European Journal of Medicinal Chemistry

Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders ()
Publication date: 5 May 2017 Source:European Journal of Medicinal Chemistry, Volume 131 Author(s): Biswanath Dinda, Subhajit Dinda, Saikat DasSharma, Rajarshi Banik, Ankita Chakraborty, Manikarna Dinda The flavonoids, baicalin (5,6-dihydroxy-2-phenyl-4H-1-benzopyran-4-one-7-O-d-β-glucuronic acid) 1 and its aglycone, baicalein 2 are found in edible medicinal plants, Scutellaria baicalensis Georgi and Oroxylum indicum (L.) Kurz in abundant quantities. The antioxidant and anti-inflammatory effects of these flavonoids have been demonstrated in various disease models, including diabetes, cardiovascular diseases, inflammatory bowel diseases, gout and rheumatoid arthritis, asthma, neurodegenerative-, liver- and kidney diseases, encephalomyelitis, and carcinogenesis. These flavonoids have almost no toxicity to human normal epithelial, peripheral and myeloid cells. Their antioxidant and anti-inflammatory activities are largely due to their abilities to scavenge the reactive oxygen species (ROS) and improvement of antioxidant status by attenuating the activity of NF-κB and suppressing the expression of several inflammatory cytokines and chemokines including monocyte chemotactic protein-1 (MCP-1), nitric oxide synthase, cyclooxygenases, lipoxygenases, cellular adhesion molecules, tumor necrosis factor and interleukins. In this review, we summarize the antioxidant and anti-inflammatory effects of baicalin and baicalein with molecular mechanisms for their chemopreventive and chemotherapeutic applications in the treatment of inflammatory-related diseases. Graphical abstract image
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Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy ()
Publication date: 5 May 2017 Source:European Journal of Medicinal Chemistry, Volume 131 Author(s): Chenzhou Hao, Wanxu Huang, Xiaodong Li, Jing Guo, Meng Chen, Zizheng Yan, Kai Wang, Xiaolin Jiang, Shuai Song, Jian Wang, Dongmei Zhao, Feng Li, Maosheng Cheng Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 μM) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 μM). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4. Graphical abstract image
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Synthesis, screening and docking of fused pyrano[3,2-d]pyrimidine derivatives as xanthine oxidase inhibitor ()
Publication date: 5 May 2017 Source:European Journal of Medicinal Chemistry, Volume 131 Author(s): Manroopraj Kaur, Amandeep Kaur, Suhani Mankotia, Harbinder Singh, Arshdeep Singh, Jatinder Vir Singh, Manish Kumar Gupta, Sahil Sharma, Kunal Nepali, Preet Mohinder Singh Bedi In view of developing effective xanthine oxidase (XO) enzyme inhibitors, a series of 100 pyrano[3,2-d]pyrimidine derivatives was synthesized and evaluated for its in vitro XO enzyme inhibition. Structure activity relationship has also been established. Among all the synthesized compounds, 4d, 8d and 9d were found to be the most potent enzyme inhibitors with IC50 values of 8μM, 8.5μM and 7μM, respectively. Compound 9d was further investigated in enzyme kinetic studies and the Lineweaver-Burk plot revealed that the compound 9d was mixed type inhibitor. Molecular properties of the most potent compounds 4d, 8d and 9d, have also been calculated. Docking study was performed to investigate the recognition pattern between xanthine oxidase and the most potent XO inhibitor, 9d. The study suggests that 9d may block the activity of XO sufficiently enough to prevent the substrate from binding to its active site. Graphical abstract image
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Coumarin sulfonates: New alkaline phosphatase inhibitors; in vitro and in silico studies ()
Publication date: 5 May 2017 Source:European Journal of Medicinal Chemistry, Volume 131 Author(s): Uzma Salar, Khalid Mohammed Khan, Jamshed Iqbal, Syeda Abida Ejaz, Abdul Hameed, Mariya al-Rashida, Shahnaz Perveen, Muhammad Nawaz Tahir A library of coumarin derived sulfonyl esters (1–38) was synthesized by reacting various hydroxy coumarins with different alkyl and aryl sulfonyl chlorides. All compounds were evaluated for their potential to inhibit alkaline phosphatases (hTNAP and hIAP). Most of the compounds were found to be inhibitors of APs. Compound 20 was found to be the most active hIAP inhibitor (IC50 = 1.11 ± 0.15 μM), whereas, compound 13 was found to be the most active hTNAP inhibitor (IC50 = 0.58 ± 0.17 μM). Detailed structure activity relationship studies (SAR), and molecular docking studies were carried out to identify structural elements necessary for AP inhibition, in addition to rationalize most probable binding site interaction of the inhibitors with the AP enzymes. Graphical abstract image
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Synthesis of heterocyclic ring-fused tricyclic diterpene analogs as novel inhibitors of RANKL-induced osteoclastogenesis and bone resorption ()
Publication date: 5 May 2017 Source:European Journal of Medicinal Chemistry, Volume 131 Author(s): Gao Wei, Yalan Wu, Xiao-Long He, Ting Liu, Mingyao Liu, Jian Luo, Wen-Wei Qiu A series of heterocyclic ring-fused tricyclic diterpene analogs were synthesized and their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated on bone marrow-derived monocytes (BMMs) by a cell based tartrate-resistant acid phosphatase (TRAP) activity assay. Among them, the most potent compound, 37 (QG368), showed 72.3% inhibition even at a low concentration of 0.1 μM, which was about 188-fold more potent than the lead compound. Cytotoxicity test on BMMs indicated that the inhibition on osteoclast differentiation of 37 did not result from its cytotoxicity. Moreover, 37 also showed no obvious effect on osteoblast differentiation. Mechanistic studies disclosed that 37 can inhibit the expression of osteoclastogenesis-related marker genes, including Nfatc1, TRAP, cathepsin K, C-src and CTR. In particular, 37 could decrease the ovariectomy-induced osteoclast activity and relieve the osteoporosis obviously in vivo. Therefore, these tricyclic diterpene analogs could be served as promising leads for the development of a new class of antiresorptive agents. Graphical abstract image
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Editorial board ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130
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Graphical contents list ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130
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Facile and efficient access to Androsten-17-(1′,3′,4′)-pyrazoles and Androst-17β-(1′,3′,4′)-pyrazoles via Vilsmeier reagents, and their antiproliferative activity evaluation in vitro ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Jian Li, Haibo Huo, Rui Guo, Biao Liu, Longbo Li, Wenjia Dan, Xinmin Xiao, Jiwen Zhang, Baojun Shi In this work, twenty-seven novel steroidal pyrazole derivatives were designed and effectively synthesized with two different commercially available staring material, Isopregnanolone 1 and 5,16-Pregnadienolone 7, via the key intermediates, 17β-(4′-formyl)pyrazolylandrost-3β-yl formate and 17-(4′-formyl)pyrazolylandrost- 5,16-dienes-3β-yl formate, which were obtained from the cyclization of steroidal phenylhydrazone with Vilsmeier reagent catalyzed by phosphorous oxychloride followed by hydrolysis, then Borch reduction to afford the target derivatives under mild conditions. Structures of these compounds were identified by 1H NMR, 13C NMR and high resolution mass spectrometry. Based on our previous work, the cytotoxicity of these derivatives were evaluated by the SRB method against 293T cell lines and three cancer cell lines: A549, Hela and MCF-7. The results indicated that compounds 5b-d, and 11a-e exhibited moderate to high cytotoxic activities with IC50 values ranging from 0.62 to 7.51 μM. Among the eight hybrids, compound 11b, with an ethyl amino and a dien-pregn moieties showed the highest potency, with an IC50 values of 0.87 μM and 0.53 μM for 293T cell lines and Hela cell lines, respectively. Some structure-activity relationships among the groups of the twenty-seven derivatives are discussed and identify several determinants important for the activity of these compounds. What's more, further molecular mechanism studies suggested that 11b one of the most potent derivatives caused Hela cell lines apoptosis and arrested the cell cycle at S phase in a concentration dependent manner. Graphical abstract image
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Combination of amino acid/dipeptide with ligustrazine-betulinic acid as antitumor agents ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Bing Xu, Wen-Qiang Yan, Xin Xu, Gao-Rong Wu, Chen-Ze Zhang, Yao-Tian Han, Fu-Hao Chu, Rui Zhao, Peng-Long Wang, Hai-Min Lei The lead compound TBA, 3β-Hydroxy-lup-20(29)-ene-28-oic acid-3, 5, 6-trimethylpyrazin-2-methyl ester, which exhibited promising antitumor activity and induced tumor cell apoptosis in various cancer cell lines, had previously been reported. Moreover, reports have revealed that the introduction of amino acid to betulinic acid could improve selective cytotoxicity as well as water solubility. Thus, a series of novel TBA amino acid and dipeptide derivatives were designed, synthesized and screened for selective cytotoxic activity against five cancer cell lines (HepG2, HT-29, Hela, BCG-823 and A549) and the not malignant cell line MDCK by standard MTT assay. Most of the tested TBA-amino acid and dipeptide analogues showed stronger anti-proliferative activity against all tested tumor cell lines than TBA. Among them, BA-25 exhibited the greatest cytotoxic activity on tumor cell lines (mean IC50 = 2.31 ± 0.78 μM), that was twofold than the positive drug cisplatin (DDP), while it showed lower cytotoxicity on MDCK cell line than DDP. Further cell apoptosis analyses indicated BA-25-induced apoptosis was associated with loss of mitochondrial membrane potential and increase of intracellular free Ca2+ concentration. Graphical abstract image
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Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Elany Barbosa da Silva, Dayane Albuquerque Oliveira e Silva, Arsênio Rodrigues Oliveira, Carlos Henrique da Silva Mendes, Thiago André Ramos dos Santos, Aline Caroline da Silva, Maria Carolina Acioly de Castro, Rafaela Salgado Ferreira, Diogo Rodrigo Magalhães Moreira, Marcos Veríssimo de Oliveira Cardoso, Carlos Alberto de Simone, Valéria Rêgo Alves Pereira, Ana Cristina Lima Leite Chagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with non-classical bioisosterism. 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 comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 μM, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce 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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Analogues of xanthones——Chalcones and bis-chalcones as α-glucosidase inhibitors and anti-diabetes candidates ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Chao-Yun Cai, Li Rao, Yong Rao, Jin-Xuan Guo, Zhi-Zun Xiao, Jing-Yu Cao, Zhi-Shu Huang, Bo Wang Two series of compounds (chalcones and bis-chalcones) were designed, synthesized, and evaluated as α-glucosidase inhibitors (AGIs) with 1-deoxynojirimycin as positive control in vitro. Most of the compounds with two or four hydroxyl groups showed better inhibitory activities than 1-deoxynojirimycin towards α-glucosidase with noncompetitive mechanism. Moreover, most of the hydroxy bis-chalcones exhibit good α-glucosidase inhibitory activities in enzyme test. Inspiringly, bis-chalcones 2g (at 1 μM concentration) has stronger effect than 1-deoxynojirimycin on reducing the glucose level in HepG-2 cells (human liver cancer cell line). Graphical abstract image
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Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Leticia Monjas, Mariana P. Arce, Rafael León, Javier Egea, Concepción Pérez, Mercedes Villarroya, Manuela G. López, Carmen Gil, Santiago Conde, María Isabel Rodríguez-Franco Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds. Graphical abstract image
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Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Ibrahim H. Eissa, Haroon Mohammad, Omar A. Qassem, Waleed Younis, Tamer M. Abdelghany, Ahmed Elshafeey, Mahmoud M. Abd Rabo Moustafa, Mohamed N. Seleem, Abdelrahman S. Mayhoub A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics. Graphical abstract image
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Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Lu Wang, Qing Zhang, Gaoyuan Zhu, Zhimin Zhang, Yanle Zhi, Li Zhang, Tianxiao Mao, Xiang Zhou, Yadong Chen, Tao Lu, Weifang Tang Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2 cell lines showed I-41 inhibited the proliferation of SK-Mel-2 cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRafV600E inhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described. Graphical abstract image
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Vicinal diaryl azole-based urea derivatives as potential cholesterol lowering agents acting through inhibition of SOAT enzymes ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Palash Pal, Hardik P. Gandhi, Ashish M. Kanhed, Nirali R. Patel, Niraj N. Mankadia, Satish N. Baldha, Mahesh A. Barmade, Prashant R. Murumkar, Mange Ram Yadav A novel series of vicinal diaryl azole-urea derivatives were synthesized and evaluated for their potential to inhibit SOAT enzyme. Among the reported compounds, compound (12d) emerged as the most potent compound with an IC50 value of 2.43 μM. In polaxamer-407 induced lipoprotein lipase inhibition model, compound (12d) reduced triglyceride turnover in vivo. Compound (12d) also showed dose-dependent prevention of serum total cholesterol and prevention of LDL-C elevation at a dose of 30 mg/kg. Furthermore, compound (12d) showed potential to stop falling levels of serum HDL-C dose-dependently and improved the atherogenic index. Effect of 12d on body weight, plaque formation and development of atherogenic lesions were studied. Toxicological study of compound (12d) indicated that at a dose of 2000 mg/kg, 12d was devoid of any signs of toxicity or mortality. Graphical abstract image
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New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): İnci Selin Doğan, Selma Saraç, Suat Sari, Didem Kart, Şebnem Eşsiz Gökhan, İmran Vural, Sevim Dalkara Azole antifungals are potent inhibitors of fungal lanosterol 14α demethylase (CYP51) and have been used for eradication of systemic candidiasis clinically. Herein we report the design, synthesis, and biological evaluation of a series of 1-phenyl/1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol esters. Many of these derivatives showed fungal growth inhibition at very low concentrations. Minimal inhibition concentration (MIC) value of 15 was 0.125 μg/mL against Candida albicans. Additionally, some of our compounds, such as 19 (MIC: 0.25 μg/mL), were potent against resistant C. glabrata, a fungal strain less susceptible to some first-line antifungal drugs. We confirmed their antifungal efficacy by antibiofilm test and their safety against human monocytes by cytotoxicity assay. To rationalize their mechanism of action, we performed computational analysis utilizing molecular docking and dynamics simulations on the C. albicans and C. glabrata CYP51 (CACYP51 and CGCYP51) homology models we built. Leu130 and T131 emerged as possible key residues for inhibition of CGCYP51 by 19. Graphical abstract image
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Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer's disease treatment ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Chun-Li Xia, Ning Wang, Qian-Liang Guo, Zhen-Quan Liu, Jia-Qiang Wu, Shi-Liang Huang, Tian-Miao Ou, Jia-Heng Tan, Hong-Gen Wang, Ding Li, Zhi-Shu Huang A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349–361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier. Graphical abstract image
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Design, synthesis, biological evaluation, molecular docking and QSAR studies of 2,4-dimethylacridones as anticancer agents ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Manikanta Murahari, Prashant S. Kharkar, Nitin Lonikar, YC Mayur Drug resistance in cancer is an unmet medical challenge and a major drawback for the failure of many chemotherapeutic drugs. Search for targeted, effective drug with minimum toxicity is an urgent need. Acridone which is an alkaloid derivative has been attributed as molecule in reversing drug resistance in cancer cells for a long time now. In the present investigation, an attempt has been made to explore the chemosensitizing ability of 2,4-dimethylacridones with alkyl side chain containing terminally substituted tertiary amino groups. Considering the structural features required for the MDR reversal activity, acridone derivatives have been synthesized with propyl and butyl side chain containing morpholinyl, piperidinyl, N-methylpiperazinyl, N,N-diethylamino, N-diethanolamino, N-[(β-hydroxylethyl)]piperazino at the terminus of the alkyl side chain. cLogP values for the synthesized compounds ranged from 2.96 to 4.72 for the propyl derivatives and 3.41 to 5.15 for the butyl derivatives. All the compounds were screened against breast cancer sensitive MCF7 and resistant MCF7/ADR cell lines. Compounds 12e and 12f have shown better cytotoxicity profiles with IC50 of 4 ± 0.05 and 2 ± 0.03 μM against MCF7 cells, 5.21 ± 0.13 and 2.56 ± 0.05 μM against MCF7/ADR cells. Photolabelling studies with [3H]-azidopine and molecular docking studies have identified that 2,4-dimethylacridones have potential to modulate the P-gp mediated multidrug resistance. Docking studies identified that compounds have shown favorable interactions with P-gp. QSAR equation was derived for cytotoxicity vs molecular descriptors of acridone derivatives. Best models with good predictive ability have been generated with very high square correlation coefficient (R2) values of 0.889, 0.964 and 0.983. Graphical abstract image
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Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Žiga Jakopin, Janez Ilaš, Michaela Barančoková, Matjaž Brvar, Päivi Tammela, Marija Sollner Dolenc, Tihomir Tomašič, Danijel Kikelj DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV. Graphical abstract image
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Oligothiophene compounds inhibit the membrane fusion between H5N1 avian influenza virus and the endosome of host cell ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Zhibo Zhu, Zhili Yao, Xiantian Shen, Zhipeng Chen, Xiangtao Liu, Jon R. Parquette, Shuwen Liu Hemagglutinin (HA) which is essential for influenza viral infection and replication has become a target for the design of anti-influenza drugs. A novel series of oligothiophene compounds focused on the target were synthesized as specific inhibitors against the H5 subtype of influenza A viruses because oligothiophene has stronger π–π interactions with residues F1102 and M241 of HA2 side chains. Oligothiophene compounds were designed and synthesized by a series of alkylation, azidation, amination and amidation reactions. The entry inhibitory activities of those compounds were tested at a cellular level against H5N1 influenza pseudovirus. Compound 3sf was revealed as the most active inhibitor in this series with an IC50 of 0.029 μM. The activity of 3sf is almost 1000 times that of the positive reference compound (CL-385319). A structure-activity analysis of these compounds demonstrated that the size of the oligothiophene compounds was very important for the inhibitory activity. Four compounds (3sk, 3sf, 3sc and 4sc) of strong inhibitiory activity against H5N1 influenza pseudovirus were assessed against H1N1 influenza virus MDCK. They also showed strong inhibitiory activity with IC50s of 3.292 μM, 1.240 μM, 1.119 μM and 0.768 μM, respectively. Graphical abstract image
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Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet β-cells from apoptosis ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Sheng Wang, Lei Xu, Yu-Ting Lu, Yu-Fei Liu, Bing Han, Ting Liu, Jie Tang, Jia Li, Jiangping Wu, Jing-Ya Li, Li-Fang Yu, Fan Yang Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC50 value of 3.15 μM. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC50 = 0.33 μM) and 41 (IC50 = 0.25 μM) were found to protect islet β-cells from apoptosis in dose-dependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes. Graphical abstract image
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Discovery of uracil-bearing DAPYs derivatives as novel HIV-1 NNRTIs via crystallographic overlay-based molecular hybridization ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Heng Zhang, Ye Tian, Dongwei Kang, Zhipeng Huo, Zhongxia Zhou, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based molecular hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50 = 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents. Graphical abstract image
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Synthesis of novel pyrazolo[3,4-b]quinolinyl acetamide analogs, their evaluation for antimicrobial and anticancer activities, validation by molecular modeling and CoMFA analysis ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Jitender Dev G, Y. Poornachandra, K. Ratnakar Reddy, R. Naresh Kumar, N. Ravikumar, D. Krishna Swaroop, P. Ranjithreddy, G. Shravan Kumar, Jagadeesh B. Nanubolu, C. Ganesh Kumar, B. Narsaiah A series of novel alkyl amide functionalized 2,3-pyrazole fused quinoline derivatives 5, 6 and 7 have been prepared starting from quinoline-2(1H)one 1 in a series of steps. All the final products were screened for antibacterial activity, the promising lead compound 5r was identified with MIC values ranging between 3.9 and 7.8 μg/mL against different bacterial strains. Compound 5r also showed good antifungal and anti-biofilm activities against the tested panel of various fungal and bacterial strains. Compound 5r when treated on mature biofilms of S. aureus strain MLS16, showed increased levels of intracellular ROS accumulation suggesting its contribution to the bactericidal activity. All the compounds were also screened for anticancer activity against a panel of four human cancer cell lines. Based on these studies, compounds 5c, 5d, 5r and 7f were considered as promising and exhibited significant cytotoxicity with IC50 values of <15 μM. The biological activity data was further validated by molecular modeling and CoMFA studies. Graphical abstract image
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Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Asger B. Petersen, Nikolaj S. Andersen, Gleb Konotop, Nur Hafzan Md Hanafiah, Marc S. Raab, Alwin Krämer, Mads H. Clausen Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2′-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2′-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2′-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro. Graphical abstract image
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Natural product-inspired esters and amides of ferulic and caffeic acid as dual inhibitors of HIV-1 reverse transcriptase ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Vijay P. Sonar, Angela Corona, Simona Distinto, Elias Maccioni, Rita Meleddu, Benedetta Fois, Costantino Floris, Nilesh V. Malpure, Stefano Alcaro, Enzo Tramontano, Filippo Cottiglia Using an HIV-1 Reverse Transcriptase (RT)-associated RNase H inhibition assay as lead, bioguided fractionation of the dichloromethane extract of the Ocimum sanctum leaves led to the isolation of five triterpenes (1–5) along with three 3-methoxy-4-hydroxy phenyl derivatives (6–8). The structure of this isolates were determined by 1D and 2D NMR experiments as well as ESI-MS. Tetradecyl ferulate (8) showed an interesting RNase H IC50 value of 12.4 μM and due to the synthetic accessibility of this secondary metabolite, a structure-activity relationship study was carried out. A series of esters and amides of ferulic and caffeic acids were synthesized and, among all, the most active was N-oleylcaffeamide displaying a strong inhibitory activity towards both RT-associated functions, ribonuclease H and DNA polymerase. Molecular modeling studies together with Yonetani-Theorell analysis, demonstrated that N-oleylcaffeamide is able to bind both two allosteric site located one close to the NNRTI binding pocket and the other close to RNase H catalytic site. Graphical abstract image
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β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Azizah M. Malebari, Lisa M. Greene, Seema M. Nathwani, Darren Fayne, Niamh M. O'Boyle, Shu Wang, Brendan Twamley, Daniela M. Zisterer, Mary J. Meegan Glucuronidation by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) is a cause of intrinsic drug resistance in cancer cells. Glucuronidation of combretastatin A-4 (CA-4) was previously identified as a mechanism of resistance in hepatocellular cancer cells. Herein, we propose chemical manipulation of β-lactam bridged analogues of Combretastatin A-4 as a novel means of overcoming drug resistance associated with glucuronidation due to the expression of UGTs in the CA-4 resistant human colon cancer HT-29 cells. The alkene bridge of CA-4 is replaced with a β-lactam ring to circumvent potential isomerisation while the potential sites of glucuronate conjugation are deleted in the novel 3-substituted-1,4-diaryl-2-azetidinone analogues of CA-4. We hypothesise that glucuronidation of CA-4 is the mechanism of drug resistance in HT-29 cells. Ring B thioether containing 2-azetidinone analogues of CA-4 such as 4-(4-(methylthio)phenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (27) and 3-hydroxy-4-(4-(methylthio)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (45) were identified as the most potent inhibitors of tumour cell growth, independent of UGT status, displaying antiproliferative activity in the low nanomolar range. These compounds also disrupted the microtubular structure in MCF-7 and HT-29 cells, and caused G2/M arrest and apoptosis. Taken together, these findings highlight the potential of chemical manipulation as a means of overcoming glucuronidation attributed drug resistance in CA-4 resistant human colon cancer HT-29 cells, allowing the development of therapeutically superior analogues. Graphical abstract image
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Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Wang Delong, Wang Lanying, Wu Yongling, Song Shuang, Feng Juntao, Zhang Xing In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50 = 10.4 μM but less cytotoxic activity with IC50 = 141.2 μM (against HepG2 cell line) and 161.2 μM (against human hepatic L02 cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C. orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure–activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents. Graphical abstract image
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Design, synthesis and biological evaluation of gentiopicroside derivatives as potential antiviral inhibitors ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Shaoping Wu, Lili Yang, Wenji Sun, Longlong Si, Sulong Xiao, Qi Wang, Luc Dechoux, Serge Thorimbert, Matthieu Sollogoub, Demin Zhou, Yongmin Zhang Based on classical drug design theory, a novel series of gentiopicroside derivatives was designed and synthesized. All synthesized compounds were then biologically evaluated for their inhibition of influenza virus and anti-HCV activity in vitro. Some of the gentiopicroside derivatives, such as 11a, 13d and 16 showed interesting anti-influenza virus activity with IC50 at 39.5 μM, 45.2 μM and 44.0 μM, respectively. However, no significant anti-HCV activity was found for all of gentiopicroside derivatives. The preliminary results indicate that modification of the sugar moiety on gentiopicroside was helpful for enhancing the anti-influenza activities. Our works demonstrate the importance of secoiridoid natural products as new leads in the development of potential antiviral inhibitors. Graphical abstract image
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Quinazoline derivatives as selective CYP1B1 inhibitors ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Mohd Usman Mohd Siddique, Glen J.P. McCann, Vinay R. Sonawane, Neill Horley, Linda Gatchie, Prashant Joshi, Sandip B. Bharate, Venkatesan Jayaprakash, Barij N. Sinha, Bhabatosh Chaudhuri CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid ‘O’ atom with ‘N’ atom led to the prediction that a ‘quinazoline’ scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells. Graphical abstract image
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Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of trifluoroacetylation ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Nikolaos Papastavrou, Maria Chatzopoulou, Jana Ballekova, Mario Cappiello, Roberta Moschini, Francesco Balestri, Alexandros Patsilinakos, Rino Ragno, Milan Stefek, Ioannis Nicolaou Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer. However, efforts to prepare small-molecule aldose reductase inhibitors (ARIs) have mostly yielded carboxylic acids with rather poor pharmacokinetics. To address this limitation, the 1-hydroxypyrazole moiety has been previously established as a bioisostere of acetic acid in a group of aroyl-substituted pyrrolyl derivatives. In the present work, optimization of this new class of ARIs was achieved by the addition of a trifluoroacetyl group on the pyrrole ring. Eight novel compounds were synthesized and tested for their inhibitory activity towards ALR2 and selectivity against aldehyde reductase (ALR1). All compounds proved potent and selective inhibitors of ALR2 (IC50/ALR2 = 0.043−0.242 μΜ, Selectivity index = 190−858), whilst retaining a favorable physicochemical profile. The most active (4g) and selective (4d) compounds were further evaluated for their ability to inhibit sorbitol formation in rat lenses ex vivo and to exhibit substrate-specific inhibition. Graphical abstract image
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Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Marco Lelle, Christoph Freidel, Stefka Kaloyanova, Ilja Tabujew, Alexander Schramm, Michael Musheev, Christof Niehrs, Klaus Müllen, Kalina Peneva We describe the synthesis and characterization of a novel bioconjugate, consisting of an octaarginine cell-penetrating peptide and a highly DNA-affine doxorubicin dimer. The linkage between the two components is composed of a cleavable disulfide bond, which enables the efficient intracellular delivery of the cytotoxic payload within the reductive environment of the cytosol, mediated through glutathione. To determine the DNA-binding affinity of the dimeric drug molecule, microscale thermophoresis was applied. This is the first utilization of this method to assess the binding interactions of an anthracycline drug with nucleic acids. The cytotoxic effect of the peptide-drug conjugate, studied with drug-sensitive and doxorubicin-resistant cancer cells, demonstrates that the bioconjugate can successfully overcome drug resistance in neuroblastoma cells. Graphical abstract image
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Ferrocene-embedded flavonoids targeting the Achilles heel of multidrug-resistant cancer cells through collateral sensitivity ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Basile Pérès, Rachad Nasr, Malik Zarioh, Florine Lecerf-Schmidt, Attilio Di Pietro, Hélène Baubichon-Cortay, Ahcène Boumendjel With the aim to develop anticancer agents acting selectively against resistant tumor cells, we investigated ferrocene embedded into chalcone, aurone and flavone skeletons. These compounds were conceived and then investigated based on the concept of collateral sensitivity, where the target is the Achilles Heel of cancer cells overexpressing the multidrug ABC transporter MRP1. The 14 synthesized compounds were evaluated for their ability to induce efflux of glutathione (GSH) from tumor cells overexpressing MRP1. When tested at 5 and 20 μM, at least one compound from each series was found to be a highly inducer of GSH efflux. The different compounds inducing a high efflux of GSH were evaluated on both sensitive and resistant cell lines, and two of them, belonging to the flavones class were found to be more cytotoxic on resistant cancer cells, with the best selectivity ratio >9.1. Our results bring chemical and biological bases for further optimization. Graphical abstract image
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Identification of dibenzyl imidazolidine and triazole acetamide derivatives through virtual screening targeting amyloid beta aggregation and neurotoxicity in PC12 cells ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Sukanya Das, Scott D. Smid Aggregation and neurotoxicity of amyloid β (Aβ) protein is a hallmark characteristic of Alzheimer's disease (AD). In this study we compared the anti-aggregatory and neuroprotective effects of five synthetic compounds against Aβ protein; four of which possessed a five membered heterocycle ring scaffold (two dibenzyl phenyl imidazolidines and two triazole sulfanyl acetamides) and one with a fused five membered heterocycle (benzoxazole) ring, selected thorough virtual screening from ZINC database. Molecular docking of their optimized structures was used to study Aβ binding characteristics. As predicted from molecular docking, strong steric binding of imidazolidines and H-bonding of both triazoles to Aβ were translated into anti Aβ aggregation properties. Subsequent transmission electron microscopy (TEM) was used to assess their effects on Aβ1-42 fibril formation. Four compounds variably altered morphology of Aβ fibrils from long, intertwined fibrils to short, loose structures. Thioflavin T assay of Aβ fibrillisation kinetics demonstrated that one imidazolidine and both triazole compounds inhibited Aβ aggregation. Rat pheochromocytoma (PC12) cells were exposed to Aβ1-42, alone and in combination with the heterocyclic compounds to assess neuroprotective effects. Aβ1-42-evoked loss of neuronal cell viability was significantly attenuated in the presence of both imidazolidine compounds, while the triazole acetamides and benzoxazole compound were toxic to PC12 cells. These findings highlight the Aβ anti-aggregative and neuroprotective propensity of a dibenzyl phenyl imidazolidine scaffold (Compound 1 and 2). While the triazole sulfanyl acetamide scaffold also possessed Aβ anti-aggregation properties, they also demonstrated significant intrinsic neurotoxicity. Overall, the predictive efficacy of in silico methods enables the identification of novel imidazolidines that act both as inhibitors of Aβ aggregation and neurotoxicity, and may provide a further platform for the development of novel Alzheimer's disease-modifying pharmacotherapies. Graphical abstract image
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Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1,3,4-oxadiazin-5(6H)-one ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Jungeun Lee, Yeongcheol Lee, So Jung Park, Joohee Lee, Yeong Shik Kim, Young-Ger Suh, Jeeyeon Lee Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-containing enzyme that plays a major role in the oxidative deamination of biogenic amines and neurotransmitters. Inhibiting MAO-B activity is a promising approach in the treatment of neurological disorders. Here, we report a series of 2-aryl-1,3,4-oxadiazin-5(6H)-one derivatives as highly selective and potent MAO-B inhibitors. Analysis of the binding sites of hMAO-A and hMAO-B led to design of linear analogs of 2-aryl-1,3,4-oxadiazin-5(6H)-one with an additional phenyl ring. Biological evaluation of the 26 new derivatives resulted in the identification of highly potent and selective inhibitors with optimal physicochemical properties to potentially cross the blood-brain barrier (BBB). Compounds 18a, 18b, 18e and 25b potently inhibited MAO-B, with IC50 values of 4–25 nM and excellent SI over MAO-A (18a > 25000, 18b > 8333 and 18e > 4000 and 25b > 4545). Docking results suggest that an optimal linker between two aromatic rings on the 2-aryl-1,3,4-oxadiazin-5(6H)-one scaffold is a key element in the binding and inhibition of MAO-B. Graphical abstract image
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Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Zhipei Sang, Wanli Pan, Keren Wang, Qinge Ma, Lintao Yu, Yan Yang, Ping Bai, Chaoliang Leng, Qian Xu, Xiaoqing Li, Zhenghuai Tan, Wenmin Liu A series of novel ferulic acid-O-alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced β-amyloid (Aβ) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor (IC50 value of 0.021 μM for equine serum BuChE, 8.63 μM for ratBuChE and 0.07 μM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50 = 2.13 μM for electric eel AChE, 1.8 μM for ratAChE and 3.82 μM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced Aβ 1-42 aggregation (50.8 ± 0.82%) and was found to disaggregate self-induced Aβ 1-42 aggregation (38.7 ± 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H2O2-induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro. Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD. Graphical abstract image
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Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): You-Guang Zheng, Jun Su, Cai-Yun Gao, Ping Jiang, Lin An, Yun-Sheng Xue, Jian Gao, Yi Liu In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50 of 8.3 μM. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR (IC50 = 0.0032 μM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential (ΔΨm), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research. Graphical abstract image
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Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Takayuki Irie, Tokiko Asami, Ayako Sawa, Yuko Uno, Mitsuharu Hanada, Chika Taniyama, Yoko Funakoshi, Hisao Masai, Masaaki Sawa Cdc7 is a serine-threonine kinase and plays a conserved and important role in DNA replication, and it has been recognized as a potential anticancer target. Herein, we report the design, synthesis and structure-activity relationship of novel furanone derivatives as Cdc7 kinase inhibitors. Compound 13 was identified as a strong inhibitor of Cdc7 with an IC50 value of 0.6 nM in the presence of 1 mM ATP and showed excellent kinase selectivity. In addition, it exhibited slow off-rate characteristics, which may offer advantages over known Cdc7 inhibitors in its potential to yield prolonged inhibitory effects in vivo. Compound 13 potently inhibited Cdc7 activity in cancer cells, and effectively induced cell death. Graphical abstract image
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Structure-activity relationship studies on 3,5-dinitrophenyl tetrazoles as antitubercular agents ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Jan Němeček, Pavel Sychra, Miloslav Macháček, Markéta Benková, Galina Karabanovich, Klára Konečná, Věra Kavková, Jiřina Stolaříková, Alexandr Hrabálek, Kateřina Vávrová, Ondřej Soukup, Jaroslav Roh, Věra Klimešová In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2H-tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1H-tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2H-tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 μM) and high activity against non-tuberculous mycobacterial strains. Graphical abstract image
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Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Kris Simone T. Dias, Cynthia T. de Paula, Thiago dos Santos, Isis N.O. Souza, Marina S. Boni, Marcos J.R. Guimarães, Fernanda M.R. da Silva, Newton G. Castro, Gilda A. Neves, Clarice C. Veloso, Márcio M. Coelho, Ivo Souza F. de Melo, Fabiana C.V. Giusti, Alexandre Giusti-Paiva, Marcelo L. da Silva, Laurent E. Dardenne, Isabella A. Guedes, Letizia Pruccoli, Fabiana Morroni, Andrea Tarozzi, Claudio Viegas A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 μM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects. Graphical abstract image
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Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[c]acridine derivatives as new c-KIT promoter G-quadruplex binding ligands ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Qian-Liang Guo, Hua-Fei Su, Ning Wang, Sheng-Rong Liao, Yu-Ting Lu, Tian-Miao Ou, Jia-Heng Tan, Ding Li, Zhi-Shu Huang It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized. Subsequent biophysical evaluation demonstrated that the derivatives could effectively bind to and stabilize c-KIT G-quadruplex with good selectivity against duplex DNA. It was found that 12-N-methylated derivatives with a positive charge introduced at 12-position of 5,6-dihydrobenzo[c]acridine ring had similar binding affinity but lower stabilizing ability to c-KIT G-quadruplex DNA, compared with those of nonmethylated derivatives. Further molecular modeling studies showed possible binding modes of G-quadruplex with the ligands. RT-PCR assay and Western blot showed that compound 2b suppressed transcription and translation of c-KIT gene in K562 cells, which was consistent with the property of an effective G-quadruplex binding ligand targeting c-KIT oncogene promoter. Further biological evaluation showed that compound 2b could induce apoptosis through activation of the caspase-3 cascade pathway. Graphical abstract image
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Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): Junwei Wang, Qiao Song, Anhua Xu, Yu Bao, Yungen Xu, Qihua Zhu Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant K i value of 15.7 nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302. In addition, compound 1c also showed potent κ antagonist activity with κ IC50 = 9.32 nM in [35S]GTP-γ-S functional assay. The potential use of the representative compounds as antidepressants was also investigated. The most potent compound 1c not only exhibited potent antidepressant activity in the mice forced swimming test, but also displayed the effect of anti-anxiety in the elevated plus-maze test. Graphical abstract image
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Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists ()
Publication date: 21 April 2017 Source:European Journal of Medicinal Chemistry, Volume 130 Author(s): James O'Brien-Brown, Alexander Jackson, Tristan A. Reekie, Melissa L. Barron, Eryn L. Werry, Paolo Schiavini, Michelle McDonnell, Lenka Munoz, Shane Wilkinson, Benjamin Noll, Shudong Wang, Michael Kassiou Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists. Graphical abstract image
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Editorial board ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129
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Graphical contents list ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129
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Strategies in the designing of prodrugs, taking into account the antiviral and anticancer compounds ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129 Author(s): Monika A. Lesniewska-Kowiel, Izabela Muszalska Prodrugs are a wide group of substances of low or no pharmacological activity. The search for prodrugs is aimed at obtaining drugs characterized by better pharmacokinetic properties, pharmaceutical availability and selective activity of the active substance. Prodrug strategies involve chemical modifications and syntheses of new structures as well as the establishment of systems that deliver active substances for therapeutic aims that is prodrug-based treatments. The paper describes decisive factors in prodrug designing, such as enzymes participating in their activation, concepts of chemical modifications in the group of antiviral drugs and new anticancer treatments based on prodrugs (ADEPT, GDEPT, LEAPT). Prodrugs are seen as a possibility to design medicines which are selective for their therapeutic aim, for example a tumorous cell or a microorganism. Such an approach is possible thanks to the knowledge on: pathogenesis of diseases at molecular level, metabolism of healthy and affected cells as well as metabolism of microorganisms (bacteria, fungi, protozoa, etc.). Many drugs which have been used for years are still studied in relation to their metabolism and their molecular mechanism of operation, providing new knowledge on active substances. Many of them meet the criteria of being a prodrug. The paper indicates methods of discovering new structures or modifications of known structures and their synthesis as well as new therapeutic strategies using prodrugs, which are expected to be successful and to broaden the knowledge on what is happening to the drug in the body, in addition to providing a molecular explanation of xenobiotics activity. Graphical abstract image
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Arylsulfonamides and selectivity of matrix metalloproteinase-2: An overview ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129 Author(s): Nilanjan Adhikari, Avinaba Mukherjee, Achintya Saha, Tarun Jha Uncontrolled regulation of specific metalloenzymes plays important roles in several diseases like tumor metastasis and inflammation. Therefore, selective metalloenzyme inhibition may be a potential target for drug design and development. Matrix metalloproteinase inhibitors (MMPIs) opened up a new horizon as the possible treatment of arthritis, cancer, and emphysema. However, due to adverse effects and poor pharmacokinetics, first generation MMPIs failed in clinical trials. Therefore, development of potential and selective MMPIs is still in demand. Moreover, the flexibility of the enzyme S1′ pocket is variable in length and shape making the designing approach more challenging. In this article, arylsulfonamides have been highlighted as potential and selective MMP-2 inhibitors through structure-activity relationships study. It may be postulated that sulfonamide moiety may provide better direction to the associated aryl group to accommodate the deep hydrophobic S1′ pocket. Tetrahedral geometry of the sulfonyl function may be favorable than planar carboxyl function regarding the interaction between the aryl group and S1′ pocket. Hydroxamates may impart higher inhibition than corresponding carboxylates due to additional hydrogen bonding. Moreover, MMP-2 selectivity is not only dependent on zinc binders but also on the aryl functions directed towards S1 and S2′ pockets. Therefore, this review may help in designing potential and selective MMP-2 inhibitors. Graphical abstract image
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Medicinal plants used as anthelmintics: Ethnomedical, pharmacological, and phytochemical studies ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129 Author(s): Juan Carlos Romero-Benavides, Ana Lucía Ruano, Ronal Silva-Rivas, Paola Castillo-Veintimilla, Sara Vivanco-Jaramillo, Natalia Bailon-Moscoso Intestinal parasites delay mental and physical development in children. Infection with these parasites can result in complications during pregnancy and alter the health of newborns, which has long-term effects on educational attainment and economic productivity. The appearance of resistance against classical drug treatments generates interest in the development of new deworming alternatives. We think that research of new plants species may reveal potential antiparasitic compounds. This review is focused on the use of plants and secondary metabolites against intestinal parasites. We discuss the use of plants in traditional medicine and the use of plant secondary metabolites tried in in vitro and in vivo models when available. Graphical abstract image
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Therapeutic journey of 2,4-thiazolidinediones as a versatile scaffold: An insight into structure activity relationship ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129 Author(s): Mohd. Javed Naim, Md. Jahangir Alam, Shujauddin Ahmad, Farah Nawaz, Neelima Shrivastava, Meeta Sahu, Ozair Alam Thiazolidinedione is an important heterocyclic ring system, a pharmacophore and a privileged scaffold in medicinal chemistry; is a derivative of thiazolidine ring which came into existence for its role as antihyperglycemic agent and a specific ligand of PPAR's (Peroxisome proliferator activated receptor). Exhaustive research has led to determination of its vast biological profile with wide range of therapeutic applications. This review covers recent pharmacological advancements of thiazolidinedione moiety along with structure activity relationship so as to provide better correlation among different structures and their receptor interactions. Graphical abstract image
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pH and reduction dual-responsive dipeptide cationic lipids with α–tocopherol hydrophobic tail for efficient gene delivery ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129 Author(s): Qiang Liu, Rong-Chuan Su, Wen-Jing Yi, Li-Ting Zheng, Shan-Shan Lu, Zhi-Gang Zhao A series of tocopherol-based cationic lipid 3a-3f bearing a pH-sensitive imidazole moiety in the dipeptide headgroup and a reduction-responsive disulfide linkage were designed and synthesized. Acid-base titration of these lipids showed good buffering capacities. The liposomes formed from 3 and co-lipid 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) could efficiently bind and condense DNA into nanoparticles. Gel binding and HPLC assays confirmed the encapsulated DNA could release from lipoplexes 3 upon addition of 10 mM glutathione (GSH). MTT assays in HEK 293 cells demonstrated that lipoplexes 3 had low cytotoxicity. The in vitro gene transfection studies showed cationic dipeptide headgroups clearly affected the transfection efficiency (TE), and arginine-histidine based dipeptide lipid 3f give the best TE, which was 30.4 times higher than Lipofectamine 3000 in the presence of 10% serum. Cell-uptake assays indicated that basic amino acid containing dipeptide cationic lipids exhibited more efficient cell uptake than serine and aromatic amino acids based dipeptide lipids. Confocal laser scanning microscopy (CLSM) studies corroborated that 3 could efficiently deliver and release DNA into the nuclei of HeLa cells. These results suggest that tocopherol-based dipeptide cationic lipids with pH and reduction dual-sensitive characteristics might be promising non-viral gene delivery vectors. Graphical abstract image
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Synthesis and biological evaluation of novel pyrazolic chalcone derivatives as novel hepatocellular carcinoma therapeutics ()
Publication date: 31 March 2017 Source:European Journal of Medicinal Chemistry, Volume 129 Author(s): Mohammed M.A. Hawash, Deniz Cansen Kahraman, Fikriye Eren, Rengul Cetin Atalay, Sultan Nacak Baytas Despite having the second highest mortality associated with cancer, currently Sorafenib is the only FDA-approved chemotherapeutic agent available for liver cancer patients which can only improve survival for few months. In this study, various pyrazolic chalcone analogous compounds were synthesized and evaluated as potential chemotherapeutic agents for the treatment of hepatocellular carcinoma (HCC). Modifying the central pyrazole ring at the C(3)-position with different heteroaryl rings and substituting the C(4)-position of pyrazole with differently substituted chalcone moiety produced fouthy two variant compounds. For all these compounds, cytotoxicity was evaluated using sulforhodamine B assay and real time cell growth tracking, respectively. Based on 50% inhibitory concentration (IC50) values, compounds 39, 42, 49, and 52 were shown to exhibit potent cytotoxic activity against all the cancer cell lines tested, and had better cytotoxic activities than the well-known chemotherapeutic drug 5-FU. Therefore, these compounds were chosen to be further evaluated in a panel of HCC cell lines. Flow cytometric analysis of HCC cells treated with compounds 39, 42, 49, and 52 demonstrated that these compounds caused cell cycle arrest at G2/M phase followed by the apoptotic cell death and impaired cell growth as shown by real-time cell growth surveillance. Consistent with these results, western blotting of HCC cells treated with the compounds resulted in molecular changes for cell cycle proteins, where p21 levels were increased independent of p53 and the levels of the key initiators of mitosis Cyclin B1 and CDK1 were shown to decrease upon treatment. In conclusion, chalcone derivatives 42 and 52 show potent bioactivities by modulating the expression of cell-cycle related proteins and resulting in cell-cycle arrest in the HCC cell lines tested here, indicating that the compounds can be considered as preclinical candidates. Graphical abstract image
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