共查询到20条相似文献,搜索用时 87 毫秒
1.
Dr. Dinakaran Murugesan Dr. Marcel Kaiser Dr. Karen L. White Suzanne Norval Jennifer Riley Prof. Paul G. Wyatt Prof. Susan A. Charman Dr. Kevin D. Read Dr. Clive Yeates Prof. Ian H. Gilbert 《ChemMedChem》2013,8(9):1537-1544
Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure–activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine‐ and pyrimethamine‐resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival. 相似文献
2.
Sergio A. Caldarelli Dr. Jean‐Frédéric Duckert Dr. Sharon Wein Michèle Calas Prof. Christian Périgaud Prof. Henri Vial Dr. Suzanne Peyrottes Dr. 《ChemMedChem》2010,5(7):1102-1109
An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis‐thiazolium salts were shown to block proliferation of the malaria parasite at concentrations in the low nanomolar range. However, due to unsuitable molecular properties such as the presence of the two polar heads and flexibility in the linker, these compounds have low oral bioavailability. To characterize the structural requirements of the linker that lead to more rigid analogues with fewer rotatable bonds but which retain antimalarial activity, a new series of compounds incorporating an aryl moiety and eventually oxygen atoms were prepared, and their biological activity was evaluated. Structure–activity relationships suggest that the optimal linker construct is an aromatic group with two n‐butyl chains branched at the para position; two new leads (compounds 39 and 40 ) were selected for further development. 相似文献
3.
Caroline de Souza Pereira Helenita Costa Quadros Dr. Diogo Rodrigo Magalhaes Moreira Dr. William Castro Romulo Ivisson Santos De Deus Da Silva Dr. Milena Botelho Pereira Soares Dr. Diana Fontinha Dr. Miguel Prudêncio Vinicius Schmitz Prof. Hélio F. Dos Santos Mathieu Gendrot Isabelle Fonta Joel Mosnier Dr. Bruno Pradines Prof. Maribel Navarro 《ChemMedChem》2021,16(4):662-678
Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ-gold(I) hybrid molecule affects essential parasite targets, it inhibits β-hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ-gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood-stage of Plasmodium falciparum and liver-stage of Plasmodium berghei and efficacy in vivo against P. berghei, thereby demonstrating its multiple-stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria. 相似文献
4.
Enantiopure Indolizinoindolones with in vitro Activity against Blood‐ and Liver‐Stage Malaria Parasites
下载免费PDF全文
![点击此处可从《ChemMedChem》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nuno A. L. Pereira Ângelo Monteiro Marta Machado Dr. Jiri Gut Dr. Elies Molins Dr. M. Jesus Perry Jorge Dourado Dr. Rui Moreira Dr. Philip J. Rosenthal Dr. Miguel Prudêncio Dr. Maria M. M. Santos 《ChemMedChem》2015,10(12):2080-2089
Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good‐to‐excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)‐ or (R)‐tryptophanol and 2‐acyl benzoic acids, followed by intramolecular α‐amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b‐cis indolizinoindolones in a two‐step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)‐tryptophanol‐derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite′s life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro. 相似文献
5.
Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action
下载免费PDF全文
![点击此处可从《ChemMedChem》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Christoph Boss Dr. Hamed Aissaoui Nathalie Amaral Aude Bauer Stephanie Bazire Dr. Christoph Binkert Prof. Reto Brun Dr. Cédric Bürki Dr. Claire‐Lise Ciana Dr. Olivier Corminboeuf Stephane Delahaye Claire Dollinger Christoph Fischli Dr. Walter Fischli Alexandre Flock Dr. Marie‐Céline Frantz Malory Girault Dr. Corinna Grisostomi Astrid Friedli Dr. Bibia Heidmann Claire Hinder Gael Jacob Amelie Le Bihan Sophie Malrieu Dr. Saskia Mamzed Aurelien Merot Dr. Solange Meyer Dr. Sabrina Peixoto Nolwenn Petit Dr. Romain Siegrist Julien Trollux Dr. Thomas Weller Dr. Sergio Wittlin 《ChemMedChem》2016,11(18):1995-2014
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub‐Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine‐based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT‐451840 [(S,E)‐N‐(4‐(4‐acetylpiperazin‐1‐yl)benzyl)‐3‐(4‐(tert‐butyl)phenyl)‐N‐(1‐(4‐(4‐cyanobenzyl)piperazin‐1‐yl)‐1‐oxo‐3‐phenylpropan‐2‐yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. 相似文献
6.
Design,Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents
下载免费PDF全文
![点击此处可从《ChemMedChem》网站下载免费的PDF全文](/ch/ext_images/free.gif)
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
7.
N‐Cinnamoylation of Antimalarial Classics: Quinacrine Analogues with Decreased Toxicity and Dual‐Stage Activity
下载免费PDF全文
![点击此处可从《ChemMedChem》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Ana Gomes Bianca Pérez Inês Albuquerque Dr. Miguel Prudêncio Dr. Fátima Nogueira Dr. Cátia Teixeira Prof. Dr. Paula Gomes 《ChemMedChem》2014,9(2):305-310
Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N‐cinnamoylated quinacrine surrogates, 9‐(N‐cinnamoylaminobutyl)‐amino‐6‐chloro‐2‐methoxyacridines, is reported. The compounds were found to be highly potent against both blood‐stage P. falciparum, chloroquine‐sensitive 3D7 (IC50=17.0–39.0 nM ) and chloroquine‐resistant W2 and Dd2 strains (IC50=3.2–41.2 and 27.1–131.0 nM , respectively), and liver‐stage P. berghei (IC50=1.6–4.9 μM ) parasites. These findings bring new hope for the possible future “rise of a fallen angel” in antimalarial chemotherapy, with a potential resurgence of quinacrine‐related compounds as dual‐stage antimalarial leads. 相似文献
8.
Dr. Ivan Bassanini Dr. Silvia Parapini Dr. Corinna Galli Dr. Nadia Vaiana Dr. Andrea Pancotti Prof. Nicoletta Basilico Prof. Donatella Taramelli Prof. Sergio Romeo 《ChemMedChem》2019,14(23):1982-1994
The treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is currently compromised by the dramatic increase and diffusion of drug resistance among the various species of Plasmodium, especially P. falciparum (Pf). In this view, the development of new antiplasmodial agents that are able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments. In one of our previous communications, we described a novel class of compounds endowed with high antiplasmodial activity, characterized by a pharmacophore never described before as antiplasmodial and identified by their 4,4’-oxybisbenzoyl amide cores. Here, through a detailed structure-activity relationship (SAR) study, we thoroughly investigated the chemical features of the reported scaffolds and successfully built a novel antiplasmodial agent active on both chloroquine (CQ)-sensitive and CQ-resistant Pf strains in the low nanomolar range, without displaying cross-resistance. Moreover, we conducted an in silico pharmacophore mapping. 相似文献
9.
Prof. Dr. Emily R. Derbyshire Dr. Vanessa Zuzarte‐Luís Dr. Andreia D. Magalhães Dr. Nobutaka Kato Dr. Paul C. Sanschagrin Dr. Jinhua Wang Dr. Wenjun Zhou Dr. Chandrasekhar V. Miduturu Prof. Dr. Ralph Mazitschek Prof. Dr. Piotr Sliz Prof. Dr. Maria M. Mota Prof. Dr. Nathanael S. Gray Prof. Dr. Jon Clardy 《Chembiochem : a European journal of chemical biology》2014,15(13):1920-1930
Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small‐molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood‐stage malaria. Most of the screening hits inhibited both liver‐ and blood‐stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin‐dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide‐3‐kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual‐stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development. 相似文献
10.
Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites
下载免费PDF全文
![点击此处可从《ChemMedChem》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Marta P. Carrasco Marta Machado Dr. Lídia Gonçalves Dr. Moni Sharma Dr. Jiri Gut Dr. Amanda K. Lukens Prof. Dyann F. Wirth Dr. Vânia André Prof. Maria Teresa Duarte Dr. Rita C. Guedes Dr. Daniel J. V. A. dos Santos Prof. Philip J. Rosenthal Prof. Ralph Mazitschek Dr. Miguel Prudêncio Prof. Rui Moreira 《ChemMedChem》2016,11(19):2194-2204
The potential of azaaurones as dual‐stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine‐resistant Plasmodium falciparum strain and the liver stage of P. berghei, yielding compounds with dual‐stage activity and sub‐micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P. falciparum Dd2‐ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron‐transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual‐stage antimalarials. 相似文献
11.
Paolo Coghi Dr. Nicoletta Basilico Dr. Donatella Taramelli Prof. Wing‐Chi Chan Richard K. Haynes Prof. Diego Monti Prof. 《ChemMedChem》2009,4(12):2045-2053
In line with the enhancement of antimalarial activities of the current clinical artemisinins against parasites cultured under CO, the artemisinins are unaffected in vitro by carboxyhemoglobin (CO–Hb–FeII) or CO–heme–FeII, but are competitively decomposed by Hb–FeII or heme–FeII. In the latter case, the heme studies are greatly facilitated by solubilization of the heme in aqueous medium by use of arginine. None of the Hb species has an appreciable effect on artemisone, or on other aminoartemisinins, and antimalarial activities are either less affected or remain essentially unchanged against parasites cultured under standard microaerophilic conditions or under CO. The findings not only indicate that artemisinins do not require Hb–FeII or heme–FeII for promotion of antimalarial activity, but are also important in relation to the therapy of severe/complicated or cerebral malaria. 相似文献
12.
Philipp Walloch Christian Hansen Till Priegann Prof. Dr. Dennis Schade Prof. Eric Beitz 《ChemMedChem》2021,16(8):1283-1289
The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub-Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate–nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro-3-hydroxy-pent-2-en-1-ones, we discovered PfFNT inhibitors that potently kill P. falciparum parasites in vitro. Four additional human-pathogenic Plasmodium species require attention, that is, P. vivax, most prevalent outside of Africa, and the regional P. malariae, P. ovale and P. knowlesi. Herein, we show that the plasmodial FNT variants are highly similar in terms of protein sequence and functionality. The FNTs from all human-pathogenic plasmodia and the rodent malaria parasite were efficiently inhibited by pentafluoro-3-hydroxy-pent-2-en-1-ones. We further established a phenotypic yeast-based FNT inhibitor screen, and found very low compound cytotoxicity and monocarboxylate transporter 1 off-target activity on human cells, particularly of the most potent FNT inhibitor BH267.meta, allowing these compounds to proceed towards animal model malaria studies. 相似文献
13.
Neil R. Norcross Caroline Wilson Beatriz Baragaña Irene Hallyburton Maria Osuna-Cabello Suzanne Norval Jennifer Riley Daniel Fletcher Robert Sinden Michael Delves Andrea Ruecker Sandra Duffy Stephan Meister Yevgeniya Antonova-Koch Benigno Crespo Cristina de Cózar Laura M. Sanz Francisco Javier Gamo Vicky M. Avery Julie A. Frearson David W. Gray Alan H. Fairlamb Elizabeth A. Winzeler David Waterson Simon F. Campbell Paul A. Willis Kevin D. Read Ian H. Gilbert 《ChemMedChem》2019,14(14):1329-1335
Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28 ) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm . Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification. 相似文献
14.
Dr. Rob Hoen Dr. Eva Maria Novoa Alba López Noelia Camacho Dr. Laia Cubells Pedro Vieira Prof. Manuel Santos Patricia Marin‐Garcia Prof. Jose Maria Bautista Prof. Alfred Cortés Prof. Lluís Ribas de Pouplana Dr. Miriam Royo 《Chembiochem : a European journal of chemical biology》2013,14(4):499-509
The resistance of malaria parasites to available drugs continues to grow, and this makes the need for new antimalarial therapies pressing. Aminoacyl‐tRNA synthetases (ARSs) are essential enzymes and well‐established antibacterial targets and so constitute a promising set of targets for the development of new antimalarials. Despite their potential as drug targets, apicoplastic ARSs remain unexplored. We have characterized the lysylation system of Plasmodium falciparum, and designed, synthesized, and tested a set of inhibitors based on the structure of the natural substrate intermediate: lysyl‐adenylate. Here we demonstrate that selective inhibition of apicoplastic ARSs is feasible and describe new compounds that that specifically inhibit Plasmodium apicoplastic lysyl‐tRNA synthetase and show antimalarial activities in the micromolar range. 相似文献
15.
Fatima Bousejra‐El Garah Jean‐Luc Stigliani Dr. Frédéric Coslédan Dr. Bernard Meunier Dr. Anne Robert Dr. 《ChemMedChem》2009,4(9):1469-1479
PfATP6, a calcium‐dependent ATPase of Plasmodium falciparum, is considered the putative target of the antimalarial drug artemisinin and its derivatives. Herein, the 3D structure of PfATP6 was modeled on the basis of the crystal structure of SERCA 1a, the mammalian homologue. Model validation was achieved using protein structure checking tools. AutoDock4 was used to predict the binding affinities of artemisinin (and analogues) and various other antimalarial agents for PfATP6, for which in vitro activity is also reported. No correlation was found between the affinity of the compounds for PfATP6 predicted by AutoDock4 and their antimalarial activity. 相似文献
16.
Endah Dwi Hartuti Takaya Sakura Mohammed S. O. Tagod Eri Yoshida Xinying Wang Kota Mochizuki Rajib Acharjee Yuichi Matsuo Fuyuki Tokumasu Mihoko Mori Danang Waluyo Kazuro Shiomi Tomoyoshi Nozaki Shinjiro Hamano Tomoo Shiba Kiyoshi Kita Daniel Ken Inaoka 《International journal of molecular sciences》2021,22(13)
Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development. 相似文献
17.
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
18.
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
19.
Marimuthu Sekar Karnam J. Rajendra Prasad 《Journal of chemical technology and biotechnology (Oxford, Oxfordshire : 1986)》1998,72(1):50-54
The 2-chloro-3-formyl quinoline derivatives ( 1a–e ) on treatment with acetic anhydride and sodium acetate, afforded the corresponding novel 2-oxo-pyrano(2,3-b) quinoline derivatives ( 2a–e ), and these were subjected to ammonia treatment to yield the corresponding naphthyridine derivatives ( 3a–e ). The prepared compounds ( 2a–e ) were tested for their antimalarial, diuretic, clastogenic and antimicrobial properties. Not all the compounds showed a diuretic effect and the significant increase in the frequency of micronuclei shows that they are non-clastogens, whereas the 7-chloro derivative ( 2e ) was a very effective antimalarial agent against the mosquito species. All the compounds were found to have optimum antimicrobial activity against Staphylococcus aureus, Escherichia coli and Salmonella typhi. Compounds 2d and 2e were found to be most active against the bacteria tested. © 1998 SCI 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