共查询到20条相似文献,搜索用时 31 毫秒
1.
N‐Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual‐Stage Antimalarials 下载免费PDF全文
Ana Gomes Marta Machado Lis Lobo Dr. Fátima Nogueira Dr. Miguel Prudêncio Dr. Cátia Teixeira Prof. Dr. Paula Gomes 《ChemMedChem》2015,10(8):1344-1349
In a follow‐up study to our reports of N‐cinnamoylated chloroquine and quinacrine analogues as promising dual‐stage antimalarial leads with high in vitro potency against both blood‐stage Plasmodium falciparum and liver‐stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N‐acylated analogues were synthesized, and their activities against blood‐ and liver‐stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N‐acylated analogues were found to be somewhat less active and more cytotoxic than their N‐cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood‐stage drug‐sensitive and drug‐resistant P. falciparum, and significant in vitro liver‐stage activity against P. berghei. Therefore, it is demonstrated that simple N‐acylated surrogates of classical antimalarial drugs are promising dual‐stage antimalarial leads. 相似文献
2.
Yu XM Ramiandrasoa F Guetzoyan L Pradines B Quintino E Gadelle D Forterre P Cresteil T Mahy JP Pethe S 《ChemMedChem》2012,7(4):587-605
New N‐alkylaminoacridine derivatives attached to nitrogen heterocycles were synthesized, and their antimalarial potency was examined. They were tested in vitro against the growth of Plasmodium falciparum, including chloroquine (CQ)‐susceptible and CQ‐resistant strains. This biological evaluation has shown that the presence of a heterocyclic ring significantly increases the activity against P. falciparum. The best compound shows a nanomolar IC50 value toward parasite proliferation on both CQ‐susceptible and CQ‐resistant strains. The antimalarial activity of these new acridine derivatives can be explained by the two mechanisms studied in this work. First, we showed the capacity of these compounds to inhibit heme biocrystallization, a detoxification process specific to the parasite and essential for its survival. Second, in our search for alternative targets, we evaluated the in vitro inhibitory activity of these compounds toward Sulfolobus shibatae topoisomerase VI‐mediated DNA relaxation. The preliminary results obtained reveal that all tested compounds are potent DNA intercalators, and significantly inhibit the activity of S. shibatae topoisomerase VI at concentrations ranging between 2.0 and 2.5 μM . 相似文献
3.
Design,Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents 下载免费PDF全文
Leon Jacobs Dr. Carmen de Kock Dr. Katherine A. de Villiers Prof. Peter J. Smith Dr. Vincent J. Smith Prof. Willem A. L. van Otterlo Dr. Margaret A. L. Blackie 《ChemMedChem》2015,10(12):2099-2110
7‐Chloroquinoline‐based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine‐sensitive (CQS) NF54 (IC50: 4.2 nm ) and chloroquine‐resistant (CQR) Dd2 (IC50: 33.7 nm ) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β‐hematin formation in an NP‐40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm . 相似文献
4.
Paul M. Wood Dr. L. W. Lawrence Woo Dr. Jean‐Robert Labrosse Dr. Mark P. Thomas Dr. Mary F. Mahon Dr. Surinder K. Chander Dr. Atul Purohit Dr. Michael J. Reed Prof. Barry V. L. Potter Prof. 《ChemMedChem》2010,5(9):1577-1593
The design and synthesis of a series of bicyclic ring containing dual aromatase–sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4‐[(4‐bromobenzyl)(4H‐1,2,4‐triazol‐4‐yl)amino]benzonitrile are reported. Biological evaluation with JEG‐3 cells revealed structure–activity relationships. The X‐ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate‐containing series, compounds containing a naphthalene ring are both the most potent AI ( 39 , IC50 AROM=0.25 nM ) and the best STS inhibitor ( 31 , IC50 STS=26 nM ). The most promising DASI is 39 (IC50 AROM=0.25 nM , IC50 STS=205 nM ), and this was evaluated orally in vivo at 10 mg kg?1, showing potent inhibition of aromatase (93 %) and STS (93 %) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone‐dependent breast cancer. 相似文献
5.
Dr. Yi‐Yu Ke Dr. Hui‐Yi Shiao Dr. Yung Chang Hsu Dr. Chang‐Ying Chu Dr. Wen‐Chieh Wang Yen‐Chun Lee Dr. Wen‐Hsing Lin Chun‐Hwa Chen Dr. John T. A. Hsu Chun‐Wei Chang Dr. Cheng‐Wei Lin Dr. Teng‐Kuang Yeh Dr. Yu‐Sheng Chao Dr. Mohane Selvaraj Coumar Dr. Hsing‐Pang Hsieh 《ChemMedChem》2013,8(1):136-148
We describe the 3D‐QSAR‐assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D‐QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC50 values toward Aurora kinase A ranging from 33 nM to 10.5 μM . The best 3D‐QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r2CV=0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R2pred=0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent‐exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC50=43 nM ; HCT‐116 IC50=400 nM ) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC50=25 nM ; HCT‐116 IC50=23 nM ). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24 , and holds potential for further development. 相似文献
6.
Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6‐Oxopurine Phosphoribosyltransferases 下载免费PDF全文
Dr. Martin M. Kaiser Dr. Dana Hocková Tzu‐Hsuan Wang Dr. Martin Dračínský Dr. Lenka Poštová‐Slavětínská Eliška Procházková Dr. Michael D. Edstein Dr. Marina Chavchich Dr. Dianne T. Keough Dr. Luke W. Guddat Dr. Zlatko Janeba 《ChemMedChem》2015,10(10):1707-1723
Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine‐guanine‐(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2‐(phosphonoethoxy)ethyl (PEE) and (R,S)‐3‐hydroxy‐2‐(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure–activity relationship studies. In this series, (S)‐3‐hydroxy‐2‐(phosphonoethoxy)propyl (HPEP), (S)‐2‐(phosphonomethoxy)propanoic acid (CPME), or (S)‐2‐(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)‐3‐hydroxy‐2‐(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM . The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM ) in a chloroquine‐resistant strain was observed for the bis‐amidate prodrug of HPEPG. 相似文献
7.
Dr. Giulio Ferino Prof. Enzo Cadoni Dr. Maria João Matos Dr. Elias Quezada Prof. Eugenio Uriarte Prof. Lourdes Santana Dr. Santiago Vilar Dr. Nicholas P. Tatonetti Matilde Yáñez Dolores Viña Dr. Carmen Picciau Dr. Silvia Serra Prof. Giovanna Delogu 《ChemMedChem》2013,8(6):956-966
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC50 values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC50=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC50=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC50=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds. 相似文献
8.
Julie G. Geist Susan Lauw Dr. Victoria Illarionova Dr. Boris Illarionov Dr. Markus Fischer Prof. Dr. Tobias Gräwert Dr. Felix Rohdich Dr. Wolfgang Eisenreich Dr. Johannes Kaiser Dr. Michael Groll Prof. Dr. Christian Scheurer Sergio Wittlin Dr. José L. Alonso‐Gómez Dr. W. Bernd Schweizer Dr. Adelbert Bacher Prof. Dr. François Diederich Prof. Dr. 《ChemMedChem》2010,5(7):1092-1101
A library of 40 000 compounds was screened for inhibitors of 2‐methylerythritol 2,4‐cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high‐throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosis, Plasmodium falciparum, and A. thaliana with IC50 values in the micromolar range. Synthetic efforts afforded derivatives that inhibit IspF protein from M. tuberculosis and P. falciparum with IC50 values in the low micromolar range. Several compounds act as weak inhibitors in the P. falciparum red blood cell assay. 相似文献
9.
Maria Grazia Perrone Dr. Laura Bleve Dr. Ernesto Santandrea Dr. Paola Vitale Dr. Mauro Niso Dr. Antonio Scilimati Prof. 《ChemMedChem》2009,4(12):2080-2097
Novel compounds were prepared in fair to good yields as human β3‐adrenoceptor (β3‐AR) agonists. In particular, aryloxypropanolamines 7 a – d (EC50=0.57–2.1 nM ) and arylethanolamines 12 a , b , e (EC50=6.38–19.4 nM ) were designed to explore the effects of modifications at the right‐hand side of these molecules on their activity as β3‐AR agonists. Piperidine sulfonamides 15 a – c , e – g (EC50=6.1–36.2 nM ) and piperazine sulfonamide derivatives 20 – 29 (EC50=1.79–49.3 nM ) were examined as compounds bearing a non‐aromatic linker on the right‐ and left‐hand sides of the molecules. Some piperazine sulfonamides were found to be potent and selective β3‐AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all β3‐AR agonists reported so far. (S)‐3‐{4‐{N‐{4‐{2‐[2‐Hydroxy‐3‐(4‐hydroxyphenoxy)propylamino]ethyl}phenyl}sulfamoyl}phenoxy}propanoic acid ( 7 d ; EC50=0.57 nM ), (R)‐N‐{4‐[2‐(2‐hydroxy‐2‐phenylethylamino)ethyl]phenyl}‐4‐(3‐octylureido)benzenesulfonamide ( 12 e ; EC50=6.38 nM ), (R)‐2‐[1‐(4‐methoxyphenylsulfonyl)piperidin‐4‐ylamino]‐1‐phenylethanol ( 15 f ; EC50=6.1 nM ), and (S)‐4‐{2‐hydroxy‐3‐[4‐(4‐methoxyphenylsulfonyl)piperazin‐1‐yl]propoxy}phenol ( 25 ; EC50=1.79 nM ) were found to be the most potent β3‐AR agonists of the aryloxypropanolamine, arylethanolamine, piperidine sulfonamide, and piperazine sulfonamide classes, respectively. The two most potent compounds were identified as possible candidates for further development of β3‐AR agonists useful in the treatment of β3‐AR‐mediated pathological conditions. 相似文献
10.
Emilia Păunescu Dr. Sophie Susplugas Dr. Emmanuelle Boll Richard Varga Dr. Elisabeth Mouray Dr. Ion Grosu Prof. Philippe Grellier Prof. Patricia Melnyk Prof. 《ChemMedChem》2009,4(4):549-561
4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM ; one compound showed in vivo activity.
11.
Heikki Käsnänen Mikko J. Myllymäki Anna Minkkilä Antti O. Kataja Susanna M. Saario Dr. Tapio Nevalainen Dr. Ari M. P. Koskinen Prof. Dr. Antti Poso Prof. Dr. 《ChemMedChem》2010,5(2):213-231
Carbamates are a well‐established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta‐substituted phenolic N‐alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3‐(oxazol‐2yl)phenyl cyclohexylcarbamate ( 2 a ), inhibited FAAH with a sub‐nanomolar IC50 value (IC50=0.74 nM ). Additionally, we developed and validated three‐dimensional quantitative structure–activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D‐QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D‐QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R2PRED) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design. 相似文献
12.
Swagatika Das Umashankar Das Dr. Ponniah Selvakumar Dr. Rajendra K. Sharma Dr. Jan Balzarini Prof. Dr. Erik De Clercq Prof. Dr. Joseph Molnár Prof. Dr. Julianna Serly Zoltán Baráth Dr. Gabriele Schatte Dr. Brian Bandy Dr. Dennis K. J. Gorecki Prof. Dr. Jonathan R. Dimmock Prof. Dr. 《ChemMedChem》2009,4(11):1831-1840
A series of 3,5‐bis(benzylidene)‐4‐piperidones 3 were converted into the corresponding 3,5‐bis(benzylidene)‐1‐phosphono‐4‐piperidones 5 via diethyl esters 4 . The analogues in series 4 and 5 displayed marked growth inhibitory properties toward human Molt 4/C8 and CEM T‐lymphocytes as well as murine leukemia L1210 cells. In general, the N‐phosphono compounds 5 , which are more hydrophilic than the analogues in series 3 and 4 , were the most potent cluster of cytotoxins, and, in particular, 3,5‐bis‐(2‐nitrobenzylidene)‐1‐phosphono‐4‐piperidone 5 g had an average IC50 value of 34 nM toward the two T‐lymphocyte cell lines. Four of the compounds displayed potent cytotoxicity toward a panel of nearly 60 human tumor cell lines, and nanomolar IC50 values were observed in a number of cases. The mode of action of 5 g includes the induction of apoptosis and inhibition of cellular respiration. Most of the members of series 4 as well as several analogues in series 5 are potent multi‐drug resistance (MDR) reverting compounds. Various correlations were noted between certain molecular features of series 4 and 5 and cytotoxic properties, affording some guidelines in expanding this study. 相似文献
13.
14.
KonstantinV. Luzyanin Vadim Yu. Kukushkin Maximilian N. Kopylovich Alexey A. Nazarov Markus Galanski Armando J.L. Pombeiro 《Advanced Synthesis \u0026amp; Catalysis》2008,350(1):135-142
Refluxing a mixture of phthalonitrile C6R1R2R3R4(CN)2 1 (R1–R4=H), or its substituted derivatives 2 (R1, R3, R4=H, R2=Me), or 3 (R1, R4=H, R2, R3=Cl) (1 equiv.) and N,N‐diethylhydroxylamine, Et2NOH, (4 equivs.) in methanol for 4 h results ( Route A ) in precipitation of the symmetrical ( 6 and 8 ) and an isomeric mixture of unsymmetrical ( 7 ) phthalocyanines, isolated in good (55–65 %) yields. The reaction of phthalonitriles 1 , 2 , or 4 (R1, R3, R4=H, R2=NO2) (4 equivs.) with Et2NOH (8 equivs.) in the presence of a metal salt MCl2 (M=Zn, Cd, Co, Ni) (1 equiv.) in n‐BuOH or without solvent results in the formation of metallated phthalocyanine species ( 9 – 17 ). Upon refluxing in freshly distilled dry chloroform, phthalonitrile 1 or its substituted analogues 2 , 3 or 5 (R1–R4=F) (1 equiv.) react with N,N‐diethylhydroxylamine (2 equivs.) affording 3‐iminoisoindolin‐1‐ones 18 – 21 ( Route B ) isolated in good yields (55–80 %). All the prepared compounds were characterized with C, H, and N elemental analyses, ESI‐MS, IR, and compounds 18 – 21 also by 1D (1H, 13C{1H}), and 2D (1H,15N‐HMBC and 1H,13C‐HMQC, 1H,13C‐HMBC) NMR spectroscopy. 相似文献
15.
Ishan Wadi Dr. Davinder Prasad Dr. Neha Batra Dr. Kumkum Srivastava Dr. Anupkumar R. Anvikar Dr. Neena Valecha Prof. Mahendra Nath 《ChemMedChem》2019,14(4):484-493
Novel 4-amino-7-chloroquinoline-based 1,2,3-triazole hybrids were synthesised in good yields by CuI-catalysed Huisgen 1,3-dipolar cycloaddition reactions of 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides with various terminal alkynes. These new hybrids were screened in vitro against asexual blood stages of the chloroquine-sensitive 3D7 strain of P. falciparum. The most active compounds were further screened against asexual and sexual stages (gametocytes) of the chloroquine-resistant RKL-9 strain of P. falciparum. Although all compounds were less potent than chloroquine against the 3D7 strain, the three best compounds were appreciably more active than chloroquine against the RKL-9 strain, displaying IC50 values of <100 nm , with one of them having an IC50 of 2.94 nm . Further, the lead compounds were gametocytocidal with IC50 values in the micromolar range, and were observed to induce morphological deformations in mature gametocytes. Most compounds demonstrated little or no cytotoxicity and exhibited good selectivity indices. The most active compounds represent promising candidates for further evaluation of their schizonticidal and gametocytocidal potential. 相似文献
16.
Bastian Tewes Dr. Bastian Frehland Dirk Schepmann Dr. Kai‐Uwe Schmidtke Thomas Winckler Prof. Dr. Bernhard Wünsch Prof. Dr. 《ChemMedChem》2010,5(5):687-695
Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil ( 1 ) leads to 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols, a novel class of NR2B‐selective NMDA receptor antagonists. The secondary amine 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ol ( 12 ), which was synthesized in six steps starting from 2‐phenylethylamine 3 , represents the central building block for the introduction of several N‐linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4‐phenylbutyl derivative 13 (WMS‐1405, Ki=5.4 nM ) and the conformationally restricted 4‐phenylcyclohexyl derivative 31 (Ki=10 nM ) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4‐phenylcyclohexyl derivative 31 also interacts with σ1 (Ki=33 nM ) and σ2 receptors (Ki=82 nM ). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate‐induced cytotoxicity with an IC50 value of 360 nM , indicating that 13 is an NMDA antagonist. 相似文献
17.
Leonardo Pisani Dr. Marco Catto Dr. Ilenia Giangreco Dr. Francesco Leonetti Dr. Orazio Nicolotti Dr. Angela Stefanachi Dr. Saverio Cellamare Prof. Angelo Carotti Prof. 《ChemMedChem》2010,5(9):1616-1630
A large series of substituted coumarins linked through an appropriate spacer to 3‐hydroxy‐N,N‐dimethylanilino or 3‐hydroxy‐N,N,N‐trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3‐hydroxy‐N,N‐dimethylanilino series was observed with a 6,7‐dimethoxy‐3‐substituted coumarin derivative, which, along with an outstanding affinity (IC50=0.236 nM ) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3‐hydroxy‐N,N,N‐trialkylbenzaminium salts display an AChE affinity in the sub‐nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure–affinity and structure–selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of π–π stacking interactions in the AChE peripheral binding site. 相似文献
18.
Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids 下载免费PDF全文
Mohamed Benchekroun Dr. Manuela Bartolini Dr. Javier Egea Dr. Alejandro Romero Dr. Elena Soriano Dr. Marc Pudlo Vincent Luzet Prof. Vincenza Andrisano Dr. María‐Luisa Jimeno Dr. Manuela G. López Sarah Wehle Prof. Tijani Gharbi Prof. Bernard Refouvelet Lucía de Andrés Clara Herrera‐Arozamena Prof. Barbara Monti Prof. Maria Laura Bolognesi Prof. María Isabel Rodríguez‐Franco Prof. Dr. Michael Decker Prof. José Marco‐Contelles Dr. Lhassane Ismaili 《ChemMedChem》2015,10(3):523-539
Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA‐blood–brain barrier (BBB) analysis of new tacrine–ferulic acid hybrids (TFAHs). We identified (E)‐3‐(hydroxy‐3‐methoxyphenyl)‐N‐{8[(7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐yl)amino]octyl}‐N‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n ) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50=68.2 nM ), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β‐amyloid (Aβ) anti‐aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA‐BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM ), affording good neuroprotection against toxic insults such as Aβ1–40, Aβ1–42, H2O2, and oligomycin A/rotenone on SH‐SY5Y cells, at 1 μM . The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer′s disease. 相似文献
19.
8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases 下载免费PDF全文
Dr. Andreas Brunschweiger Dr. Pierre Koch Dr. Miriam Schlenk Dr. Felipe Pineda Dr. Petra Küppers Dr. Sonja Hinz Dr. Meryem Köse Dr. Stefan Ullrich Dr. Jörg Hockemeyer Prof. Dr. Michael Wiese Dr. Jag Heer Prof. Dr. Christa E. Müller 《ChemMedChem》2014,9(8):1704-1724
8‐Benzyl‐substituted tetrahydropyrazino[2,1‐f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual‐target‐directed A1/A2A adenosine receptor antagonists were identified. Several compounds showed triple‐target inhibition; one of the best compounds was 8‐(2,4‐dichloro‐5‐fluorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione ( 72 ) (human AR: Ki A1 217 nM , A2A 233 nM ; IC50 MAO‐B: 508 nM ). Dichlorinated compound 36 [8‐(3,4‐dichlorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione] was found to be the best triple‐target drug in rat (Ki A1 351 nM , A2A 322 nm; IC50 MAO‐B: 260 nM ), and may serve as a useful tool for preclinical proof‐of‐principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease‐modifying treatment of neurodegenerative diseases are expected to show advantages over single‐target therapeutics. 相似文献
20.
Dr. Paulo André Teixeira de Moraes Gomes Prof. Marcos Veríssimo de Oliveira Cardoso Ignes Regina dos Santos Fabiano Amaro de Sousa Juliana Maria da Conceição Vanessa Gouveia de Melo Silva Denise Duarte Raquel Pereira Rafael Oliveira Prof. Fátima Nogueira Dr. Luiz Carlos Alves Dr. Fabio André Brayner Dr. Aline Caroline da Silva Santos Dr. Valéria Rêgo Alves Pereira Prof. Ana Cristina Lima Leite 《ChemMedChem》2020,15(22):2164-2175
Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones ( 3 a – x ) and 14 phthalimido-thiazoles ( 4 a – n ) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC50=3.60 μM), 3 h (IC50=3.75 μM), and 4 j (IC50=4.48 μM), were more active than the control drug benznidazole (IC50=14.6 μM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h , 3 t , and 4 j at IC50 concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarial activity were the phthalimido-thiazoles 4 l (IC50=1.2 μM), 4 m (IC50=1.7 μM), and 4 n (IC50=2.4 μM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics. 相似文献