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1.
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
2.
Structure‐Based Design of Microsomal Prostaglandin E2 Synthase‐1 (mPGES‐1) Inhibitors using a Virtual Fragment Growing Optimization Scheme
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Dr. Gianluigi Lauro Prof. Paolo Tortorella Dr. Alessia Bertamino Dr. Carmine Ostacolo Dr. Andreas Koeberle Katrin Fischer Prof. Ines Bruno Dr. Stefania Terracciano Dr. Isabel Maria Gomez‐Monterrey Dr. Marilena Tauro Prof. Fulvio Loiodice Prof. Ettore Novellino Prof. Raffaele Riccio Prof. Oliver Werz Prof. Pietro Campiglia Prof. Giuseppe Bifulco 《ChemMedChem》2016,11(6):612-619
A small library of 2,3‐dihydroxybenzamide‐ and N‐(2,3‐dihydroxyphenyl)‐4‐sulfonamide‐based microsomal prostaglandin E2 synthase‐1 (mPGES‐1) inhibitors was identified following a step‐by‐step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES‐1. During the virtual optimization process, the 2,3‐dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure‐guided replacement of the 2,3‐dihydroxybenzamide by the N‐(2,3‐dihydroxyphenyl)sulfonamide moiety led to the identification of N‐(2,3‐dihydroxyphenyl)‐4‐biphenylsulfonamide ( 6 ), the most potent small molecule of the series (IC50=0.53±0.04 μm ). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES‐1‐inhibitory activity, with potential application as anti‐inflammatory and anticancer agents. 相似文献
3.
Andrea Cappelli Prof. Chiara Nannicini Dr. Salvatore Valenti Dr. Germano Giuliani Dr. Maurizio Anzini Prof. Laura Mennuni Dr. Antonio Giordani Dr. Gianfranco Caselli Dr. Luigi Piero Stasi Dr. Francesco Makovec Dr. Gianluca Giorgi Prof. Salvatore Vomero Prof. 《ChemMedChem》2010,5(5):739-748
A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline frameworks bearing a 4‐(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS‐5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS‐5 and ADAMTS‐4. Among the compounds containing the pyrrolo[3,4‐c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS‐5 and ADAMTS‐4, with IC50 values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11 . Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS‐5 and ‐4. The structure–activity relationship analysis of pyrroloquinolinone derivatives 2 a – i suggests that the carboxylate or hydroxamate groups of compounds 2 a , b play a key role in the interaction of these compounds with ADAMTS‐5 and ‐4. On the other hand, the oxoisoindoline derivatives 3 a , b lack significant ADAMTS‐4 inhibitory activity and inhibit ADAMTS‐5 showing IC25 values in the micromolar range. 相似文献
4.
Design,Synthesis, and Evaluation of 2‐Amino‐6‐nitrobenzothiazole‐Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group
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A series of 2‐amino‐6‐nitrobenzothiazole‐derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO‐A/MAO‐B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO‐B isoform. N′‐(5‐Chloro‐2‐oxoindolin‐3‐ylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide (compound 31 ) showed the highest MAO‐B inhibitory activity (IC50=1.8±0.3 nm , selectivity index [SI]=766.67), whereas compound 6 [N′‐(1‐(4‐bromophenyl)ethylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide] was found to be the most active MAO‐A inhibitor (IC50=0.42±0.003 μm ). Kinetic studies revealed that compounds 6 and 31 exhibit competitive‐type reversible inhibition against both MAO‐A and MAO‐B, respectively. Structure–activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO‐B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π–π stacking and hydrogen bond interactions for effective stabilization of virtual ligand–protein complexes. Further optimization studies of compound 31 , including co‐crystallization of inhibitor–MAO‐B complexes, are essential to develop these compounds as potential therapeutic agents for MAO‐B‐associated neurodegenerative diseases. 相似文献
5.
Design,Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents
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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
6.
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
7.
Dr. Roberta Ettari Dr. Lucia Tamborini Dr. Ilenia C. Angelo Prof. Silvana Grasso Prof. Tanja Schirmeister Dr. Leonardo Lo Presti Prof. Carlo De Micheli Dr. Andrea Pinto Prof. Paola Conti 《ChemMedChem》2013,8(12):2070-2076
Novel rhodesain inhibitors were obtained by combining an enantiomerically pure 3‐bromoisoxazoline warhead with a specific peptidomimetic recognition moiety. All derivatives behaved as inhibitors of rhodesain, with low micromolar Ki values. Their activity against the enzyme was found to be paralleled by an in vitro antitrypanosomal activity, with IC50 values in the mid‐micromolar range. Notably, a preference for parasitic over human proteases, specifically cathepsins B and L, was observed. 相似文献
8.
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
9.
Marcel K. W. Mackwitz Eva Hesping Dr. Yevgeniya Antonova-Koch Dr. Daniela Diedrich Dr. Tamirat Gebru Woldearegai Assoc. Prof. Dr. Tina Skinner-Adams Mary Clarke Andrea Schöler Laura Limbach Prof. Dr. Thomas Kurz Prof. Dr. Elizabeth A. Winzeler Dr. Jana Held Prof. Dr. Katherine T. Andrews Prof. Dr. Finn K. Hansen 《ChemMedChem》2019,14(9):912-926
Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure–activity and structure–toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, with IC50 values in the range of 0.0052–0.25 μm and promising selectivity over mammalian cells (SIPf3D7/HepG2: 170–1483). In addition, several compounds showed encouraging sub-micromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide ( 2 h ) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC50 Pf3D7=0.0052 μm , IC50 PbEEF=0.016 μm ). 相似文献
10.
The inhibitors of histone deacetylases (HDACs) have drawn a great deal of attention due to their promising potential as small‐molecule therapeutics for the treatment of cancer. By means of virtual screening with docking simulations under consideration of the effects of ligand solvation, we were able to identify six novel HDAC inhibitors with IC50 values ranging from 1 to 100 μM . These newly identified inhibitors are structurally diverse and have various chelating groups for the active site zinc ion, including N‐[1,3,4]thiadiazol‐2‐yl sulfonamide, N‐thiazol‐2‐yl sulfonamide, and hydroxamic acid moieties. The former two groups are included in many drugs in current clinical use and have not yet been reported as HDAC inhibitors. Therefore, they can be considered as new inhibitor scaffolds for the development of anticancer drugs by structure–activity relationship studies to improve the inhibitory activities against HDACs. Interactions with the HDAC1 active site residues responsible for stabilizing these new inhibitors are addressed in detail. 相似文献
11.
Dr. Elena Casanova Dr. David Moreno Alba Gigante Dr. Eva Rico Carlos Mario Genes Cristina Oliva Prof. María‐José Camarasa Prof. Federico Gago Prof. Antonio Jiménez‐Ruiz Prof. María‐Jesús Pérez‐Pérez 《ChemMedChem》2013,8(7):1161-1174
Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3′‐O‐(isoleucylisoleucyl)‐5′‐O‐(3,3,3‐triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds. 相似文献
12.
Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis
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Mokhitli Morake Dr. Dina Coertzen Dr. Andile Ngwane Dr. Johannes F. Wentzel Dr. Ho Ning Wong Dr. Frans J. Smit Prof. Lyn‐Marie Birkholtz Ray‐Dean Pietersen Dr. Bienyameen Baker Prof. Ian Wiid Prof. David D. N'Da Prof. Richard K. Haynes 《ChemMedChem》2018,13(1):67-77
To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm . Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm , respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx. 相似文献
13.
Hariharan Moorthy Mamta Yadav Nitesh Tamang Sai Kiran Mavileti Labhini Singla Angshuman Roy Choudhury Dinkar Sahal Prof. Nageswara Rao Golakoti 《ChemMedChem》2023,18(1):e202200411
A series of 22 different 3,5-diarylidenetetrahydro-2H-pyran-4(3H)-ones (DATPs) were synthesized, characterized, and screened for their in vitro antiplasmodial activities against chloroquine (CQ)-sensitive Pf3D7, CQ-resistant PfINDO, and artemisinin-resistant PfMRA-1240 strains of Plasmodium falciparum. DATP 19 ( 3,5-bis(4-hydroxy-3,5-dimethoxybenzylidene)tetrahydro-2H-pyran-4(3H)-one) was found to be the most potent (IC50 1.07 μM) against PfMRA-1240, whereas 21 (3,5-bis(3,4,5-trimethoxybenzylidene)tetrahydro-2H-pyran-4(3H)-one) showed IC50 values of 1.72 and 1.44 μM against Pf3D7 and PfINDO, respectively. Resistance indices (RI) as low as 0.2 to 0.5 for 10 (3,5-bis(4-nitrobenzylidene)tetrahydro-2H-pyran-4(3H)-one) and 20 (3,5-bis(3-nitrobenzylidene)tetrahydro-2H-pyran-4(3H)-one), and <1 for most other DATPs reveals their greater potency against resistant strains than the sensitive one. The single-crystal XRD data for DATP 21 are reported. In silico support was obtained through docking studies. Killing all three strains within 4–8 h, these DATPs showed rapid kill kinetics toward the trophozoite stage. Furthermore, DATP 18 (3,5-bis(quinolin-4-ylmethylene)tetrahydro-2H-pyran-4(3H)-one) inhibited PfPdx1 enzyme activity with IC50 20.34 μM, which is about twofold lower than that (IC50 43 μM) for an already known inhibitor 4PEHz. At an oral dose of 300 mg/kg body weight, DATPs 19 and 21 were found to be nontoxic to mice, and at 100 mg/kg body weight, DATP 19 was found to suppress parasitaemia, which led to an increase in median survival time by three days relative to untreated control mice in a malaria curative study. 相似文献
14.
Florian Thaler Dr. Mario Varasi Dr. Andrea Colombo Dr. Roberto Boggio Dr. Davide Munari Dr. Nickolas Regalia Dr. Marco G. Rozio Dr. Veronica Reali Dr. Anna E. Resconi Dr. Antonello Mai Prof. Dr. Stefania Gagliardi Dr. Giulio Dondio Dr. Saverio Minucci Prof. Dr. Ciro Mercurio Dr. 《ChemMedChem》2010,5(8):1359-1372
A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at <100 nM in the HDAC inhibition assays, sub‐micromolar IC50 values in tests against three tumor cell lines, and remarkable stability in human and mouse microsomes was observed. Three representative compounds were selected for further characterization and submitted to a selectivity profile against a series of class I and class II HDACs as well as to preliminary in vivo pharmacokinetic (PK) experiments. Despite their high microsomal stability, the compounds showed medium‐to‐high clearance rates in in vivo PK studies as well as in rat and human hepatocytes, indicating that a major metabolic pathway is catalyzed by non‐microsomal enzymes. 相似文献
15.
Carbazole Aminoalcohols Induce Antiproliferation and Apoptosis of Human Tumor Cells by Inhibiting Topoisomerase I
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Dr. Weisi Wang Xiao Sun Deheng Sun Dr. Shizhu Li Yang Yu Tingyuan Yang Junmin Yao Dr. Zhuo Chen Dr. Liping Duan 《ChemMedChem》2016,11(24):2675-2681
Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine‐chain‐substituted compounds showed the most promising antiproliferative activity, with IC50 values in the single‐digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single‐strand DNA damage by stabilizing the topo I–DNA cleavage complex. In particular, the most potent compound, 1‐(butylamino)‐3‐(3,6‐dichloro‐9H‐carbazol‐9‐yl)propan‐2‐ol ( 6 ), was shown to be able to induce G2‐phase cell‐cycle arrest and apoptosis in HeLa cells. 相似文献
16.
Development of 3‐Phenyl‐N‐(2‐(3‐phenylureido)ethyl)‐thiophene‐2‐sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl‐2 Family Proteins
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Dr. Chengwen Yang Sha Chen Mi Zhou Dr. Yan Li Yangfeng Li Zhengxi Zhang Dr. Zhen Liu Dr. Qian Ba Dr. Jingquan Li Prof. Hui Wang Prof. Xiaomei Yan Prof. Dawei Ma Prof. Renxiao Wang 《ChemMedChem》2014,9(7):1436-1452
Antiapoptotic Bcl‐2 family proteins, such as Bcl‐xL, Bcl‐2, and Mcl‐1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure‐based virtual screening, a lead compound with micromolar binding affinity to Mcl‐1 (inhibition constant (Ki)=3 μM ). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl‐2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold‐hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence‐polarization binding assay to measure their binding affinities to Bcl‐xL, Bcl‐2, and Mcl‐1. Some of the compounds with a 3‐phenylthiophene‐2‐sulfonamide core moiety showed sub‐micromolar binding affinities to Mcl‐1 (Ki=0.3–0.4 μM ) or Bcl‐2 (Ki≈1 μM ). They also showed obvious cytotoxicity on tumor cells (IC50<10 μM ). Two‐dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW‐E5, YCW‐E10, and YCW‐E11, indicated that they bind to the BH3‐binding groove on Bcl‐xL in a similar mode to ABT‐737. Several apoptotic assays conducted on HL‐60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3‐phenylthiophene‐2‐sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl‐1 and Bcl‐2. 相似文献
17.
Dr. Florian C. Schrader Dr. Serghei Glinca Dr. Julia M. Sattler Dr. Hans‐Martin Dahse Gustavo A. Afanador Prof. Dr. Sean T. Prigge Prof. Dr. Michael Lanzer Dr. Ann‐Kristin Mueller Prof. Dr. Gerhard Klebe Prof. Dr. Martin Schlitzer 《ChemMedChem》2013,8(3):442-461
Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood‐ and pre‐erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver‐stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood‐stage parasite growth with IC50 values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver‐stage parasites than the gold‐standard drug, primaquine. 相似文献
18.
A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC50 values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide ( 3 ) was identified as a lead AChE inhibitor with IC50=0.052±0.006 μm . N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide ( 2 ) was the lead MAO-B inhibitor with IC50=0.034±0.007 μm , and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents. 相似文献
19.
Dr. Ahmed Kamal G. Bharath Kumar Sowjanya Polepalli Anver Basha Shaik Vangala Santhosh Reddy M. Kashi Reddy Ch. Ratna Reddy Rasala Mahesh Jeevak Sopanrao Kapure Dr. Nishant Jain 《ChemMedChem》2014,9(11):2565-2579
A series of aminostilbene—arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI50) values in the range from <0.01 to 19.9 μM . One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI50 value of <0.01 μM . All of the synthesized compounds displayed cytotoxicity against A549 (non‐small‐cell lung cancer), HeLa (cervical carcinoma), MCF‐7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC50) values ranging from 0.011 to 8.56 μM . A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79 μM . Moreover, dot‐blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin. 相似文献
20.
Dr. Jozef Stec Alina Fomovska Gustavo A. Afanador Prof. Dr. Stephen P. Muench Dr. Ying Zhou Bo‐Shiun Lai Prof. Dr. Kamal El Bissati Dr. Mark R. Hickman Patty J. Lee Susan E. Leed Jennifer M. Auschwitz Dr. Caroline Sommervile Dr. Stuart Woods Prof. Dr. Craig W. Roberts Prof. Dr. David Rice Dr. Sean T. Prigge Dr. Rima McLeod Prof. Dr. Alan P. Kozikowski 《ChemMedChem》2013,8(7):1138-1160
Through our focused effort to discover new and effective agents against toxoplasmosis, a structure‐based drug design approach was used to develop a series of potent inhibitors of the enoyl‐acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well‐known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM , respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme‐based assay. With respect to their excellent in vitro activity as well as improved drug‐like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections. 相似文献