European Journal of Medicinal Chemistry

Success stories of natural product-based hybrid molecules for multi-factorial diseases ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Shalki Choudhary, Pankaj Kumar Singh, Himanshu Verma, Harpreet Singh, Om Silakari Complex diseases comprises of highly complicated etiology resulting in limited applicability of conventional targeted therapies. Consequently, conventional medicinal compounds suffer major failure when used for such disease conditions. Additionally, development of multidrug resistance (MDR), adverse drug reactions and clinical specificity of single targeted drug therapy has increased thrust for novel drug therapy. In this rapidly evolving era, natural product-based discovery of hybrid molecules or multi-targeted drug therapies have shown promising results and are trending now a days. Historically, nature has blessed human with different sources viz. plant, animal, microbial, marine and ethnopharmaceutical sources which has given a wide variety of medicinally active compounds. These compounds from natural origin are always choice of interest of medicinal chemists because of their minimum side effects. Hybrid molecules synthesized by fusing or conjugating different active molecules obtained from these sources are reported to synergistically block different pathways which contribute in the pathogenesis of complex diseases. This review strives to encompass all natural product-derived hybrid molecules which act as multi-targeting agents striking various targets involved in different pathways of complex diseased conditions reported in literature. Graphical abstract image
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Benzopyrroloxazines containing a bridgehead nitrogen atom as promising scaffolds for the achievement of biologically active agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Fedora Grande, Maria A. Occhiuzzi, Giuseppina Ioele, Gaetano Ragno, Antonio Garofalo The present review lists the papers and patents dealing with the class of polycondensed heterocycles called benzopyrroloxazines published in the last decades. The survey is limited to substances characterized by the presence of a bridgehead N atom, which means that the present N atom serves to connect different rings within the same molecule. In the case of benzopyrroloxazines, the bridgehead N atom belongs at the same time to the pyrrole and oxazine rings. All other compounds not possessing this feature were kept out accordingly. Relevant synthetic methods to such compounds have been outlined. Many different biological properties have been attributed to several functionalized derivatives of these heterocycles and cited within the review. Graphical abstract image
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Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Rajesh K. Singh, Sahil Kumar, D.N. Prasad, T.R. Bhardwaj Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate “aziridinium ion” which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards. Graphical abstract image
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Recent progress of the development of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Ning Li, Li-Jun Wang, Bo Jiang, Xiang-qian Li, Chuan-long Guo, Shu-ju Guo, Da-Yong Shi Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments. Graphical abstract image
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Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Kai Lv, Zeyu Tao, Qian Liu, Lu Yang, Bin Wang, Shuo Wu, Apeng Wang, Menghao Huang, Mingliang Liu, Yu Lu We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way. Graphical abstract image
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Recent advances in trimethoxyphenyl (TMP) based tubulin inhibitors targeting the colchicine binding site ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Ling Li, Sibo Jiang, Xiaoxun Li, Yao Liu, Jing Su, Jianjun Chen Microtubules (composed of α- and β-tubulin heterodimers) play a pivotal role in mitosis and cell division, and are regarded as an excellent target for chemotherapeutic agents to treat cancer. There are four unique binding sites in tubulin to which taxanes, vinca alkaloids, laulimalide and colchicine bind respectively. While several tubulin inhibitors that bind to the taxane or vinca alkaloid binding sites have been approved by FDA, currently there are no FDA approved tubulin inhibitors targeting the colchicine binding site. Tubulin inhibitors that bind to the colchicine binding site have therapeutic advantages over taxanes and vinca alkaloids, for example, they can be administered orally, have less drug-drug interaction potential, and are less prone to develop multi-drug resistance. Typically, tubulin inhibitors that bind to the colchicine binding site bear the trimethoxyphenyl (TMP) moiety which is essential for interaction with tubulin. Over the last decade, a variety of molecules bearing the TMP moiety have been designed and synthesized as tubulin inhibitors for cancer treatment. In this review, we focus on the TMP analogs that are designed based on CA-4, indole, chalcone, colchicine and natural product scaffolds which are known to interact with the colchicine binding site in tubulin. The challenges and future direction of the TMP based tubulin inhibitors are also discussed in detail. Graphical abstract image
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The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Chengyuan Liang, Danni Tian, Xiaodong Ren, Shunjun Ding, Minyi Jia, Minhang Xin, Suresh Thareja Bruton's tyrosine kinase (BTK) has emerged as a promising drug target for multiple diseases, particularly haematopoietic malignancies and autoimmune diseases related to B lymphocytes. This review focuses on the diverse, small-molecule inhibitors of BTK kinase that have shown good prospects for clinical application. Individual examples of these inhibitors, including both reversible and irreversible inhibitors and a recently developed reversible covalent inhibitor of BTK, are discussed. Considerable progress has been made in the development of irreversible inhibitors, most of which target the SH3 pocket and the cysteine 481 residue of BTK. The present review also surveys the pharmacological advantages and deficiencies of both reversible and irreversible BTK drugs, with a focus on the structure-activity relationship (SARs) and binding modes of representative drugs, which could inspire critical thinking and new ideas for developing potent BTK inhibitors with less unwanted off-target effects. Graphical abstract image
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Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Chen-Chen Ma, Cheng-Mei Zhang, Long-Qian Tang, Zhao-Peng Liu PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89–97%) against PI3Kδ at the concentration of 1 μM, with the IC50 values of 8.4 nM–106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%. Graphical abstract image
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Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB) ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Giovanni Marzaro, Ilaria Lampronti, Elisabetta D'Aversa, Gianni Sacchetti, Giorgia Miolo, Christian Vaccarin, Giulio Cabrini, Maria Cristina Dechecchi, Roberto Gambari, Adriana Chilin A series of trimethylangelicin (TMA) derivatives were designed and synthesized to overcome the unwanted effects of TMA, promising agent for treatment of inflammation-related diseases and other pathologies, such as cystic fibrosis. The new generation TMA analogues bore hindered substituents at the 4 position in order to minimize or avoid the photoreactions with DNA. Among them, the 4-isopropyl-6-ethyl derivative 23 exhibited TMA-like inhibitory activity on NF-κB/DNA interactions but it proved unable to photoreact with pyrimidine bases of DNA, nor to induce any other DNA damage. The isopropyl analogue 23 was proven to lack mutagenicity when assayed through Ames test and exhibited no anti-proliferative activity on cystic fibrosis IB3-1 cells, displaying at the same time inhibition of the TNF-α induced release of the NF-κB regulated PDGF-B chain, IL-10, IL-15, IL-17 and IFN-γ. Therefore compound 23 deserves further assay to determine its anti-inflammatory properties, since it lacks photoreaction properties and mutagenicity-related side effects. Graphical abstract image
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Optimization of the pharmacokinetic properties of potent anti-trypanosomal triazine derivatives ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Irene G. Salado, Adrienn Baán, Tomas Verdeyen, An Matheeussen, Guy Caljon, Pieter Van der Veken, Filip Kiekens, Louis Maes, Koen Augustyns Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of sub-saharan Africa. There is a high unmet medical need since the approved drugs are poorly efficacious, show considerable toxicity and are not easy to administer. This work describes the optimization of the pharmacokinetic properties of a previously published family of triazine lead compounds. One compound (35 (UAMC-03011)) with potent anti-trypanosomal activity and no cytotoxicity was selected for further study because of its good microsomal stability and high selectivity for Trypanosoma brucei over a panel including Trypanosoma cruzi, L.eishmania infantum, and Plasmodium falciparum. In vivo pharmacokinetic parameters were determined and the compound was studied in an acute in vivo mouse disease model. One of the important learnings of this study was that the rate of trypanocidal activity is an important parameter during the lead optimization process. Graphical abstract image
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Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Linkui Zhang, Ying Zhao, Jian Wang, Donglin Yang, Chenwen Zhao, Changli Wang, Chao Ma, Maosheng Cheng Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and 5q exhibited excellent neuroprotective activity. The compound 5q was selected for further investigation. We found that 5q could attenuate Ca2+ influx induced by NMDA, meanwhile, 5q could suppress the NR2B up-regulation and increase p-ERK1/2 expression. The molecular docking results showed that 5q might fit well in the binding pocket of 4 and interact with some key residues in the binding pocket of 1 simultaneously. Besides, 5q exhibited acceptable metabolic stability. These results suggested that 5q was a promising lead for further development of new potent and orally bioavailable NR2B-selective NMDAR antagonists. Graphical abstract image
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Design, synthesis and activity of BBI608 derivatives targeting on stem cells ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Qifan Zhou, Chen Peng, Fangyu Du, Linbo Zhou, Yajie Shi, Yang Du, Dongdong Liu, Wenjiao Sun, Meixia Zhang, Guoliang Chen STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC50 = 11.2 μM), but had considerable activity on normal liver cells L-02. Compounds LD-17 (IC50 = 3.5 μM) and LD-19 (IC50 = 2.9 μM) were found to possess significant inhibitory activities and good selectivity. The results showed that compound LD-19 was worthy to investigate further as a lead compound according to its potent inhibitory activity, ideal ClogP value and better water solubility. Graphical abstract image
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Design, synthesis and biological evaluation of C(4) substituted monobactams as antibacterial agents against multidrug-resistant Gram-negative bacteria ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Qunhuan Kou, Ting Wang, Feng Zou, Shuhua Zhang, Qian Chen, Yushe Yang A series of novel pyridone conjugated monobactams with various substituents at the (4) position were synthesized and evaluated for their antibacterial activities against a panel of multidrug-resistant (MDR) Gram-negative bacteria in vitro. Compounds 46d, 54 and 75e displayed good to moderate activities against P. aeruginosa, among which the activity of 75e against P. aeruginosa was comparable to that of BAL30072 under iron limitation condition. Compounds 35, 46d, 54, 56a, 56c and 56d exhibited good to excellent antibacterial activities against E. coli and K. pneumoniae, which were comparable or superior to that of BAL30072. In vitro liver microsomal stability was further evaluated and the results manifested that Compounds 35, 46d and 54 were metabolically stable in human liver microsomes. Graphical abstract image
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Phenylthiazoles with tert-Butyl side chain: Metabolically stable with anti-biofilm activity ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Ahmed Kotb, Nader S. Abutaleb, Mohamed A. Seleem, Mohamed Hagras, Haroon Mohammad, Ashraf Bayoumi, Adel Ghiaty, Mohamed N. Seleem, Abdelrahman S. Mayhoub A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h. Graphical abstract image
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Incorporation of nitric oxide donor into 1,3-dioxyxanthones leads to synergistic anticancer activity ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Jie Liu, Cao Zhang, Huailing Wang, Lei Zhang, Zhenlei Jiang, Jianrun Zhang, Zhijun Liu, Heru Chen Fifty 1,3-dioxyxanthone nitrates (4a ∼ i-n, n = 1–6) were designed and synthesized based on molecular similarity strategy. Incorporation of nitrate into 1,3-dioxyxanthones with electron-donating groups at 6–8 position brought about synergistic anticancer effect. Among them, compound 4g-4 was confirmed the most active agent against HepG-2 cells growth with an IC50 of 0.33 ± 0.06 μM. It dose-dependently increased intramolecular NO levels. This activity was attenuated by either NO scavenger PTIO or mitochondrial aldehyde dehydrogenase (mtADH) inhibitor PCDA. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for different dose of 4g-4. 4g-4 arrested more cells on S phase. Results from Western Blot implied that 4g-4 regulated p53/MDM2 to promote cancer cell apoptosis. All the evidences support that 4g-4 is a promising anti-cancer agent. Graphical abstract image
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Microwave-assisted one-pot synthesis of new phenanthrene fused-tetrahydrodibenzo-acridinones as potential cytotoxic and apoptosis inducing agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Niggula Praveen Kumar, Pankaj Sharma, T. Srinivasa Reddy, Nagula Shankaraiah, Suresh K. Bhargava, Ahmed Kamal An expeditious microwave-assisted one-pot synthesis of new cytotoxic phenanthrene fused-tetrahydrodibenzo-acridinones has been successfully accomplished. This protocol offers wide substrate scope, catalyst-free synthesis, atom-economy, simple recrystallization, high yields, and ethanol was used as green solvent. These new compounds were tested for their in vitro cytotoxicity against cervical (HeLa), prostate (PC-3), fibrosarcoma (HT-1080), ovarian (SKOV-3) cancer cells, and were safer to normal (Hek-293T) kidney cell line. All the compounds have displayed significant cytotoxicity profile, among them 8m being the most potent compound with an IC50 0.24 ± 0.05 μM against SKOV-3 ovarian cancer cells. Flow cytometry analysis revealed that cells were blocked at the G2/M phase of the cell cycle. The effect of 8m on F-actin polymerisation was also studied. Hoechst staining clearly showed the decreased number of viable cells and indicated apoptosis progression. Compound 8m caused the collapse of mitochondrial membrane potential as observed via JC-1 staining and also enhanced the generation of reactive oxygen species. The increase of caspase-3 activation by 3.7 folds supported the strong apoptosis induction. In addition, an in vitro 3D-spheroid progression assay was performed with 8m that significantly suppressed the tumor cells. Graphical abstract image
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Antiproliferative efficacy of curcumin mimics through microtubule destabilization ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Sadiya Khwaja, Kaneez Fatima, Mohammad Hasanain, Chittaranjan Behera, Avneet Kour, Arjun Singh, Suaib Luqman, Jayanta Sarkar, Debabrata Chanda, Karuna Shanker, A.K. Gupta, D.M. Mondhe, Arvind S. Negi Curcumin possesses an attractive chemical structure with highly conjugated diferuloylmethane core. Curcumin mimics have been designed and prepared with an additional bridged phenyl ring in conjugation. Fourteen diverse analogues were evaluated against a panel of human cancer cell lines. The best analogue of the series i.e. compound 6a exhibited potent cytotoxicity against A431, epidermoid carcinoma cell line (IC50 = 1.5 μM) and DLD1, colorectal adenocarcinoma cell line (IC50 = 6.9 μM). In tubulin kinetics experiment, compound 6a destabilized polymerisation process (IC50 = 4.68 μM). In cell cycle analysis, compound 6a exerted G2/M phase arrest in A431 cells and induced apoptosis. In Ehrlich Ascites Carcinoma in Swiss-albino mice, compound 6a showed 78.6% tumour reduction at 80 mg/kg dose and 57% solid tumour reduction at 150 mg/kg dose. Further, in acute-oral toxicity experiment in rodent model, compound 6a was given in three different oral doses to Swiss albino mice. There were non-significant changes in various biochemical parameters and major body organs studied, including their absolute and relative weights. It was tolerable up to 300 mg/kg dose in Swiss-albino mice. The present study shows that the novel curcumin mimic 6a is a safe and efficacious anticancer compound. However, it needs to be optimized for better efficacy. Graphical abstract image
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Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Seokmin Kang, Jung Moo Lee, Borami Jeon, Ahmed Elkamhawy, Sora Paik, Jinpyo Hong, Soo-Jin Oh, Sun Ha Paek, C. Justin Lee, Ahmed H.E. Hassan, Sang Soo Kang, Eun Joo Roh Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4–5 times more potent inhibitory activity than trifluoperazine with IC50 = 2.3 and 2.2 μM against U87MG glioblastoma cells, as well as, IC50 = 2.2 and 2.1 μM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma. Graphical abstract image
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New potent and selective A1 adenosine receptor antagonists as potential tools for the treatment of gastrointestinal diseases ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Catia Lambertucci, Gabriella Marucci, Diego Dal Ben, Michela Buccioni, Andrea Spinaci, Sonja Kachler, Karl-Norbert Klotz, Rosaria Volpini The synthesis of 9-alkyl substituted adenine derivatives presenting aromatic groups and cycloalkyl rings in 8- and N 6-position, respectively, is reported. The compounds were tested with radioligand binding studies showing, in some cases, a low nanomolar A1 adenosine receptor affinity and a very good selectivity versus the other adenosine receptor subtypes. Functional assays at human adenosine receptors and at a mouse ileum tissue preparation clearly demonstrate the antagonist profile of these molecules, with inhibitory potency at nanomolar level. A molecular modeling study, consisting in docking analysis at the recently reported A1 adenosine receptor crystal structure, was performed for the interpretation of the obtained pharmacological results. The N 6-cyclopentyl-9-methyl-8-phenyladenine (17), resulting the most active derivative of the series (Ki = 2.8 nM and IC50 = 14 nM), was also very efficacious in counteracting the effect of the agonist CCPA on mouse ileum contractility. This new compound represents a tool for the development of new agents for the treatment of intestinal diseases as constipation and postoperative ileus. Graphical abstract image
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Synthesis and anticancer activity evaluation of novel azacalix[2]arene[2]pyrimidines ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Yesu Addepalli, Xiaohong Yang, Minghui Zhou, D. Prabhakar Reddy, Shao-Lin Zhang, Zhen Wang, Yun He A series of novel azacalix[2]arene[2]pyrimidines were synthesized, and evaluated for their antiproliferative activities against A549, MCF7, SH-SY5Y and CNE human cancer cell lines in vitro by using the CCK-8 assay. A number of compounds showed low micromolar antiproliferative activities against MCF7 cell line. Compound 4j, containing a pyrrolidine moiety, exhibited the strongest inhibitory activity with an IC50 value of 0.58 μM. Furthermore, breast cancer cells were used to explore the inhibition mechanism of these azacalix[2]arene[2]pyrimidines. The results suggested these compounds were involved in inducing cell apoptosis via up-regulation of caspase-3 and caspase-9 protein expression, and the cell cycle was arrested at the S phase. Our reports here represent the first studies on the biological activities of azacalix[2]arene[2]pyrimidines. Graphical abstract image
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Preparation of Rhodium(III) complexes with 2(1H)-quinolinone derivatives and evaluation of their in vitro and in vivo antitumor activity ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Xing Lu, Yi-Ming Wu, Jing-Mei Yang, Feng-E. Ma, Liang-Ping Li, Sheng Chen, Ye Zhang, Qing-Ling Ni, Ying-Ming Pan, Xue Hong, Yan Peng A series of 2(1H)-quinolinone derivatives and their rhodium (III) complexes were designed and synthesized. All the rhodium (III) complexes exhibited higher in vitro cytotoxicity for Hep G2, HeLa 229, MGC80-3, and NCI-H460 human tumor cell lines than their ligands and cisplatin, and among them complex 9 was found to be selectively cytotoxic to tumor cells. Further investigation revealed that complex 9 caused cell cycle arrest at the G2/M phase and induced apoptosis, and inhibited the proliferation of Hep G2 cells by impeding the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream enzymes. Complex 9 also up-regulated the proapoptotic proteins Bak, Bax, and Bim, which altogether activated caspase-3/9 to initiate cell apoptosis. Notably, complex 9 effectively inhibited tumor growth in the NCI-H460 xenograft mouse model with less adverse effect than cisplatin. Graphical abstract image
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Phthalimide conjugations for the degradation of oncogenic PI3K ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Wenlu Li, Chunmei Gao, Lei Zhao, Zigao Yuan, Yuzong Chen, Yuyang Jiang PI3K/Akt/mTOR pathway is crucial for carcinogenesis and its inhibitors have made a great progress in cancer treatment. However, there is still a great developing space for PI3K inhibitors as the acquired drug resistance hindered their application in clinical. Proteolysis-targeting chimeras (PROTACs) with the potential to handle the challenges faced in drug development could be an alternative therapeutic strategy. Moreover, the past two years have witnessed remarkable advances in the development of phthalimide conjugation as a strategy for the degradation instead of inhibition of the targets, including BET family proteins, Sirtuin 2, CDK 9, Smad 3, and BCR-ABL proteins. Here, we designed and synthesized a series of potential small molecular PROTACs for the degradation of PI3K. Four compounds induced remarkable PI3K degradation and down-regulated the phosphorylation of Akt, S6K and GSK-3β in liver cancer cells HepG2. Furthermore, the representative compound D proved to inhibit tumor cells proliferation by the induction of autophagy instead of apoptosis or cell cycle arrest. Graphical abstract image
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Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Cleudiomar Inácio Lino, Igor Gonçalves de Souza, Beatriz Martins Borelli, Thelma Tirone Silvério Matos, Iasmin Natália Santos Teixeira, Jonas Pereira Ramos, Elaine Maria de Souza Fagundes, Philipe de Oliveira Fernandes, Vinícius Gonçalves Maltarollo, Susana Johann, Renata Barbosa de Oliveira In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents. Graphical abstract image
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Synthesis and biological evaluation of clovamide analogues as potent anti-neuroinflammatory agents in vitro and in vivo ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Xiao-Long Hu, Jun Lin, Xian-Yu Lv, Jia-Hao Feng, Xiao-Qi Zhang, Hao Wang, Wen-Cai Ye A series of clovamide analogues, namely, 1a–13a and 1b–13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b–8b) showed NO inhibition with no or weak cytotoxicity (CC50 > 100 μM), especially 4b, and showed an IC50 value of 2.67 μM. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC50 values ranging from 1.01 μM to 29.23 μM 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase-positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy. Graphical abstract image
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Lipid reducing activity and toxicity profiles of a library of polyphenol derivatives ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Ralph Urbatzka, Sara Freitas, Andreia Palmeira, Tiago Almeida, João Moreira, Carlos Azevedo, Carlos Afonso, Marta Correia-da-Silva, Emilia Sousa, Madalena Pinto, Vitor Vasconcelos Obesity is an increasing epidemic worldwide and novel treatments are urgently needed. Polyphenols are natural compounds derived from plants, which are known in particular for their antioxidant properties. However, some polyphenols were described to possess anti-obesity activities in vitro and in vivo. In this study, we aimed to screen a library of 85 polyphenol derivatives for their lipid reducing activity and toxicity. Compounds were analyzed at 5 μM with the zebrafish Nile red fluorescence fat metabolism assay and for general toxicity in vivo. To improve the safety profile, compounds were screened at 50 μM in murine preadipocytes in vitro for cytotoxicity. Obtained activity data were used to create a 2D-QSAR (quantitative structure activity relationship) model. 38 polyphenols showed strong lipid reducing activity. Toxicity analysis revealed that 18 of them did not show any toxicity in vitro or in vivo. QSAR analysis revealed the importance of the number of rings, fractional partial positively charged surface area, relative positive charge, relative number of oxygen atoms, and partial negative surface area for lipid-reducing activity. The five most potent compounds with EC50 values in the nanomolar range for lipid reducing activity and without any toxic effects are strong candidates for future research and development into anti-obesity drugs. Molecular profiling for fasn, sirt1, mtp and ppary revealed one compound that reduced significantly fasn mRNA expression. Graphical abstract image
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A tumor-targeted Ganetespib-zinc phthalocyanine conjugate for synergistic chemo-photodynamic therapy ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Liangfeng Huang, Gaofei Wei, Xiaoqi Sun, Yali Jiang, Zeqian Huang, Yanjuan Huang, Yifeng Shen, Xiaoyu Xu, Yunhui Liao, Chunshun Zhao Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan-ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation. Besides, Gan-ZnPc can arrest cell proliferation and induce apoptosis by the inhibition of Hsp90. Herein, with combination of the inhibition of Hsp90 and the generation of cytotoxic ROS, Gan-ZnPc implements tumor selectivity, concentrated PDT and chemotherapy in a synergistic manner, which results in highly effective anti-tumor activity in vitro and in vivo. Graphical abstract image
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Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK) ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Chengwei Zhang, Xiao-Ran Han, Xiaobao Yang, Biao Jiang, Jing Liu, Yue Xiong, Jian Jin Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5–8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs. Graphical abstract image
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Discovery of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purines containing a carboxamide moiety as potential selective anti-lung cancer agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Tao-Qian Zhao, Yuan-Di Zhao, Xin-Yang Liu, Bo Wang, Zhong-Hua Li, Zhang-Xu He, Xin-Hui Zhang, Jian-Jia Liang, Li-Ying Ma, Hong-Min Liu A new series of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purine-8-caboxamide derivatives were designed, synthesized, and further evaluated for their antiproliferative activities on four human cancer cell lines (A549, MGC803, PC-3 and TE-1). The structure-activity relationships (SARs) studies were conducted through the variation in the two regions, which including position 8 and 9, of purine core. One of the compounds, 8, containing a terminal piperazine appendage with a carboxamide moiety at position 8 and phenyl group at position 9 of 6-chloro-8,9-dihydro-7H-purine core, showed the most potent antiproliferative activity and good selectivity between cancer and normal cells (IC50 values of 2.80 μM against A549 and 303.03 μM against GES-1, respectively). In addition, compound 8 could inhibit the colony formation and migration of A549 cells in a concentration-dependent manner, as well as induce the apoptosis possibly through the intrinsic pathway. Graphical abstract image
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Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Ye Tian, Zhaoqiang Liu, Jinghan Liu, Boshi Huang, Dongwei Kang, Heng Zhang, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque, Kuo-Hsiung Lee, Chin-Ho Chen, Peng Zhan, Xinyong Liu Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a “triazole tail” occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02–1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed. Graphical abstract image
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Novel sarsasapogenin-triazolyl hybrids as potential anti-Alzheimer's agents: Design, synthesis and biological evaluation ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Wenbao Wang, Wei Wang, Guodong Yao, Qiang Ren, Di Wang, Zedan Wang, Peng Liu, Pinyi Gao, Yan Zhang, Shaojie Wang, Shaojiang Song Sarsasapogenin, an active ingredient in Rhizoma anemarrhenae, is a promising bioactive lead compound in the treatment of Alzheimer's disease. To search for more efficient anti-Alzheimer agents, a series of novel sarsasapogenin-triazolyl hybrids were designed, synthesized, and evaluated for their Aβ 1−42 aggregation inhibitory activities. Most of these new hybrids displayed potent Aβ 1−42 aggregation inhibition. In particular, the promising compounds 6j and 6o displayed a better ability to interrupt the formation of Aβ 1−42 fibrils than curcumin. Moreover, 6j and 6o exhibited moderate neuroprotective effects against H2O2-induced neurotoxicity in SH-SY5Y cells. To investigate whether 6j and 6o could improve cognitive deficits, we performed behavioral tests to examine the learning and memory impairments induced by intracerebroventricular injection of Aβ 1−42 (ICV-Aβ 1−42) in mice and TUNEL staining to observe neuronal apoptosis in the hippocampus. The results obtained indicated that oral treatment with 6j and 6o significantly ameliorated cognitive impairments in behavioral tests and TUNEL staining showed that 6j and 6o attenuated neuronal loss in the brain. Taken together, the results we obtained showed that the sarsasapogenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compounds 6j and 6o have the potential to be important lead compounds for further research. Graphical abstract image
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2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Niccolò Chiaramonte, Silvia Bua, Marta Ferraroni, Alessio Nocentini, Alessandro Bonardi, Gianluca Bartolucci, Mariaconcetta Durante, Laura Lucarini, Donata Chiapponi, Silvia Dei, Dina Manetti, Elisabetta Teodori, Paola Gratteri, Emanuela Masini, Claudiu T. Supuran, Maria Novella Romanelli Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies. Graphical abstract image
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Antiproliferative hydrogen sulfide releasing evodiamine derivatives and their apoptosis inducing properties ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Xu Hu, Runwei Jiao, Haonan Li, Xianhua Wang, Haoda Lyu, Xiang Gao, Fanxing Xu, Zhanlin Li, Huiming Hua, Dahong Li To explore antitumor agents with high efficiency and selectivity, two series of 16 H2S donating evodiamine derivatives 8–12 were synthesized and characterized by 1H NMR, 13C NMR and HRMS. Their antiproliferative activities were tested against five cancer cell lines (Bel-7402, MCF-7, SGC-7901, Caco-2 and HL-60) and human normal peripheral blood mononuclear cells. Among them, compound 12c showed the most potent inhibitory activities against human leukemia HL-60 and epithelial colorectal adenocarcinoma Caco-2 cells with IC50 values of 0.58 and 2.02 μM, respectively. Additionally, high selectivity was also observed between human normal peripheral blood mononuclear cells and human leukemia HL-60 cells. Further mechanism studies confirmed that 12c could induce apoptosis, arrest cell cycle at the G2/M phase and lead to mitochondrial dysfunction in HL-60 cells. Furthermore, western blot assay demonstrated that 12c induced the intrinsic apoptotic mitochondrial pathway by upregulating protein expression of Bax, cytochrome c, caspase-3, -9 and p53, and downregulating the relative levels of Bcl-2. The levels of cell cycle related proteins cyclin B1 and cdc2 were also downregulated in which G2/M phase arrest was confirmed. Overall, 12c possessed immense potential for the discovery of antitumor candidates with high efficiency and selectivity. Graphical abstract image
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Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Kan Yang, Keyi Nong, Qinlan Gu, Jibin Dong, Jinxin Wang Acid sphingomyelinase (ASM) has been shown to be involved in many physiological processes, emerging to be a promising drug target. In this study, we constructed a ligand-based pharmacophore model of ASM inhibitors and applied this model to optimize the lead compound α-mangostin, a known inhibitor of ASM. 23 compounds were designed and evaluated in vitro for ASM inhibition, of these, 10 compounds were found to be more potent than α-mangostin. This high hit ratio confirmed that the presented model is very effective and practical. The most potent hit, 1c, was found to selectively and competitively inhibit the enzyme and inhibit the generation of ceramide in a dose-dependent manner. Furthermore, 1c showed favorable anti-apoptosis and anti-inflammatory activity. Interactions with key residues and the Zn2+ cofactor of 1c were found by docking simulation. These results provide promising leads and important guidance for further development of efficient ASM inhibitors and drug candidates. Graphical abstract image
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Design, synthesis, cytotoxicity and mechanism of novel dihydroartemisinin-coumarin hybrids as potential anti-cancer agents ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Haonan Yu, Zhuang Hou, Ye Tian, Yanhua Mou, Chun Guo To develop novel agents with anticancer activities, thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized in this study. Those compounds were identified that had great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29). The structure-activity relationships of the derivatives were also discussed, and the results of docking analysis had shown that carbonic anhydrases IX (CA IX) was very likely to be one of the drug targets of the hybrids. Meanwhile, to clarify the mechanism of the anticancer activity of the hybrids molecule, we did further exploration in the bioactivity of the hybrids. The results had shown that these derivatives obviously inhibited proliferation of HT-29 cell lines, arrested G0/G1 phase of HT-29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells. Interestingly, the hybrids also induced the other cell death pathway-ferroptosis. Graphical abstract image
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Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Zhiqing Liu, Bing Tian, Haiying Chen, Pingyuan Wang, Allan R. Brasier, Jia Zhou A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H2O molecule. Both compounds 28 and 35 exhibited submicromolar potency of inhibiting the TLR3-dependent innate immune gene program, including ISG54, ISG56, IL-8, and Groβ genes in cultured human small airway epithelial cells (hSAECs). More importantly, they also demonstrated potent efficacy reducing airway inflammation in a mouse model with low toxicity, indicating a proof of concept that BRD4 inhibitors may offer the therapeutic potential to block the viral-induced airway inflammation. Graphical abstract image
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Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Seung-Hwa Kwak, Seungheon Shin, Ji-Hyun Lee, Jin-Kyoung Shim, Minjeong Kim, So-Deok Lee, Aram Lee, Jinsu Bae, Jin-Hee Park, Aliaa Abdelrahman, Christa E. Müller, Steve K. Cho, Seok-Gu Kang, Myung Ae Bae, Jung Yoon Yang, Hyojin Ko, William A. Goddard, Yong-Chul Kim Screening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at three different positions, R1, R2 and R3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R1 position, an adamantyl carboxamide group at R2 and a 4-methoxy substitution at the R3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1β ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative (16c) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative (17k), with IC50 values of 4 and 3 nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds (16c and 17k) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells. Graphical abstract image
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Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Tiina J. Ahonen, Maiju Rinne, Peter Grutschreiber, Kert Mätlik, Mikko Airavaara, Dieter Schaarschmidt, Heinrich Lang, David Reiss, Henri Xhaard, Claire Gaveriaux-Ruff, Jari Yli-Kauhaluoma, Vânia M. Moreira Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron(II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ7,8-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest. Graphical abstract image
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Design, synthesis, anti-lung cancer activity, and chemosensitization of tumor-selective MCACs based on ROS-mediated JNK pathway activation and NF-κB pathway inhibition ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Liping Chen, Qian Li, Bixia Weng, Jiabing Wang, Yangyang Zhou, Dezhi Cheng, Thanchanok Sirirak, Peihong Qiu, Jianzhang Wu EF24 and F35 both were effective monocarbonyl curcumin analogues (MCACs) with excellent anti-tumor activity, however, drug defect such as toxicity may limit their further development. To get anti-lung cancer drugs with high efficiency, low toxicity and chemosensitization, a series of analogues based on EF24 and F35 were designed and synthesized. A number of compounds were found to exhibit cytotoxic activities selectively towards lung cancer cells compared to normal cells. Among these compounds, 5B was considered as an optimal anti-tumor agent for lung cancer cells with IC50 values ranging from 1.0 to 1.7 μM, selectivity index (SI, as a logarithm of a ratio of IC50 value for normal and cancer cells) were all above 1.1, while the SI of EF24 and F35 were less than 0.8. Consistent with selectivity in vitro, 5B was observed to show lower toxicity in acute toxicity experiment than EF24 and F35 respectively. Further, 5B was found to exert anti-tumor effects through ROS-mediated activation of JNK pathway and inhibition of NF-κB pathway. 5B could significantly enhance the sensitivity of A549 cells to cisplatin or 5-Fu. These findings suggested that 5B was an effective and less toxic MCAC and provided a promising candidate for anti-tumor drugs. Graphical abstract image
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Discovery of novel Methylsulfonyl phenyl derivatives as potent human Cyclooxygenase-2 inhibitors with effective anticonvulsant action: Design, synthesis, in-silico, in-vitro and in-vivo evaluation ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Chandra Bhushan Mishra, Shikha Kumari, Amresh Prakash, Rajesh Yadav, Ankit Kumar Tiwari, Preeti Pandey, Manisha Tiwari A novel series of methylsulfonyl phenyl derivatives has been designed and synthesized to evaluate their COX-2 inhibitory activity along with anti-convulsant potential. In-vitro evaluation revealed that two compounds MTL-1 and MTL-2 appeared as most potent and selective COX-2 inhibitors in the entire series. Anti-convulsant activity of both potent COX-2 inhibitors was assessed in sc-PTZ induced seizure test and MTL-1 excellently protected animals against PTZ induced seizure at the dose of 30 mg/kg. MTL-1 also indicates long duration of action in time course study and displayed significant seizure protection up to 6 h of drug administration. Further, the anti-epileptogenic effect of MTL-1 has been examined in PTZ induced chronic model of epilepsy. The results indicated that MTL-1 had a significant anti-epileptogenic effect in PTZ kindled rats as compared to Etoricoxib (ETX) and PTZ alone treated group. Additionally, MTL-1 successfully improved cognition deficit in PTZ kindled rats, which was confirmed by social recognition, novel object recognition and light-dark chamber tests. Moreover, molecular docking and molecular simulation (MD simulation) studies were also performed to elucidate the interaction of MTL-1 with the active site of COX-2 and results showed that MTL-1 suitably binds within active site of COX-2. To investigate the safety profile of MTL-1, a sub-acute toxicity study was also performed and MTL-1 emerged as a new non-toxic chemical entity. Thus, the present investigation discovered a potent and safe COX-2 inhibitor, which is endowed with an effective anti-epileptic action. Graphical abstract image
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Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Yi-Yu Ke, Chun-Ping Chang, Wen-Hsing Lin, Chia-Hua Tsai, I-Chen Chiu, Wan-Ping Wang, Pei-Chen Wang, Pei-Yi Chen, Wen-Hsin Lin, Chun-Feng Chang, Po-Chu Kuo, Jen-Shin Song, Chuan Shih, Hsing-Pang Hsieh, Ya-Hui Chi Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea. Compounds 3m and 3n, both of which harbor a tertiary amino group at the meta position of the phenylurea, showed 10–16 fold inhibition selectivity for Aurora-A over Aurora-B. The in vitro kinase inhibition results were verified by Western blot analysis, and indicated that compounds 3m and 3n were more than 75-fold superior in inhibiting T-loop autophosphorylation of Aurora-A (Thr288), compared to Aurora-B (Thr232) in HCT116 colon carcinoma cells. The computational docking analysis suggested that the tertiary amine at the meta position of the phenylurea formed a more stable interaction with residues in the back pocket of Aurora-A than in Aurora-B, a possible explanation for the observed discrepancy in the selectivity. These results support an alternative small molecule design strategy targeting the back pocket of Aurora kinases for selective isoform inhibition. Graphical abstract image
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Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-glycoprotein inhibitors for Doxorubicin resistance in MCF-7/ADR cell ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Ya-Sheng Li, Dong-Sheng Zhao, Xing-Yu Liu, Yi-Xian Liao, Hong-Wei Jin, Gao-Peng Song, Zi-Ning Cui Multidrug resistance (MDR) is a tendency in which cells become resistant to structurally and mechanistically unrelated drugs, which is mediated by P-glycoprotein (P-gp). It is one of the noteworthy problems in cancer therapy. As one of the most important drugs in cancer therapy, doxorubicin has not good effectiveness if used independently. So targeting the P-gp protein is one of the key points to solve the MDR. Three series of furan derivatives containing tetrahydroquinoline or tetrahydroisoquinoline were designed and synthesized as P-gp inhibitors in this paper. Compound 5m containing 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline possessed good potency against P-gp (EC50 = 0.89 ± 0.11 μM). The preliminary structure–activity relationship and docking studies demonstrated that compound 5m would be great promise as a lead compound for further study. Most worthy of mention is drug combination of doxorubicin and 5m displayed antiproliferative effect of about 97.8%. This study provides highlighted P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance especially doxorubicin resistance setting the basis for further studies. Graphical abstract image
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Investigating isoindoline, tetrahydroisoquinoline, and tetrahydrobenzazepine scaffolds for their sigma receptor binding properties ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Kathryn Linkens, Hayden R. Schmidt, James J. Sahn, Andrew C. Kruse, Stephen F. Martin Substituted norbenzomorphans are known to display high affinity and selectivity for the two sigma receptor (σR) subtypes. In order to study the effects of simplifying the structures of these compounds, a scaffold hopping strategy was used to design several novel sets of substituted isoindolines, tetrahydroisoquinolines and tetrahydro-2-benzazepines. The binding affinities of these new compounds for the sigma 1 (σ1R) and sigma 2 (σ2R) receptors were determined, and some analogs were identified that exhibit high affinity (K i ≤ 25 nM) and significant selectivity (>10-fold) for σ1R or σ2R. The preferred binding modes of selected compounds for the σ1R are predicted by modeling studies, and the nature of substituents on the aromatic ring and the nitrogen atom of the bicyclic skeleton appears to affect the preferred binding orientation of σ1R-preferring ligands. Graphical abstract image
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Photoinduced anticancer activity studies of iridium(III) complexes targeting mitochondria and tubules ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Wen-Yao Zhang, Qian-Yan Yi, Yang-Jie Wang, Fan Du, Miao He, Bing Tang, Dan Wan, Yun-Jun Liu, Hong-Liang Huang Three new iridium (III) complexes [Ir (ppy)2 (ipbc)](PF6) (1), [Ir (bzq)2 (ipbc)](PF6) (2) and [Ir (piq)2 (ipbc)](PF6) (3) were designed and synthesized. All the complexes were tested for anticancer activity using 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) method. The complexes show no cytotoxic activity toward cancer BEL-7402, SGC-7901, Eca-109, A549, HeLa and HepG2 cells. However, upon irradiation with white light, the complexes display high cytotoxicity against BEL-7402 cells with an IC50 value of 5.5 ± 0.8, 7.3 ± 1.3 and 11.5 ± 1.6 μM for 1, 2 and 3, respectively. AO/EB staining and comet assay show that the complexes can induce apoptosis in BEL-7402 cells. The complexes can increase intracellular ROS and Ca2+ levels and cause a decrease in the mitochondrial membrane potential. Autophagic assays exhibit that the complexes can induce autophagy and regulate the expression of Beclin-1 and LC3 proteins. The cell cycle distribution in BEL-7402 cells was carried out by flow cytometry. The expression of Bcl-2 family proteins was studied by western blot. Additionally, the complexes can release cytochrome c and inhibit the polymerization of α-tubulin. Our study reveals that the complexes inhibit the cell growth in BEL-7402 cells through an ROS-mediated mitochondria dysfunction and targeting tubules pathways. These complexes are a promising new entity for the development of multi-target anticancer drugs. Graphical abstract image
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Anti-leishmanial click modifiable thiosemicarbazones: Design, synthesis, biological evaluation and in silico studies ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Mohamed G. Temraz, Perihan A. Elzahhar, Alaa El-Din A. Bekhit, Adnan A. Bekhit, Hala F. Labib, Ahmed S.F. Belal Leishmaniasis is a devastating tropical disease with limited therapeutic options. Depending on recently reported active anti-leishmanial compounds, we designed and synthesized a series of click modifiable 1,2,3-triazole and thiosemicarbazone hybrids. Most of the synthesized compounds showed comparable to superior activity to a well-established anti-leishmanial drug miltefosine. Compounds 2 and 10a showed nanomolar IC50s against promastigotes of L. major (227.4 nM and 140.3 nM respectively, vs 7.8 μM for miltefosine). Their antiamastigote IC50s were 1.4 μM and 1 μM respectively, which are 6 and 8 times the activity of miltefosine (IC50 8.09 μM). Folic and folinic acids reversed the anti-leishmanial effects of compounds 2 and 10a and hence we anticipate they act via an anti-folate mechanism. They exhibited better safety profiles than that of miltefosine on VERO cell lines. Also they were relatively safe on experimental mice when administered via oral and parenteral routes. Docking experiments on PTR1 identified preferential binding interactions and docking scores. Finally, drug-likeness and ligand efficiency were assessed indicating that both 2 and 10a are promising hits and/or leads as anti-leishmanial chemotherapeutic agents. Graphical abstract image
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Quinonoid compounds via reactions of lawsone and 2-aminonaphthoquinone with α-bromonitroalkenes and nitroallylic acetates: Structural diversity by C-ring modification and cytotoxic evaluation against cancer cells ()
Publication date: 10 May 2018 Source:European Journal of Medicinal Chemistry, Volume 151 Author(s): Thekke V. Baiju, Renata G. Almeida, Sudheesh T. Sivanandan, Carlos A. de Simone, Lucas M. Brito, Bruno C. Cavalcanti, Claudia Pessoa, Irishi N.N. Namboothiri, Eufrânio N. da Silva Júnior Morita-Baylis-Hillman acetates and α-bromonitroalkenes have been employed in cascade reactions with lawsone and 2-aminonaphthoquinone for the one-pot synthesis of heterocycle fused quinonoid compounds. The reactions reported here utilized the 1,3-binucleophilic potential of hydroxy- and aminonaphthoquinones and the 1,2/1,3-bielectrophilic potential of bromonitroalkenes and Morita-Baylis-Hillman acetates for the synthesis of pyrrole and furan fused naphthoquinones. The synthesized compounds were evaluated against HCT-116 (human colon carcinoma cells), PC3 (human prostate cancer cells), HL-60 (human promyelocytic leukemia cells), SF295 (human glioblastoma cells) and NCI-H460 (human lung cancer cells) and exhibited antitumor activity with IC50 values as low as < 2 μM. Selected compounds were also evaluated against OVCAR-8 (ovary), MX-1 (breast) and JURKAT (leukemia) cell lines. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC) and L929 cells. Graphical abstract image
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Editorial Board ()
Publication date: 25 April 2018 Source:European Journal of Medicinal Chemistry, Volume 150
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Drug discovery in tuberculosis. New drug targets and antimycobacterial agents ()
Publication date: 25 April 2018 Source:European Journal of Medicinal Chemistry, Volume 150 Author(s): André Campaniço, Rui Moreira, Francisca Lopes Tuberculosis (TB) remains a major health problem worldwide. The infectious agent, Mycobacterium tuberculosis, has a unique ability to survive within the host, alternating between active and latent disease states, and escaping the immune system defences. The extended duration of anti-TB regimens and the increasing prevalence of multidrug- (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains have created an urgent need for new antibiotics active against drug-resistant organisms and that can shorten standard therapy. However, despite success in identifying active compounds through phenotypic screens, the conversion of hits into novel chemical series and ultimately into clinical candidates is hampered by the poor efficacy in eliminating M. tuberculosis within different host compartments, including macrophages, as well as a lack of knowledge about the specific target(s) inhibited and/or upregulated. The current status of anti-TB lead generation has much improved over the last decade, as exemplified by the recent approval of bedaquiline and delamanid to treat MDR-TB and XDR-TB. This review provides a critical analysis on the strategies used to progress hit compounds into viable lead candidates, and how emerging targets may play a role in TB drug discovery in the near future. Four new relevant targets are addressed: the enoyl-acyl carrier protein reductase, InhA; the transmembrane transport protein large, MmpL3; the decaprenylphospho-beta-d-ribofuranose 2-oxidase, DprE1; and the ubiquinol-cytochrome C reductase, QcrB. Validated hit compounds for each target are presented and explored, and the medicinal chemistry strategies to expand SAR around novel chemotypes analyzed. In addition, very recent emerging targets are also discussed. Graphical abstract image
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Inhibitors of phosphodiesterase as cancer therapeutics ()
Publication date: 25 April 2018 Source:European Journal of Medicinal Chemistry, Volume 150 Author(s): Ting Peng, Jun Gong, Yongzhe Jin, Yanping Zhou, Rongsheng Tong, Xin Wei, Lan Bai, Jianyou Shi Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development. A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets. This review will give a brief overview of the expression and regulation of PDE families in the process of tumorigenesis and their anti-tumor inhibitors, which may guide the design of novel therapeutic drugs targeting PDEs for anticancer agent. Graphical abstract image
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A comprehensive review of chalcone derivatives as antileishmanial agents ()
Publication date: 25 April 2018 Source:European Journal of Medicinal Chemistry, Volume 150 Author(s): Marcos Vinícius Palmeira de Mello, Barbara de Azevedo Abrahim-Vieira, Thaisa Francielle Souza Domingos, Jessica Barbosa de Jesus, Ana Carolina Corrêa de Sousa, Carlos Rangel Rodrigues, Alessandra M. Teles de Souza Leishmaniasis is a group of infectious neglected tropical diseases caused by more than 20 pathogenic species of Leishmania sp. Due to the limitations of the current treatments available, chalcone moiety has been drawn with a lot of attention due to the simple chemistry and synthesis, being reported with antileishmanial activity in particular against amastigote form. This review aims to provide an overview towards antileishmanial activity of chalcones derivatives against amastigote form for Leishmania major, L. amazonensis, L. panamensis, L. donovani and L. infantum as well as their structure-activity relationship (SAR), molecular targets and in silico ADMET evaluation. In this way, it is expected that this review may support the research and development of new promising chalcones candidates a leishmanicidal drugs. Graphical abstract image
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Recent advances of imidazole-containing derivatives as anti-tubercular agents ()
Publication date: 25 April 2018 Source:European Journal of Medicinal Chemistry, Volume 150 Author(s): Yi-Lei Fan, Xiao-Hong Jin, Zhong-Ping Huang, Hai-Feng Yu, Zhi-Gang Zeng, Tao Gao, Lian-Shun Feng Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity. As the most emblematic example, 4-nitroimidazole delamanid has already received approval for treatment of multidrug-resistant tuberculosis infected patients. Thus, imidazole-containing derivatives have caused great interests in discovery of new anti-tubercular agents. Numerous of imidazole-containing derivatives were synthesized and screened for their in vitro and in vivo anti-mycobacterial activities against both drug-sensitive and drug-resistant Mycobacterium tuberculosis pathogens. This review aims to outline the recent advances of imidazole-containing derivatives as anti-tubercular agents, and summarize the structure-activity relationship of these derivatives. The enriched structure-activity relationship may pave the way for the further rational development of imidazole-containing derivatives as anti-tubercular agents. Graphical abstract image
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