivatives were synthesized and evaluated for their anti-dengue virus (DENV) activity. Among them, 6-fluoro-2-(1-(4-fluorophenyl)-3- (4-methoxyphenyl)-1H-pyrazol-5-yl)quinoline (11c), 2-[1,3-bis(4-methoxyphenyl)-1H-pyrazol- 5-yl]-6-fluoroquinoline (12c), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1H-pyrazol- 1-yl]benzenesulfonamide (13c) exhibited approximately 10-folds more active anti-DENV-2 activity (IC50 of 1.36, 1.09 and 0.81 μM, respectively) than that of ribavirin (IC50 = 12.61 μM). Compound 13c was also potent inhibited other sero-types of DENV. It reduced DENV replication in both viral protein and mRNA levels, and no significant cell cytotoxicity was detected, with greater than 50% viability of Huh-7-DV-Fluc cells at a concentration of 200 μM. Furthermore, compound 13c can effectively protect mice from DENV infection by reducing disease symptoms and mortality of DENV-infected mice. It represents a potential antiviral agent to block DENV replication in vitro and in vivo. Structural optimization of the initial lead compound, 13c, and the detailed molecular mechanism of action are ongoing. Graphical abstract image
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Synthesis, antiproliferative, anti-tubulin activity, and docking study of new 1,2,4-triazoles as potential combretastatin analogues ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Muhamad Mustafa, Dalia Abdelhamid, ElShimaa M.N. Abdelhafez, Mahmoud A.A. Ibrahim, Amira M. Gamal-Eldeen, Omar M. Aly Combretastatin A4 (CA4) is a natural product characterized by a powerful inhibition of tubulin polymerization and a potential anticancer activity. However, therapeutic application of CA4 is substantially hindered due to geometric isomerization. In the current study, new cis-restricted Combretastatin A4 analogues containing 1,2,4-triazle in place of the olefinic bond were designed and synthesized. The synthesized compounds were evaluated for their in vitro antiproliferative activity in human hepatocellular carcinoma HepG2 and leukemia HL-60 cell lines using MTT assay. Moreover, fourteen compounds were selected and tested for their antiproliferative activity by the National Cancer Institute. Some of the tested compounds showed moderate activity against sixty cell lines. In vitro tubulin polymerization inhibitory activity was evaluated on HepG2 cells. The assay revealed that 6a showed a remarkable tubulin inhibition compared to CA4. Moreover, the cell cycle analysis revealed significant G2/M cell cycle arrest of the analogue 6c in HepG2 cells. Molecular docking combined with AMBER-based molecular mechanical minimization results showed several noncovalent interactions, including van der Waals and hydrogen-bonding with several amino acids within the colchicine binding site of β-subunit of tubulin. Graphical abstract image
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Design, synthesis, kinetic mechanism and molecular docking studies of novel 1-pentanoyl-3-arylthioureas as inhibitors of mushroom tyrosinase and free radical scavengers ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Fayaz Ali Larik, Aamer Saeed, Pervaiz Ali Channar, Urooj Muqadar, Qamar Abbas, Mubashir Hassan, Sung-Yum Seo, Michael Bolte A series of novel 1-pentanoyl-3-arylthioureas was designed as new mushroom tyrosinase inhibitors and free radical scavengers. The title compounds were obtained in excellent yield and characterized by FTIR, 1H NMR, 13C NMR and X-ray crystallography in case of compound (4a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 1-Pentanoyl-3-(4-methoxyphenyl) thiourea (4f) showed tyrosinase inhibitory activity (IC50 1.568 ± 0.01 mM) comparable to Kojic acid (IC50 16.051 ± 1.27 mM). Interestingly compound 4f exhibited higher antioxidant potential compared to other derivatives. The docking studies of synthesized 1-Pentanoyl-3-arylthioureas analogues were also carried out against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC50 values. The predicted binding affinities are in good agreement with the IC50 values as compound (4f) showed highest binding affinity (−7.50 kcal/mol) compared to others derivatives. The kinetic mechanism analyzed by Line-weavere Burk plots exhibited that compound (4f) inhibit the enzyme inhibits the tyrosinase non-competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (4f) is 1.10 μM. It was also found from kinetic analysis that derivative 4f irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound (4f) may serve as lead structure for the design of more potent tyrosinase inhibitors. Graphical abstract image
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Discovery of new indomethacin-based analogs with potentially selective cyclooxygenase-2 inhibition and observed diminishing to PGE2 activities ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Shaymaa E. Kassab, Mohammed A. Khedr, Hamed I. Ali, Mohamed M. Abdalla New ring-extended analogs of indomethacin were designed based on the structure of active binding site of both COX-1 and COX-2 isoenzymes and the interaction pattern required for selective inhibition of COX-2 to improve its selectivity against COX-2. The strategy adopted for designing the new inhibitors involved i) ring extension of indomethacin to reduce the possibility of analogs to be accommodated into the narrow hydrophobic tunnel of COX-1, ii) deletion of carboxylic acid to reduce the possibility of inhibitor to form salt bridge with Arg120 and eventually prevent COX-1 inhibition, and iii) introduction of methylsulfonyl group to increase the opportunity of the analogs to interact with the polar side pocket that's is crucial for inhibition process of COX-2. The three series of tetrahydrocarbazoles involving 4, 5, 9, 10 and 12 were synthesized in quantitative yields adopting limited number of reaction steps, and applying laboratory friendly reaction conditions. In vitro and in vivo assays for data profiling the new candidates revealed the significant improvement in the potency and selectivity against COX-2 of 6-methoxytetrahydrocarbazole 4 (IC50 = 0.97 μmol) to verify the effect of ring extension in comparison to indomethacin (IC50 = 2.63 μmol), and 6-methylsulfonyltetrahydrocarbazole 10a (IC50 = 0.28 μmol) to verify the effect of ring extension and introduction of methylsulfonyl group. 9-(4-chlorobenzoyl)-6-(methylsulfonyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one 12a showed the most potential and selective activity against COX-2 (IC50 = 0.23 μmol) to be with superior potency to Celecoxib (IC50 = 0.30 μmol). Consistently, 12a was the most active with all the other anti-inflammatory test descriptors and its activity in diminishing the PGE2 with the other analogs confirmed the elaboration of new class of selective COX-2 inhibitors beyond the diarylsulfonamides as a previously common class of selective COX-2 inhibitors. Molecular docking study revealed the high binding score of compound 12a (−30.78 kcal/mol), with less clash contribution (7.2) that is close to indomethacin. Also, 12a showed low conformation entropy score (1.40). Molecular dynamic (MD) simulation identified the equilibrium of both potential and kinetic energies. Graphical abstract image
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Synthesis and evaluation of new pyridyl/pyrazinyl thiourea derivatives: Neuroprotection against amyloid-β-induced toxicity ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Jung-eun Park, Ahmed Elkamhawy, Ahmed H.E. Hassan, Ae Nim Pae, Jiyoun Lee, Sora Paik, Beoung-Geon Park, Eun Joo Roh Herein, we report synthesis and evaluation of new twenty six small molecules against β amyloid (Aβ)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The neuroprotective effect of seventeen compounds against Aβ-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Fifteen derivatives eliciting increased green to red fluorescence percentage less than 40.0% were evaluated for their impact on ATP production, cell viability and neuroprotection against Aβ-induced neuronal cell death. Among evaluated compounds, derivatives 9w, 9r and 9k had safe profile regarding ATP production and cell viability. In addition, they exhibited significant neuroprotection (69.3, 51.8 and 48.2% respectively). Molecular modeling study using CDocker algorithm predicted plausible binding modes explaining the elicited mPTP blocking activity. Hence, this study suggests compounds 9w, 9r and 9k as leads for further development of novel therapy to Alzheimer's disease. Graphical abstract image
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Structural design, synthesis and pharmacological evaluation of thiazoles against Trypanosoma cruzi ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Gevanio Bezerra de Oliveira Filho, Marcos Veríssimo de Oliveira Cardoso, José Wanderlan Pontes Espíndola, Dayane Albuquerque Oliveira e Silva, Rafaela Salgado Ferreira, Pollyanne Lacerda Coelho, Pâmela Silva dos Anjos, Emanuelle de Souza Santos, Cássio Santana Meira, Diogo Rodrigo Magalhaes Moreira, Milena Botelho Pereira Soares, Ana Cristina Lima Leite Chagas disease is one of the most significant health problems in the American continent. benznidazole (BDZ) and nifurtimox (NFX) are the only drugs approved for treatment and exhibit strong side effects and ineffectiveness in the chronic stage, besides different susceptibility among T. cruzi DTUs (Discrete Typing Units). Therefore, new drugs to treat this disease are necessary. Thiazole compounds have been described as potent trypanocidal agents. Here we report the structural planning, synthesis and anti-T. cruzi evaluation of a new series of 1,3-thiazoles (7–28), which were designed by placing this heterocycle instead of thiazolidin-4-one ring. The synthesis was conducted in an ultrasonic bath with 2-propanol as solvent at room temperature. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity. In some cases, methyl at position 5 of the thiazole (compounds 9, 12 and 23) increased trypanocidal property. The exchange of phenyl for pyridinyl heterocycle resulted in increased activity, giving rise to the most potent compound against the trypomasigote form (14, IC50trypo = 0.37 μM). Importantly, these new thiazoles were toxic for trypomastigotes without affecting macrophages and cardiomyoblast viability. The compounds were also evaluated against cruzain, and five of the most active compounds against trypomastigotes (7, 9, 12, 16 and 23) inhibited more than 70% of enzymatic activity at 10 μM, among which compound 7 had an IC50 in the submicromolar range, suggesting a possible mechanism of action. In addition, examination of T. cruzi cell death showed that compound 14 induces apoptosis. We also examined the activity against intracellular parasites, revealing that compound 14 inhibited T. cruzi infection with potency similar to benznidazole. The antiparasitic effect of 14 and benznidazole in combination was also investigated against trypomastigotes and revealed that they have synergistic effects, showing a promising profile for drug combination. Finally, in mice acutely-infected with T. cruzi, 14 treatment significanty reduced the blood parasitaemia and had a protective effect on mortality. In conclusion, we report the identification of compounds (7), (12), (15), (23) and (26) with similar trypanocidal activity of benznidazole; compounds (9) and (21) as trypanocidal agents equipotent with BDZ, and compound 14 with potency 28 times better than the reference drug without affecting macrophages and cardiomyoblast viability. Mechanistically, the compounds inhibit cruzain, and 14 induces T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates. Graphical abstract image
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Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Ying Sun, Yuanyuan Shan, Chuansheng Li, Ru Si, Xiaoyan Pan, Binghe Wang, Jie Zhang VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4. Graphical abstract image
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Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer's disease ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Giulia Nesi, Qiuhe Chen, Simona Sestito, Maria Digiacomo, Xiaohong Yang, Shengnan Wang, Rongbiao Pi, Simona Rapposelli Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC50 values ranging from 340 to 378 nM. Analogously, all the compounds were able to inhibit the self β-amyloid1-42 aggregation. The gallic acid hybrid GA2 as well as the 2-chromonecarboxylic acid hybrids CA1 and CA2 prevented the self-mediated Aβ aggregation with percentages of inhibition ranging from 53% to 59%. Finally, some of them also show potent neuroprotective effects against glutamate-induced cell death and low toxicity in HT22 cells. Graphical abstract image
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Design, synthesis and biological evaluation of N-(4-alkoxy-3-cyanophenyl)isonicotinamide/nicotinamide derivatives as novel xanthine oxidase inhibitors ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Ting-jian Zhang, Song-ye Li, Lin Wang, Qi Sun, Qing-xia Wu, Yi Zhang, Fan-hao Meng A series of N-(4-alkoxy-3-cyanophenyl)isonicotinamide/nicotinamide derivatives was designed, synthesized and evaluated for inhibitory potency in vitro against xanthine oxidase. The isonicotinamide series was considerably more effective than the nicotinamide series. SARs analysis revealed that the isonicotinoyl moiety played a significant role on the inhibition and that a benzyl ether tail (e.g., ortho-cyanobenzoxy) linked to the benzonitrile moiety benefits the inhibitory potency. Among these compounds, 10q (IC50 = 0.3 μM) was identified to be the most potent in this work and was observed to be 28.3-fold more potent than allopurinol but 20-fold less potent than topiroxostat. The Lineweaver-Burk plot showed that 10q acted as a mixed-type inhibitor on xanthine oxidase. Molecular modeling provided a reasonable explanation for the SARs observed in this study. Graphical abstract image
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Effect of mofezolac-galactose distance in conjugates targeting cyclooxygenase (COX)-1 and CNS GLUT-1 carrier ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): Maria Grazia Perrone, Paola Vitale, Savina Ferorelli, Angelina Boccarelli, Mauro Coluccia, Alessandra Pannunzio, Federica Campanella, Giuseppe Di Mauro, Carmela Bonaccorso, Cosimo G. Fortuna, Antonio Scilimati Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15–20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5 and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0 (3) was found to be a selective COX-1 inhibitor (COX-1 IC50 = 0.27 μM and COX-2 IC50 = 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0 (3) powerfully inhibits PGE2 release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site. Graphical abstract image
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Therapeutic investigations of novel indoxyl-based indolines: A drug target validation and Structure-Activity Relationship of angiotensin-converting enzyme inhibitors with cardiovascular regulation and thrombolytic potential ()
Publication date: 1 December 2017 Source:European Journal of Medicinal Chemistry, Volume 141 Author(s): A. Manikandan, Pearl Moharil, M. Sathishkumar, C. Muñoz-Garay, A. Sivakumar A family of 12 members of Naphthalene-2-ol-indolin-2-one-thiocarbamides (5a-l) with pharmacological potentials of cardiovascular modulator were efficiently synthesized and evaluated. These compounds show inhibitory activity on angiotensin-converting enzyme (ACE), which is a principal constituent of the renin–angiotensin system and causative source for hypertension (HTN) (elevated blood pressure) and congestive heart failure (CHF), a parameter that was tested in this report. Prior to this, to get more insight into the binding mode and inhibition of human ACE C-domain (PDB ID: 2XY9) and N-domain (PDB ID: 3NXQ) compounds 5a-l was docked into the active site of them. The established inhibitory constant (Ki) (range 40–500 nM) and least binding affinities (−18.52 to −30.57 kcal/mol) indicated the therapeutic selectivity of compounds 5a-l towards ACE C-domain inhibition over ACE N-domain. The cytotoxicity effect of most potent compounds among 5a-l were tested in normal breast cells and MCF-7 cell lines. Simultaneously, H2O2 induced antioxidant and DNA damage assessment was executed. Eventually, a thrombolytic activity followed by a human red blood cell (HRBC) membrane stabilization study to ensure the relaxation of blood and stabilization of RBC was executed. Structure-Activity Relationship (SAR) study discloses the potential of 5c, 5h, and 5k as cardiovascular protective therapeutic agents among 5a-l. Graphical abstract image
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A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Ankit C. Borisa, Hardik G. Bhatt Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc. IC50 values of tumor growth inhibition, in-vitro and in-vivo activity along with clinical trial data. Here, we took efforts to describe essence of Aurora kinase and its inhibition which could be used to develop anti-mitotic drug for the treatment of cancer. In conclusion, we also discuss future perspectives for development of novel inhibitors and their scope in drug development process. Graphical abstract image
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Research progress in modern structure of platinum complexes ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Linkui Bai, Chuanzhu Gao, Qinghua Liu, Congtao Yu, Zhuxin Zhang, Linxiang Cai, Bo Yang, Yunxu Qian, Jian Yang, Xiali Liao Since the antitumor activity of cisplatin was discovered in 1967 by Rosenberg, platinum-based anticancer drugs have played an important role in chemotherapy in clinic. Nevertheless, platinum anticancer drugs also have caused severe side effects and cross drug resistance which limited their applications. Therefore, a significant amount of efforts have been devoted to developing new platinum-based anticancer agents with equal or higher antitumor activity but lower toxicity. Until now, a large number of platinum-based complexes have been prepared and extensively investigated in vitro and in vivo. Among them, some platinum-based complexes revealing excellent anticancer activity showed the potential to be developed as novel type of anticancer agents. In this account, we present such platinum-based anticancer complexes which owning various types of ligands, such as, amine carrier ligands, leaving groups, reactive molecule, steric hindrance groups, non-covalently binding platinum (II) complexes, Platinum(IV) complexes and polynuclear platinum complexes. Overall, platinum-based anticancer complexes reported recently years upon modern structure are emphasized. Graphical abstract image
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Synthesis and bioevaluation of 1-phenyl-pyrazole-4-carboxylic acid derivatives as potent xanthine oxidoreductase inhibitors ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Jing Li, Fangping Wu, Xingguo Liu, Yake Zou, Huixiong Chen, Zheng Li, Lei Zhang A diverse library of 1-phenyl-pyrazole-4-carboxylic acid derivatives were synthesized and evaluated for their inhibitory potency against xanthine oxidoreductase (XOR) in vitro and vivo, and the structure-activity relationship (SAR) analyses were also presented. Approximately half of the target compounds exhibited the inhibitory potency for XOR at the nanomolar level. Compounds 16c, 16d, and 16f emerged as the most potent xanthine oxidoreductase inhibitors with IC50 values of 5.7, 5.7 and 4.2 nM, respectively, in comparison to febuxostat (IC50 of 5.4 nM). Steady-state kinetics measurements indicated that 16c is a mixed-type inhibitor. A computer molecular docking study of 16c bound to XOR was performed to gain an insight into its bind mode and SAR for the series. A potassium oxonate-hypoxanthine-induced hyperuricemia model in mice was chosen to further confirm the hypouricemic effects of 16c and 16f, and the results demonstrated that 16c exhibits similar hypouricemic potency to febuxostat. Graphical abstract image
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Lipid lowering agents of natural origin: An account of some promising chemotypes ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Suriya P. Singh, Koneni V. Sashidhara The role of natural products in the drug development and discovery has been phenomenal. There has been an enormous interest in exploring all possible natural sources to identify structures exhibiting pronounced hypolipidemic activity albeit with no toxicity. The present review describes the profile of some interesting naturally occurring compounds and their derivatives as potential hypolipidemic agents. Some of the interesting natural chemotypes that can control the increased levels of plasma lipids and discussed in this review are compactin, lovastatin, gugglesterone, berberine, lupeol, phytol, polyprenol, aegeline, 4-hydroxyisoleucine, α-asarone, resveratrol, esculeoside A, swertiamarin, rutin, saucerneol B, curcumin and a clerodane diterpene. Graphical abstract image
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Identifying novel factor XIIa inhibitors with PCA-GA-SVM developed vHTS models ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Jonathan Jun Feng Chen, Donald P. Visco There currently is renewed interest in blood clotting Factor XII as a potential target for thrombosis inhibition. Historically untargeted, there is little drug information with which to start drug candidate searches. Typical high-throughput screening can identify potential drug candidates, but is inefficient. Virtual high-throughput screening can be used to raise efficiency by focusing experimental efforts on compounds predicted to be active and is applied here to identify new Factor XIIa inhibitors. We combine principal component analysis, genetic algorithm and support vector machine to create the models used in the virtual high-throughput screening. In this work, experimental data from a PubChem Bioassay was used to train predictive models of Factor XIIa inhibition activity. The models created were then used to virtually screen the entire 72 million PubChem Compound database. Experimental validation of select candidates identified by this process resulted in a 42.9% hit-rate in the first-pass and 100% hit-rate in the second-pass, suggesting the effectiveness of the approach. Graphical abstract image
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Targeting breast cancer stem cells by novel HDAC3-selective inhibitors ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Hao-Yu Hsieh, Hsiao-Ching Chuang, Fang-Hsiu Shen, Kinjal Detroja, Ling-Wei Hsin, Ching-Shih Chen Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of β-catenin. Graphical abstract image
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2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Khurshed Bozorov, Li Fei Nie, Jiangyu Zhao, Haji A. Aisa 2-Aminothiophenes are important five-membered heterocyclic building blocks in organic synthesis, and the chemistry of these small molecules is still developing based on the discovery of cyclization by Gewald. Another attractive feature of 2-aminothiophene scaffolds is their ability to act as synthons for the synthesis of biological active thiophene-containing heterocycles, conjugates and hybrids. Currently, the biological actions of 2-aminothiophenes or their 2-N-substituted analogues are still being investigated because of their various mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). Likewise, the 2-aminothiophene family is used as diverse promising selective inhibitors, receptors, and modulators in medicinal chemistry, and these compounds even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. In this review, major biological and pharmacological reports on 2-aminothiophenes and related compounds have been highlighted; most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. In addition, we focused on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives, which have been published from 2010 to 2017. Graphical abstract image
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Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Gabriel G. Llanos, Liliana M. Araujo, Ignacio A. Jiménez, Laila M. Moujir, Jaime Rodríguez, Carlos Jiménez, Isabel L. Bazzocchi Apoptosis inducers represent an attractive approach for the discovery and development of anticancer agents. Herein, we report on the development by molecular fine tuning of a withaferin A-based library of 63 compounds (2–64), 53 of them reported for the first time. Their antiproliferative evaluation on HeLa, A-549 and MCF-7 human tumor cell lines identified fifteen analogues displaying higher activity (IC50 values ranging 0.3–4.8 μM) than the lead (IC50 values ranging 1.3–10.1 μM) either in lag or log growth phases. SAR analysis revealed that acylation enhances cytotoxicity, suggesting the hydrophobic moiety contributes to the activity, presumably by increasing affinity and/or cell membrane permeability. Further investigation clearly indicated that compounds 3, 11, 12, and 18 induce apoptosis evidenced by chromatin condensation, phosphatidylserine externalization, and caspase-3 activation effects on HeLa cells. The potent capacity to induce apoptosis with concomitant cell loss in G2/M highlights the potential of 27-benzyl analogue (18) as an apoptotic inducer drug candidate. Graphical abstract image
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5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Danylo Kaminskyy, Anna Kryshchyshyn, Roman Lesyk The presented review is an attempt to summarize a huge volume of data on 5-ene-4-thiazolidinones being a widely studied class of small molecules used in modern organic and medicinal chemistry. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivatives: modification of the C5 position of the basic core; synthesis of the target compounds in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacological profiles of 5-ene derivatives of different 4-thiazolidinone subtypes belonging to hit-, lead-compounds, drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compounds (especially 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compounds (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacological effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: i) complication of the fragment in the C5 position; ii) introduction of the substituents in the N3 position (especially fragments with carboxylic group or its derivatives); iii) annealing in complex heterocyclic systems; iv) combination with other pharmacologically attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compounds with potent pharmacological application is described. The chemical transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification. Graphical abstract image
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Characterization and structure-activity relationship study of iminodipyridinopyrimidines as novel hepatitis C virus inhibitor ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Dong-Sik Park, Eunji Jo, Jihyun Choi, MyungEun Lee, Soohyun Kim, Hee-Young Kim, Jiyon Nam, Sujin Ahn, Jong Yeon Hwang, Marc Peter Windisch Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound (12c) with excellent potency (EC50 = 10 nM), high safety margin (SI > 2000), and an acceptable stability in human and rat liver microsomes (t1/2 >60 min) was identified. Overall, our results suggest that the IDPP scaffold could be used for the development of novel HCV interventions. Graphical abstract image
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Synthesis of cytotoxically active derivatives based on alkylated 2,3-seco-triterpenoids ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Anastasia V. Konysheva, Vladimir O. Nebogatikov, Irina A. Tolmacheva, Maxim V. Dmitriev, Victoria V. Grishko Extremely low content of biologically active triterpenoids with the fragmented or contracted ring A extractable from plants is the main disadvantage of their use in drug discovery and practical pharmacology. Development of new methods for synthesis of these compounds and their structural analogs from bioavailable triterpene precursors gives an opportunity to obtain promising agents for pharmacology with excellent yields. A new approach to synthesis of alkylated A-seco-triterpenoids, including the Beckmann fragmentation of 3-methyl-substituted allobetulin or betulinic acid methyl ester with 2-hydroxyimino group in the ring A was proposed. These compounds were used to prepare a series of 2,3-seco- and five-membered ring A lupane and oleanane derivatives, cytotoxicity of which was screened in vitro against the cancer (HEp-2, HCT 116, A549, RD TE32, MS) and non-cancerous (HEK 293) cell lines. Methyl 3-bromomethyl-1-cyano-3-oxo-2,3-seco-2-norlup-20(29)-en-30-al-28-oate was selected as the most active compound (IC50 3.4–10.4 μM for HEp-2, HCT 116, RD TE32, MS cells) capable of triggering caspase-8-mediated apoptosis in HCT 116 cells accompanied by typical apoptotic chromatin condensation, without any loss of mitochondrial membrane permeability. Graphical abstract image
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1,4-Naphthoquinones as inhibitors of Itch, a HECT domain-E3 ligase, and tumor growth suppressors in multiple myeloma ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Yi-Min Liu, Wei-Chun HuangFu, Han-Li Huang, Wei-Cheng Wu, Yi-Lin Chen, Yun Yen, Hsiang-Ling Huang, Chih-Ying Nien, Mei-Jung Lai, Shiow-Lin Pan, Jing-Ping Liou A series of 1,4-naphthoquinones (10a-10q) were synthesized and evaluated for anticancer activity. Compound 10e was identified as an inhibitor of Itch, a HECT domain-E3 ligase. In an evaluation of in vivo efficacy, 10e exhibited remarkable anticancer activity with TGI values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with 10e also showed a decrease of Itch level in human RPMI-8226 multiple myeloma cells. Thus 10e is a lead compound for further development of inhibitors targeting E3 ligase for treatment of multiple myeloma. Graphical abstract image
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Synthesis, characterization, cellular uptake and apoptosis-inducing properties of two highly cytotoxic cyclometalated ruthenium(II) β-carboline complexes ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Jincan Chen, Fa Peng, Yao Zhang, Baojun Li, Ji She, Xinming Jie, Zhilin Zou, Man Chen, Lanmei Chen Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)2(1-Ph-βC)](PF6), where N–N = 4,4′-dimethyl-2,2′-bipyridine (dmb, Ru1), 2,2′-bipyridine (bpy, Ru2), and 1-Ph-βC (1-phenyl-9H-pyrido[3,4-b]indole) is a β-carboline alkaloids derivatives, have been synthesized and characterized. The in vitro cytotoxicities, cellular uptake and localization, cell cycle arrest and apoptosis-inducing mechanisms of these complexes have been extensively explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, inductively coupled plasma mass spectrometry (ICP-MS), flow cytometry, comet assay, inverted fluorescence microscope as well as western blotting experimental techniques. Notably, Ru1 and Ru2 exhibit potent antiproliferative activities against selected human cancer cell lines with IC50 values lower than those of cisplatin and other non-cyclometalated Ru(II) β-carboline complexes. The cellular uptake and localization exhibit that these complexes can accumulate in the cell nuclei. Further antitumor mechanism studies show that Ru1 and Ru2 can cause cell cycle arrest in the G0/G1 phase by regulating cell cycle relative proteins and induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage. Graphical abstract image
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Novel deoxyvasicinone derivatives as potent multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Fang Ma, Hongtao Du A series of multitarget ligands was designed by introducing several structurally diverse aminoacetamide groups at position 6 of the deoxyvasicinone group, with the aim of obtaining novel multifunctional anti-Alzheimer's disease agents using deoxyvasicinone as the substrate. In vitro studies showed that almost all of the derivatives were potent inhibitors of human recombinant acetylcholinesterase (hAChE) and human serum butyrylcholinesterase (hBChE), with IC50 values in the low nanomolar range, and exhibited moderate to high inhibition of Aβ 1−42 self-aggregation. In particular, compounds 12h, 12n, and 12q showed promising inhibitory activity for hAChE, with IC50 values of 5.31 ± 2.8, 4.09 ± 0.23, and 7.61 ± 0.53 nM, respectively. Compounds 12h and 12q also exhibited the greatest ability to inhibit hBChE, with IC50 values of 4.35 ± 0.32 and 2.35 ± 0.14 nM, respectively. Moreover, enzyme kinetics confirmed that compound 12q caused a mixed type of AChE inhibition, by binding to both the active sites (PAS and CAS) of AChE. Remarkably, compound 12q also demonstrated the highest potential inhibitory activity for Aβ 1−42 self-aggregation (63.9 ± 4.9%, 10 μM), and it was also an excellent metal chelator. Graphical abstract image
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Synthesis of substituted phenanthrene-9-benzimidazole conjugates: Cytotoxicity evaluation and apoptosis inducing studies ()
Publication date: 10 November 2017 Source:European Journal of Medicinal Chemistry, Volume 140 Author(s): Niggula Praveen Kumar, Pankaj Sharma, S. Sujana Kumari, Umarani Brahma, Shalini Nekkanti, Nagula Shankaraiah, Ahmed Kamal A series of new phenanthrene-9-benzimidazole conjugates has been synthesized by condensing phenanthrene aldehydes with various substituted o-phenylenediamines. The title compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines like breast (BT-549), prostate (PC-3 and DU145), triple negative breast cancer (MDA-MB-453), and human colon cancer (HCT-116 and HCT-15) cells. Among the tested compounds, 10o displayed significant in vitro cytotoxic activity against PC-3 prostate cancer cells with an IC50 value of 6.32 ± 0.09 μM. Further, the cell cycle analysis indicated that it blocks G2/M phase of the cell cycle in a dose dependent manner. In order to determine the effect of the compound 10o on cell viability; phase contrast microscopy, AO/EB staining, DAPI staining, and DCFDA staining studies were performed. In these studies, apoptotic features were clearly observed indicating that the compound inhibited cell proliferation by apoptosis. JC-1 staining and annexin binding assays indicated the extent of apoptosis in PC-3 cells. Further, relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation. Graphical abstract image
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