European Journal of Medicinal Chemistry

Synthesis and antimicrobial activity of pyrimidinyl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): M. Madhu Sekhar, U. Nagarjuna, V. Padmavathi, A. Padmaja, N. Vasudeva Reddy, T. Vijaya A new class of methylthio linked pyrimidinyl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles were prepared under conventional and ultrasound irradiation methods. All the compounds were obtained in higher yields and in shorter reaction times in ultrasound irradiation method when compared with the conventional method. The title compounds were tested for antimicrobial activity. The compounds 12c and 12f exhibited promising antibacterial activity against P. aeruginosa whereas the compounds 13c and 13f showed pronounced antifungal activity against A. niger. Graphical abstract image
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Biotin conjugated organic molecules and proteins for cancer therapy: A review ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Santanu Maiti, Priyankar Paira The main transporter for biotin is sodium dependent multivitamin transporter (SMVT), which is overexpressed in various aggressive cancer cell lines such as ovarian (OV 2008, ID8), leukemia (L1210FR), mastocytoma (P815), colon (Colo-26), breast (4T1, JC, MMT06056), renal (RENCA, RD0995), and lung (M109) cancer cell lines. Furthermore, its overexpression was found higher to that of folate receptor. Therefore, biotin demand in the rapidly growing tumors is higher than normal tissues. Several biotin conjugated organic molecules has been reported here for selective delivery of the drug in cancer cell. Biotin conjugated molecules are showing higher fold of cytotoxicity in biotin positive cancer cell lines than the normal cell. Nanoparticles and polymer surface modified drugs and biotin mediated cancer theranostic strategy was highlighted in this review. The cytotoxicity and selectivity of the drug in cancer cells has enhanced after biotin conjugation. Graphical abstract image
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Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Yun-Kai Shi, Bo Wang, Xiao-Li Shi, Yuan-Di Zhao, Bin Yu, Hong-Min Liu A series of new steroidal pyridines have been synthesized through the based-promoted three-component reaction and preliminarily evaluated for their antiproliferative activity against different types of cancer cell lines. SARs studies showed that the heterocyclic rings attached to the 4-position of the pyridine ring were preferred over the phenyl rings for the activity. Among these compounds, the most potent compound exhibited good growth inhibition against all the tested cancer cells, especially for PC-3 cells with an IC50 value of 1.55 μM. Further mechanistic studies revealed that the most potent compound inhibited colony formation, migration and evasion of PC-3 cells in a concentration-dependent manner as well as induced apoptosis of PC-3 cells possibly through the mitochondria-related apoptotic pathways. Caspase-3/-9 and PARP were activated, finally leading to the apoptosis of PC-3 cells. For the androgen-sensitive (AR+) prostate cancer cell line LNCaP, the most potent compound was less potent than abiraterone with the IC50 value of 8.48 and 3.29 μM, respectively. The most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity. The synthesized steroidal pyridines contain the functional -OEt and CN groups, which could be used for further modifications for the construction of the steroid library. Graphical abstract image
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Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Prasanthi Malapati, Vagolu Siva Krishna, Radhika Nallangi, Rudraraju Reshma Srilakshmi, Dharmarajan Sriram In the present study, we attempted to develop novel class of Mycobacterium tuberculosis (Mtb) inhibitors by exploring the pharmaceutically underexploited enzyme targets which are majorly involved in cell wall biosynthesis of mycobacteria. For this purpose glutamate racemase was selected which racemizes d-glutamate from l-glutamate, a key step in peptidoglycan synthesis. Furthermore, enzyme is neither expressed nor its product, d-glutamate is produced in mammals, and hence inhibiting this enzyme will have no vulnerable effect in host organism. A library of our in-house compounds were screened against glutamate racemase using a biophysical technique; thermal shift assay and further by enzyme inhibition assay to identify Lead 1 molecule. Lead 1 optimization and expansion resulted in twenty four compounds. Among the synthesized compounds twelve compounds shown good enzyme inhibition than Lead 1 (IC50 20.07 ± 0.29 μM). Among all the compounds; compound 22 (IC50 1.1 ± 0.52 μM) showed potent non-competitive mode of inhibition in enzyme assay. Further showed good susceptibility (in replicating bacteria) of MIC 8.72 μM and bactericidal time dependant kill on dormant culture. It also exhibited significant activity in Mtb nutrient starvation model (2.5) and Mtb biofilm model (2.4) and in vivo M. marinum infected Zebra fish model studies (3.6) reduction at logarithmic scale. Graphical abstract image
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Design, synthesis and biological evaluations of novel pyridone-thiazole hybrid molecules as antitumor agents ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Wenlin Xie, Yiqiang Wu, Jingai Zhang, Qihong Mei, Yahan Zhang, Ning Zhu, Renzhi Liu, Huilin Zhang A hybrid pharmacophore approach was adopted to design and synthesize new series of pyridone-thiazole hybrid compounds. The structures of the compounds were established by IR, 1H NMR, 13C NMR, and HRMS. All the newly prepared compounds (3a-3m) were in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely Colon cancer (HCT-116), gastric carcinoma (MGC803) and hepatocellular cancer (Huh7). Bioassay results demonstrated that most of the tested compounds showed potent anti-tumor activities against various cancer cells in vitro, and some compounds exhibited stronger effects than positive control 5-Fluorouracil (5-FU). Compound 3b showed the best anti-tumor activity with IC50 values of 8.17 μM and 3.15 μM against HCT116 and MGC803 cell lines, respectively, which was 1.4–8.1 times more potent than 5-Fluorouracil (IC50 = 11.29 μM and 25.54 μM against HCT116 and MGC803 respectively). These findings suggest that compound 3b may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs. Graphical abstract image
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Picolyl amides of betulinic acid as antitumor agents causing tumor cell apoptosis ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Uladzimir Bildziukevich, Lucie Rárová, David Šaman, Zdeněk Wimmer A series of picolyl amides of betulinic acid (3a–3c and 6a–6c) was prepared and subjected to the cytotoxicity screening tests. Structure-activity relationships studies resulted in finding differences in biological activity in dependence on o-, m- and p-substitution of the pyridine ring in the target amides, when cytotoxicity data of 3a–3c and 6a–6c were obtained and compared. The amides 3b and 3a displayed cytotoxicity (given in the IC50 values) in G-361 (0.5 ± 0.1 μM and 2.4 ± 0.0 μM, respectively), MCF7 (1.4 ± 0.1 μM and 2.2 ± 0.2 μM, respectively), HeLa (2.4 ± 0.4 μM and 2.3 ± 0.5 μM, respectively) and CEM (6.5 ± 1.5 μM and 6.9 ± 0.4 μM, respectively) tumor cell lines, and showed weak effect in the normal human fibroblasts (BJ). Selectivity against all tested cancer cells was determined and compared to normal cells with therapeutic index (TI) between 7 and 100 for compounds 3a and 3b. The therapeutic index (TI = 100) was calculated for human malignant melanoma cell line (G-361) versus normal human fibroblasts (BJ). The cytotoxicity of other target amides (3c and 6a–6c) revealed lower effects than 3a and 3b in the tested cancer cell lines. Graphical abstract image
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New 1,5 and 2,5-disubstituted tetrazoles-dependent activity towards surface barrier of Candida albicans ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Monika Staniszewska, Małgorzata Gizińska, Ewa Mikulak, Klaudia Adamus, Mirosława Koronkiewicz, Edyta Łukowska-Chojnacka A series of novel tetrazole derivatives was synthetized using N-alkylation or Michael-type addition reactions, and screened for their fungistatic potential against Candida albicans (the lack of endpoint = 100%). Among them, the selected compounds 2d, 4b, and 6a differing in substituents at the tetrazole ring were non-toxic to Galleria mellonella larvae in vivo and exerted slight toxicity against Caco-2 in vitro (CC50 at 256 μg/mL). An antagonistic effect of tetrazole derivatives 2d, 4b, and 6a respectively in combination with Fluconazole was shown using the checker board and colorimetric methods (fractional inhibitory concentration indexes FICIs >1). The most active 2d and 6a displayed an inverse relation between MICs in the presence of exogenous ergosterol, the effect was opposite to Itraconazole and Amphotericin B. The differences between 6a's and 2d's action mode were noted. Combining both flow cytometry and fluorescence image analyses respectively showed the complexity of planktonic and biofilm cell demise mode under the tetrazole derivatives tested. The following evidences for 6a's interaction with fungal membrane were noted: necrosis-like programmed cell death (97.03 ± 0.88), DNA denaturation (no laddering), mitochondrial damage (XTT assay), reduced adhesion to human epithelium (>50% at 0.0313 μg/mL, p ≤ .05), irregular deposit of chitin, and attenuated morphogenesis in mature biofilm. The treatment with 6a reduced pathogenicity of C. albicans during infection in G. mellonella. Contrariwise, 2d enhancing fungal adhesion displayed mechanism targeted to the cell wall (due to the presence of 3-chloropropyl clubbed with aryltetrazole) in the presence of osmotic protector. Under 2d, the accidental cell death (88.60% ± 4.81) was observed. In conclusion, all tetrazole derivatives were obtained in satisfactory yields (60–95%) using efficient, simple and not expensive methods. Fungistatic and slightly anticancer tetrazole derivatives with the novel action mode can circumvent an appearance of antifungal-resistant strains. These results indicate that they are worthy of further studies. Graphical abstract image
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Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): A. Sergi Capilla, Richard Soucek, Laura Grau, Manel Romero, Jaime Rubio-Martínez, Daniel H. Caignard, Maria Dolors Pujol This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4]dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38. Graphical abstract image
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Anti-biofilm effect of novel thiazole acid analogs against Pseudomonas aeruginosa through IQS pathways ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Shengrong Li, Siyu Chen, Jilin Fan, Zhen Cao, Weihao Ouyang, Ning Tong, Xin Hu, Jie Hu, Peishan Li, Zifeng Feng, Xi Huang, Yuying Li, Mingshan Xie, Ruikun He, Jingyi Jian, Biyuan Wu, Chen Xu, Weijian Wu, Jialiang Guo, Jing Lin, Pinghua Sun IQS has been proven to be a new quorum sensing (QS) system against bacterial biofilm formation, which is activated in the common phosphate-limiting environment of infected tissues taking over the central las system. Up to now, numerous biofilm inhibitors which function by affecting traditional QS system have been reported. However, no compound has been reported to exert anti-biofilm activity through IQS system. Herein, various novel IQS derivatives were synthesized by the reaction of thiazole-4-carboxylic acid with different linear alcohols (R-OH) or amines (R-NH2). IQS derivatives with four carbon chain length of R group were found to present the best biofilm inhibition activity. Compound B-11 as the model molecule was observed to inhibit biofilm formation only under phosphate-limiting condition, and increase in B-11 concentration significantly reduced the expression of rhlA-gfp and pqsA-gfp, but lasB-gfp. Moreover, B-11 reduced production of virulence factors of rhamnolipid and pyocyanin under phosphate limitation. These observations indicated that the synthesized compounds possessed the anti-biofilm activity through IQS pathways rather than traditional QS pathways, which pave a path for future molecular design against bacterial biofilm formation. Graphical abstract image
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Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Mingshuo Xu, Yu Wang, Feipu Yang, Chunhui Wu, Zhen Wang, Bin Ye, Xiangrui Jiang, Qingjie Zhao, Jianfeng Li, Yongjian Liu, Junchi Zhang, Guanghui Tian, Yang He, Jingshan Shen, Hualiang Jiang In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In animal behavioral studies, 3d reduced phencyclidine-induced hyperlocomotion with a high threshold for catalepsy induction. Compound 3d was selected as a potential antipsychotic candidate for further development. Graphical abstract image
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Synthesis and biological characterization of novel rose bengal derivatives with improved amphiphilicity for sono-photodynamic therapy ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Hai-Jun Chen, Xiao-Bin Zhou, Ai-Lan Wang, Bi-Yuan Zheng, Chih-Kuang Yeh, Jian-Dong Huang Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT. Graphical abstract image
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Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as selective Btk inhibitors with improved pharmacokinetic properties for the treatment of rheumatoid arthritis ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Linhong He, Heying Pei, Chufeng Zhang, Mingfeng Shao, Dan Li, Mingli Tang, Taijing Wang, Xiaoxin Chen, Mingli Xiang, Lijuan Chen Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16. B16 preferentially inhibited Btk (IC50 = 21.70 ± 0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto-phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC50 values over 30 μM. Moreover, B16 showed very weak potential to block the hERG channel (IC50 = 11.10 μM) in comparison to ibrutinib (IC50 = 0.97 μM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t1/2 = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis. Graphical abstract image
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Efficient synthesis and first regioselective C-6 direct arylation of imidazo[2,1-c][1,2,4]triazine scaffold and their evaluation in H2O2-induced oxidative stress ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Mohammed Loubidi, Jabrane Jouha, Zahira Tber, Mostafa Khouili, Franck Suzenet, Mohamed Akssira, Mümin Alper Erdogan, Fadime Aydın Köse, Taner Dagcı, Güliz Armagan, Luciano Saso, Gérald Guillaumet Oxidative stress and apoptosis are both associated with various acute and chronic disorders. Thus, the aim of the present study is to synthesize imidazo[2,1-c][1,2,4]triazines derivatives and to evaluate their effects in H2O2-induced oxidative stress in human neuroblastoma cell line (SH-SY5Y cells). The effects of the compounds on cell viability were measured by MTT assay and the changes in stress and apoptosis-related proteins were investigated by PathScan® Stress and Apoptosis Signaling Antibody Array kit and Western Blot technique. In particular, four compounds were found to protect SH-SY5Y cells from H2O2-induced toxicity by increasing Bcl-2/Bax ratio, regulating PI3-K/Akt cascade and inhibiting the ERK pathway. Graphical abstract image
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Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Atta Ullah, Fatima Iftikhar, Muhammad Arfan, Syeda Tayyaba Batool Kazmi, Muhammad Naveed Anjum, Ihsan-ul Haq, Muhammad Ayaz, Sadia Farooq, Umer Rashid Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC50 = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out. Graphical abstract image
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Identification of novel 2-benzoxazolinone derivatives with specific inhibitory activity against the HIV-1 nucleocapsid protein ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Elia Gamba, Mattia Mori, Lesia Kovalenko, Alessia Giannini, Alice Sosic, Francesco Saladini, Dan Fabris, Yves Mély, Barbara Gatto, Maurizio Botta In this report, we present a new benzoxazole derivative endowed with inhibitory activity against the HIV-1 nucleocapsid protein (NC). NC is a 55-residue basic protein with nucleic acid chaperone properties, which has emerged as a novel and potential pharmacological target against HIV-1. In the pursuit of novel NC-inhibitor chemotypes, we performed virtual screening and in vitro biological evaluation of a large library of chemical entities. We found that compounds sharing a benzoxazolinone moiety displayed putative inhibitory properties, which we further investigated by considering a series of chemical analogues. This approach provided valuable information on the structure-activity relationships of these compounds and, in the process, demonstrated that their anti-NC activity could be finely tuned by the addition of specific substituents to the initial benzoxazolinone scaffold. This study represents the starting point for the possible development of a new class of antiretroviral agents targeting the HIV-1 NC protein. Graphical abstract image
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Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine “bio-oxidizable” prodrugs: Synthesis, biological evaluation and structure-activity relationship ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Rabah Azzouz, Ludovic Peauger, Vincent Gembus, Mihaela-Liliana Ţînţaş, Jana Sopková-de Oliveira Santos, Cyril Papamicaël, Vincent Levacher As an extension of our previous work on donepezil-based “bio-oxidizable” prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC50 > 10 μM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC50 = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC50 ranging from 173 nM to 10 μM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive “bio-oxidizable” prodrug strategy. Graphical abstract image
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Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Geraldo Célio Brandão, Franciele C. Rocha Missias, Lucas Miquéias Arantes, Luciana Ferreira Soares, Kuldeep K. Roy, Robert J. Doerksen, Alaide Braga de Oliveira, Guilherme Rocha Pereira Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5–197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between −9.375 and −14.55 units, compared to −9.137 for lapachol and −12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives. Graphical abstract image
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Peramivir conjugates as orally available agents against influenza H275Y mutant ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Peng-Cheng Wang, Din-Chi Chiu, Jia-Tsrong Jan, Wen-I Huang, Yin-Chen Tseng, Ting-Ting Li, Ting-Jen Cheng, Keng-Chang Tsai, Jim-Min Fang Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses. Graphical abstract image
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Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Hanwen Wei, Fei Mao, Shuaishuai Ni, Feifei Chen, Baoli Li, Xiaoxia Qiu, Linghao Hu, Manjiong Wang, Xinyu Zheng, Jin Zhu, Lefu Lan, Jian Li Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271. Graphical abstract image
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Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): Serdar Durdagi, Busecan Aksoydan, Ismail Erol, Isik Kantarcioglu, Yavuz Ergun, Gulay Bulut, Melih Acar, Timucin Avsar, George Liapakis, Vlasios Karageorgos, Ramin E. Salmas, Barış Sergi, Sara Alkhatib, Gizem Turan, Berfu Nur Yigit, Kutay Cantasir, Bahar Kurt, Turker Kilic AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents – due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [125I-Sar1-Ile8] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. Graphical abstract image
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Synthesis of gold(I) phosphine complexes containing the 2-BrC6F4PPh2 ligand: Evaluation of anticancer activity in 2D and 3D spheroidal models of HeLa cancer cells ()
Publication date: 10 February 2018 Source:European Journal of Medicinal Chemistry, Volume 145 Author(s): T. Srinivasa Reddy, Steven H. Privér, Nedaossadat Mirzadeh, Suresh K. Bhargava Newly synthesised mononuclear gold complexes containing the 2-BrC6F4PPh2 ligand have been fully characterised and their anticancer activity towards five human tumor [prostate (PC3), glioblastoma (U87MG), cervical (HeLa), fibrosarcoma (HT1080), ovarian (SKOV-3)] and normal human embryonic kidney (Hek-293T) cell lines investigated. Some of the synthesised gold complexes displayed higher cytotoxicity than cisplatin towards PC-3, HeLa and U87MG cells and inhibited the thioredoxin reductase (TrxR) enzyme, which is considered a potential target for new compounds in cancer treatment. The more physiologically relevant tumor spheroid assay demonstrated the superior potency of these gold phosphine complexes in inhibiting the growth of cervical carcinoma cell line HeLa (3D) spheroidal models. The mechanism of cell death was shown to be apoptotic cell death through cell cycle arrest, mitochondrial membrane depolarisation and increased ROS production. Graphical abstract image
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Colchicine prodrugs and codrugs: Chemistry and bioactivities ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Abdullah A. Ghawanmeh, Kwok Feng Chong, Shaheen M. Sarkar, Muntaz Abu Bakar, Rizafizah Othaman, Rozida M. Khalid Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as intentions for toxicity reduction and structure-activity relationship (SAR) studying. Hybrid system of colchicine structure with nontoxic biofunctional compounds modified further affords a new entity in chemical structure with enhanced activity and selectivity. Moreover, nanocarrier formulation strategies have been used for colchicine delivery. This review paper focuses on colchicine nanoformulation, chemical synthesis of colchicine prodrugs and codrugs with different linkers, highlights linker chemical nature and biological activity of synthesized compounds. Additionally, classification of colchicine prodrugs based on type of conjugates is discussed, as biopolymers prodrugs, fluorescent prodrug, metal complexes prodrug, metal-labile prodrug and bioconjugate prodrug. Finally, we briefly summarized the biological importance of colchicine nanoformulation, colchicine prodrugs and codrugs. Graphical abstract image
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A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Lei Yin, Heng Li, Wenjian Liu, Zhenglin Yao, Zhenzhen Cheng, Huabei Zhang, Hui Zou Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p < 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM. Graphical abstract image
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Targeting pattern-recognition receptors to discover new small molecule immune modulators ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Gengzheng Zhu, Yao Xu, Xiaohong Cen, Kutty Selva Nandakumar, Shuwen Liu, Kui Cheng Pattern recognition receptors (PRRs) are key immune receptors of the innate immune system, which recognize the conserved pathogen-associated molecular patterns (PAMPs) of the invading pathogens. Compared to the adaptive immune receptors, PRRs have three distinguishing features, viz., universal expression, fast response and recognizing many kinds of microbes. Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and NOD-like receptors (NLRs) recognize viral nucleic acid/bacterial fragments and trigger anti-microbial innate immune responses. Upon recognition of their ligand species, PRRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in the activation of nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinases and interferon regulatory factors (IRFs) that control the transcription of genes encoding pro-inflammatory factors including type I interferon and other inflammatory cytokines, which are critical for eliminating the potential threat to the host. Here, we summarize the effects of small molecule regulators acting on signaling pathways initiated by TLR, RLR and NLR as well as their influence on innate and adaptive immune responses leading to therapy. Graphical abstract image
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Polymeric bile acid sequestrants: Review of design, in vitro binding activities, and hypocholesterolemic effects ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Eva Heřmánková, Aleš Žák, Lenka Poláková, Radka Hobzová, Róbert Hromádka, Jakub Širc Polymeric bile acid sequestrants (BAS) have recently attracted much attention as lipid-lowering agents. These non-absorbable materials specifically bind bile acids (BAs) in the intestine, preventing bile acid (BA) reabsorption into the blood through enterohepatic circulation. Therefore, it is important to understand the structure-property relationships between the polymer sequestrant and its ability to bind specific BAs molecules. In this review, we describe pleiotropic effects of bile acids, and we focus on BAS with various molecular architectures that result in different mechanisms of BA sequestration. Here, we present 1) amphiphilic polymers based on poly(meth)acrylates, poly(meth)acrylamides, polyalkylamines and polyallylamines containing quaternary ammonium groups, 2) cyclodextrins, and 3) BAS prepared via molecular imprinting methods. The synthetic approaches leading to individual BAS preparation, as well as results of their in vitro BA binding activities and in vivo lipid-lowering activities, are discussed. Graphical abstract image
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Investigating the structure-activity relationships of N’-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Fanny Palace-Berl, Kerly Fernanda Mesquita Pasqualoto, Bianca Zingales, Carolina Borsoi Moraes, Mariana Bury, Caio Haddad Franco, Adelson Lopes da Silva Neto, João Sussumu Murayama, Solange Lessa Nunes, Marcelo Nunes Silva, Leoberto Costa Tavares Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N’-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25–30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI′) greater than 200, in contrast to the SI′ values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease. Graphical abstract image
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Recent advance in oxazole-based medicinal chemistry ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Hui-Zhen Zhang, Zhi-Long Zhao, Cheng-He Zhou Oxazole compounds containing nitrogen and oxygen atoms in the five-membered aromatic ring are readily able to bind with a variety of enzymes and receptors in biological systems via diverse non-covalent interactions, and thus display versatile biological activities. The related researches in oxazole-based derivatives including oxazoles, isoxazoles, oxazolines, oxadiazoles, oxazolidones, benzoxazoles and so on, as medicinal drugs have been an extremely active topic, and numerous excellent achievements have been acquired. Noticeably, a large number of oxazole compounds as clinical drugs or candidates have been frequently employed for the treatment of various types of diseases, which have shown their large development value and wide potential as medicinal agents. This work systematically reviewed the recent researches and developments of the whole range of oxazole compounds as medicinal drugs, including antibacterial, antifungal, antiviral, antitubercular, anticancer, anti-inflammatory and analgesic, antidiabetic, antiparasitic, anti-obesitic, anti-neuropathic, antioxidative as well as other biological activities. The perspectives of the foreseeable future in the research and development of oxazole-based compounds as medicinal drugs are also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic oxazole medicinal drugs. Graphical abstract image
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Synthesis and biological evaluation of novel 1-(aryl-aldehyde-oxime)uracil derivatives as a new class of thymidine phosphorylase inhibitors ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Shuyue Zhao, Ke Li, Yi Jin, Jun Lin A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC50 values ranging between 0.12 ± 0.05 and 7.2 ± 1.4 μM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC50 is from 10.7 to 39.9 μM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis. Graphical abstract image
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BODIPYs to the rescue: Potential applications in photodynamic inactivation ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Andrés M. Durantini, Daniel A. Heredia, Javier E. Durantini, Edgardo N. Durantini 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivatives have been proposed in several potential biomedical applications. BODIPYs absorb strongly in blue-green region with high fluorescence emission, properties that convert them in effective fluorophores in the field of biological labeling. However, BODIPY structures can be conveniently modified by heavy atoms substitution to obtain photosensitizers with applications in photodynamic therapy. Also, external heavy atoms effect can be used to increase the photodynamic activity of these compounds. In recent years, BODIPYs have been proposed as phototherapeutic agents for the photodynamic inactivation of microorganisms. Therefore, BODIPY structures need to be optimized to produce an efficient photocytotoxic activity. In this way, amphiphilic cationic BODIPYs can selectively bind to microbial cells, inducing an effective photokilling of pathogenic microbial cells. This review summarizes the attributes of BODIPY derivatives for applications as antimicrobial photosensitizing agents. Graphical abstract image
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Structure-activity studies on N-Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Johannes Schulz-Fincke, Mirjam Hau, Jessica Barth, Dina Robaa, Dominica Willmann, Andreas Kürner, Julian Haas, Gabriele Greve, Tinka Haydn, Simone Fulda, Michael Lübbert, Steffen Lüdeke, Tobias Berg, Wolfgang Sippl, Roland Schüle, Manfred Jung FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase-inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N-substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals. Here, we show that N-substituted 2-PCPA derivatives without a basic function or even a polar group are still potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture. Yet, these lipophilic inhibitors also block the structurally related monoamine oxidases (MAO-A and MAO-B), which may be of interest for the treatment of neurodegenerative disorders, but this property is undesired for applications in cancer treatment. The introduction of a polar, non-basic function led to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells. Cellular target engagement is shown via a Cellular Thermal Shift Assay (CETSA) for LSD1. Graphical abstract image
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Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Nafiz Öncü Can, Derya Osmaniye, Serkan Levent, Begüm Nurpelin Sağlık, Büşra Korkut, Özlem Atlı, Yusuf Özkay, Zafer Asım Kaplancıklı In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC50 values of 0.012 μM and 0.011 μM and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound. Graphical abstract image
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Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): A. Prasanth Saraswati, S.M. Ali Hussaini, Namballa Hari Krishna, Bathini Nagendra Babu, Ahmed Kamal Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase which is ubiquitously expressed and is regarded as a regulator for various cellular events and signalling pathways. It exists in two isoforms, GSK-3α and GSK-3β and can phosphorylate a wide range of substrates. Aberrancy in the GSK-3 activity can lead to various diseases like Alzheimer's, diabetes, cancer, neurodegeneration etc., rendering it an attractive target to develop potent and specific inhibitors. The present review focuses on the recent developments in the area of GSK-3 inhibitors and also enlightens its therapeutic applicability in various disease conditions. Graphical abstract image
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Natural compounds and combination therapy in colorectal cancer treatment ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): A. Rejhová, A. Opattová, A. Čumová, D. Slíva, P. Vodička Colorectal cancer (CRC) therapy using conventional chemotherapeutics represents a considerable burden for the patient's organism because of high toxicity while the response is relatively low. Our review summarizes the findings about natural compounds as chemoprotective agents for decreasing risk of CRC. It also identifies natural compounds which possess anti-tumor effects of various characteristics, mainly in vitro on colorectal cell lines or in vivo studies on experimental models, but also in a few clinical trials. Many of natural compounds suppress proliferation by inducing cell cycle arrest or induce apoptosis of CRC cells resulting in the inhibition of tumor growth. A novel employment of natural substances is a so-called combination therapy - administration of two or more substances - conventional chemotherapeutics and a natural compound or more natural compounds at a time. Some natural compounds may sensitize to conventional cytotoxic therapy, reinforce the drug effective concentration, intensify the combined effect of both administered therapeutics or exert cytotoxic effects specifically on tumor cells. Moreover, combined therapy by targeting multiple signaling pathways, uses various mechanisms to reduce the development of resistance to antitumor drugs. The desired effect could be to diminish burden on the patient's organism by replacing part of the dose of a conventional chemotherapeutic with a natural substance with a defined effect. Many natural compounds are well tolerated by the patients and do not cause toxic effects even at high doses. Interaction of conventional chemotherapeutics with natural compounds introduces a new aspect in the research and therapy of cancer. It could be a promising approach to potentially achieve improvements, while minimizing of adverse effects associated with conventional chemotherapy. Graphical abstract image
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Emimycin and its nucleoside derivatives: Synthesis and antiviral activity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Elzbieta Plebanek, Eveline Lescrinier, Graciela Andrei, Robert Snoeck, Piet Herdewijn, Steven De Jonghe The synthesis of emimycin, 5-substituted emimycin analogues and the corresponding ribo- and 2′-deoxyribonucleoside derivatives is described. Emimycin, its 5-substituted congeners and the ribonucleoside derivatives are completely devoid of antiviral activity against RNA viruses. In contrast, some of the 2′-deoxyribosyl emimycin derivatives are potent inhibitors of the replication of herpes simplex virus-1 and varicella-zoster virus, lacking cytotoxicity. Graphical abstract image
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Design, synthesis and biological evaluation of 1, 4-dihydro indeno[1,2-c] pyrazole linked oxindole analogues as potential anticancer agents targeting tubulin and inducing p53 dependent apoptosis ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Irfan Khan, Koteswara Rao Garikapati, Anver Basha Shaik, Venkata Krishna Kanth Makani, Abdul Rahim, Mohd Adil Shareef, V. Ganga Reddy, Manika Pal-Bhadra, Ahmed Kamal, C. Ganesh Kumar A series of 1, 4-dihydroindeno-[1,2-c] pyrazole linked oxindole conjugates have been synthesized by using Knoevenagel condensation method and further evaluated for their antiproliferative activity against HeLa, A549 and MDA-MB-231 human cancer cell lines along with HEK-293 (normal human embryonic kidney cells). Among the derivatives, compounds 12a, 12b, and 12d showed excellent cytotoxicity with IC50 values ranging between 1.33 to 4.33 μM. Furthermore, detailed biological assays showed that there was accumulation of mitotic cells in G2/M phase, disruption of microtubule network and increase in the G2/M checkpoint proteins (Cyclin B1 and CDK1). Moreover, compound 12d with IC50 value of 1.33 μM showed significant upregulation of tumor suppressor proteins like p53, p21 and pro-apoptotic Bax. The molecular docking analysis demonstrated that these congeners occupy the colchicine binding pocket of the tubulin. Graphical abstract image
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2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Behzad Jafari, Meirambek Ospanov, Syeda Abida Ejaz, Nazym Yelibayeva, Shafi Ullah Khan, Sayyeda Tayyeba Amjad, Sayfidin Safarov, Zharylkasyn A. Abilov, Mirgul Zh. Turmukhanova, Sergey N. Kalugin, Peter Ehlers, Joanna Lecka, Jean Sévigny, Jamshed Iqbal, Peter Langer Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (Pi/PPi) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4-thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies. Graphical abstract image
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Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Juan Cen, Huiyan Guo, Chen Hong, Jianwu Lv, Yacheng Yang, Ting Wang, Dong Fang, Wen Luo, Chaojie Wang A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver–Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation. Graphical abstract image
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Design and characterization of α-lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Hong-Yan Lin, Hong-Wei Han, Wen-Xue Sun, Yu-Shun Yang, Cheng-Yi Tang, Gui-Hua Lu, Jin-Liang Qi, Xiao-Ming Wang, Yong-Hua Yang Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, α-lipoic acid, the naturally-occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of α-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, 1c displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC50 value of 3.14 ± 0.58 μM and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy. Graphical abstract image
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Antagonists of the adenosine A2A receptor based on a 2-arylbenzoxazole scaffold: Investigation of the C5- and C7-positions to enhance affinity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Romain Duroux, Laurence Agouridas, Nicolas Renault, Jamal El Bakali, Christophe Furman, Patricia Melnyk, Saïd Yous We have recently reported a series of 2-furoyl-benzoxazoles as potential A2A adenosine receptor (A2AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hA2AR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hA2AR, we explored the C5- and C7-position of hits 1 and 2 based on docking studies. These modifications led to compounds with nanomolar-range affinity (e.g. 6a, Ki = 40 nM) and high antagonist activity (e.g. 6a, IC50 = 70.6 nM). Selected compounds also exhibited interesting in vitro DMPK (Drug Metabolism and Pharmacokinetics) properties including high solubility and low cytotoxicity. Therefore, the benzoxazole ring appears as a highly effective scaffold for the design of new A2A antagonists. Graphical abstract image
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4-arylamidobenzyl substituted 5-bromomethylene-2(5H)-furanones for chronic bacterial infection ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Xing-Jun Xu, Fang Wang, Ting Zeng, Jing Lin, Jun Liu, Yi-Qun Chang, Ping-Hua Sun, Wei-Min Chen Bacterial quorum-sensing (QS) can cause bacterial biofilm formation, thus induce antibiotic resistance and inflammation in chronic bacterial infections. A series of novel 4-arylamidobenzyl substituted 5-bromomethylene-2(5H)-furanones were designed by introducing of brominated furanones into rosiglitazone skeleton, and their potential application in the treatment of chronic bacterial infection was evaluated with regard to their disruption of quorum sensing and anti-inflammatory activities in vitro as well as in animal infection model. Compound 2e displayed both potent QS inhibitory activity and anti-inflammatory activity. Further mechanism studies revealed that the biological effects of 2e and 2k could be attributed, at least in part, to their interaction with PPARγ, and consequent suppression of the activation of NF-κB and MAPK cascades. Importantly, pretreatment with 2e significantly protects mice from lethal-dose LPS challenge. Thus, these data suggest that the dual effective derivative 2e may serve as a valuable candidate for the treatment of chronic bacterial infection. Graphical abstract image
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Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Nara Liessi, Elena Cichero, Emanuela Pesce, Maria Arkel, Annalisa Salis, Valeria Tomati, Matteo Paccagnella, Gianluca Damonte, Bruno Tasso, Luis J.V. Galietta, Nicoletta Pedemonte, Paola Fossa, Enrico Millo The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity. Graphical abstract image
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Substrate-derived triazolo- and azapeptides as inhibitors of cathepsins K and S ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Matthieu Galibert, Mylène Wartenberg, Fabien Lecaille, Ahlame Saidi, Sylvie Mavel, Alix Joulin-Giet, Brice Korkmaz, Dieter Brömme, Vincent Aucagne, Agnès F. Delmas, Gilles Lalmanach Cathepsin (Cat) K is a critical bone-resorbing protease and is a relevant target for the treatment of osteoporosis and bone metastasis, while CatS is an attractive target for drugs in autoimmune diseases (e.g. rheumatoid arthritis), emphysema or neuropathic pain. Despite major achievements, current pharmacological inhibitors are still lacking in safety and may have damaging side effects. A promising strategy for developing safer reversible and competitive inhibitors as new lead compounds could be to insert non-cleavable bonds at the scissile P1-P1′ position of selective substrates of CatS and CatK. Accordingly, we introduced a 1,4-disubstituted 1,2,3-triazole heterocycle that mimics most of the features of a trans-amide bond, or we incorporated a semicarbazide bond (azaGly residue) by replacing the α-carbon of the glycyl residue at P1 by a nitrogen atom. AzaGly-containing peptidomimetics inhibited powerfully their respective target proteases in the nM range, while triazolopeptides were weaker inhibitors (Ki in the μM range). The selectivity of the azaGly CatS inhibitor (1b) was confirmed by using spleen lysates from wild-type vs CatS-deficient mice. Alternatively, the azaGly bradykinin-derived CatK inhibitor (2b) potently inhibited CatK (Ki = 9 nM) and impaired its kininase activity in vitro. Molecular modeling studies support that the semicarbazide bond of 2b is more favorable than the 1,2,3-triazole linkage of the bradykinin-derived pseudopeptide 2a to preserve an effective affinity towards CatK, its protease target. Graphical abstract image
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Branching tryptamines as a tool to tune their antiproliferative activity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Rinat F. Salikov, Konstantin P. Trainov, Irina K. Belousova, Aleksandr Yu. Belyy, Ulyana Sh. Fatkullina, Regina V. Mulyukova, Liana F. Zainullina, Yulia V. Vakhitova, Yury V. Tomilov The influence of a series of tryptamine derivatives on the viability of normal (HEK293) and tumor (HepG2, Jurkat and SH-SY5Y) cells has been evaluated. All tryptamines tested were three different substitution types: C- and N-branching, and indole benzylation. All the derivations enhance the activity of compounds separately, although the effects of different substitutions were not additive. Thus, combinations of C- and N-branchings as well as C-branching and indole benzylation gave little or no increase in activity. Graphical abstract image
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Photoactive platinum(II) complexes of nonsteroidal anti-inflammatory drug naproxen: Interaction with biological targets, antioxidant activity and cytotoxicity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Payal Srivastava, Khushbu Singh, Madhu Verma, Sri Sivakumar, Ashis K. Patra The effect on the therapeutic efficacy of Pt(II) complexes on combining non-steroidal anti-inflammatory drugs (NSAIDs) is an attractive strategy to circumvent chronic inflammation mediated by cancer and metastasis. Two square-planar platinum(II) complexes: [Pt(dach)(nap)Cl] (1) and [Pt(dach)(nap)2] (2), where dach = (1R,2R)-dichloro(cyclohexane-1,2-diamine) and NSAID drug naproxen (nap), have been designed for studying their biological activity. The naproxen bound to the Pt(II) centre get released upon photoirradiation with low-power UV-A light as confirmed by the significant enhancement in emission intensities of the complexes. The compounds were evaluated for their photophysical properties, photostability, reactivity with 5′-guanosine monophophosphate (5′-GMP), interactions with CT-DNA and BSA, antioxidant activity and reactive oxygen species mediated photo-induced DNA damage properties. ESI-MS studies demonstrated the formation of bis-adduct with 5′-GMP and the formation of PtII-DNA crosslinks by gel electrophoretic mobility shift assay and ITC studies. The interaction of the complexes 1 and 2 with the CT-DNA exhibits potential binding affinity (K b ∼ 104 M−1, K app∼ 105 M−1), implying intercalation to CT-DNA through planar naphthyl ring of the complexes. Both the complexes also exhibit strong binding affinity towards BSA (K BSA∼ 105 M−1). The complexes exhibit efficient DNA damage activity on irradiation at 365 nm via formation of singlet oxygen (1O2) and hydroxyl radical (•OH) under physiological conditions. Both the complexes were cytotoxic in dark and exhibit significant enhancement of cytotoxicity upon photo-exposure against HeLa and HepG2 cancer cells giving IC50 values ranging from 8 to 12 μM for 1 and 2. The cellular internalization data showed cytosolic and nuclear localization of the complexes in the HeLa cells. Graphical abstract image
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The synthesis, antifungal and apoptotic effects of triazole-oxadiazoles against Candida species ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Betül Kaya Çavuşoğlu, Leyla Yurttaş, Zerrin Cantürk In search of potent and safe antifungal agents, herein, we report the synthesis, characterization and biological activities of triazole-oxadiazole compounds. The structural verification of the molecules was carried out by 1H NMR, 13C NMR and mass spectral data. The in vitro antifungal and apoptotic activity were investigated against C. albicans, C. parapsilosis, C. krusei and C. glabrata. The compounds namely N-(4-nitrophenyl)-2-[(5-(2-((4-methyl-4H-1,2,4-triazol-3-yl)thio)ethyl)-1,3,4-oxadiazol-2-yl)thio]acetamide (4e) and N-(6-fluorobenzothiazol-2-yl)-2-[(5-(2-((4-methyl-4H-1,2,4-triazol-3-yl)thio)ethyl)-1,3,4-oxadiazol-2-yl)thio]acetamide (4i) were detected as the most potent compounds against C. albicans and C. glabrata (MIC90 = 62.5 μg/mL). According to studies on their mechanism of action, it was confirmed that compound 4i has apoptotic effect on four Candida via Annexin V-PI with flow cytometry. The MTT assay revealed that all compounds were determined to be non-toxic against healthy cells in the tested concentrations. Graphical abstract image
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1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Xuan Yang, Wassihun Wedajo, Yoshiyuki Yamada, Sue-Li Dahlroth, Jason Jun-Long Neo, Thomas Dick, Wai-Keung Chui The emergence of multi- and extensively-drug resistant tubercular (MDR- and XDR-TB) strains of mycobacteria has limited the use of existing therapies, therefore new drugs are needed. Dihydrofolate reductase (DHFR) has recently attracted much attention as a target for the development of anti-TB agents. This study aimed to develop selective M. tuberculosis DHFR inhibitors using rationale scaffolding design and synthesis, phenotype-oriented screening, enzymatic inhibitory study, whole cell on-target validation, molecular modeling, and in vitro DMPK determination to derive new anti-TB agents. 2,4-diamino-1-phenyl-1,3,5-triazaspiro[5.5]undeca-2,4-dienes 20b and 20c were identified as selective M. tuberculosis DHFR inhibitors, showing promising antimycobacterial activities (MIC50: 0.01 μM and MIC90: 0.025 μM on M. tuberculosis H37Rv). This study provided compelling evidence that compound 20b and 20c exerted whole cell antimycobacterial activity through DHFR inhibition. In addition, these two compounds exhibited low cytotoxicity and low hemolytic activity. The in vitro DMPK and physiochemical properties suggested their potential in vivo efficacy. Graphical abstract image
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Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Alessandra Mascarello, Angela Camila Orbem Menegatti, Andrea Calcaterra, Priscila Graziela Alves Martins, Louise Domeneghini Chiaradia-Delatorre, Ilaria D'Acquarica, Franco Ferrari, Valentina Pau, Adriana Sanna, Alessandro De Logu, Maurizio Botta, Bruno Botta, Hernán Terenzi, Mattia Mori Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (K i = 1.6 ± 0.1 μM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed K i values of 0.39 ± 0.27 and 0.20 ± 0.01 μM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interaction of these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB. Graphical abstract image
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Synthesis and biological evaluation of diarylheptanoids as potential antioxidant and anti-inflammatory agents ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Kelly Maurent, Corinne Vanucci-Bacqué, Michel Baltas, Anne Nègre-Salvayre, Nathalie Augé, Florence Bedos-Belval Reactive oxygen species (ROS) are key signaling molecules and their overproduction plays an important role in the inflammation process, the secretion of inflammatory cytokines such as IL-1β and IL-6 and the progression of inflammatory disorders. Decreasing oxidative stress represents a promising challenge in the design of antioxidant and anti-inflammatory agents. In the present study, a series of new diarylheptanoids containing allylic alcohol, amide, hydantoin or triazole fragments were synthesized and fully characterized. We evaluated the ability of these agents to block the production of intracellular ROS and the subsequent inflammatory events exerted by lipopolysaccharide (LPS) on murine macrophage RAW 264.7. Five diarylheptanoids were found to exhibit the dual required properties. Graphical abstract image
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Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Miryam Pastor, Rosalía Fernández-Calle, Bruno Di Geronimo, Marta Vicente-Rodríguez, José María Zapico, Esther Gramage, Claire Coderch, Carmen Pérez-García, Amy W. Lasek, Leonor Puchades-Carrasco, Antonio Pineda-Lucena, Beatriz de Pascual-Teresa, Gonzalo Herradón, Ana Ramos A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC50 = 0,1 μM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity. Docking and molecular dynamics experiments have been used to analyze the binding mode and to explain the observed selectivity against PTP1B. An In vivo experiment has demonstrated that 10a can cross the BBB, thus promoting the possibility of moving forward these candidates for the development of drugs for the treatment of CNS disorders, such as drug addiction and neurodegenerative diseases. Graphical abstract image
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Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity ()
Publication date: 20 January 2018 Source:European Journal of Medicinal Chemistry, Volume 144 Author(s): Monia Hossam, Deena S. Lasheen, Nasser S.M. Ismail, Ahmed Esmat, Ahmed M. Mansour, Abdel Nasser B. Singab, Khaled A.M. Abouzid Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V–FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively). Graphical abstract image
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