Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials.
Paul M O'Neill, Amira Mukhtar, Paul A Stocks, Laura E Randle, Stephen Hindley, Stephen A Ward, Richard C Storr, Jamie F Bickley, Ian A O'Neil, James L Maggs, Ruth H Hughes, Peter A Winstanley, Patrick G Bray, B Kevin Park
Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK. email@example.com
Amodiaquine (AQ)(2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a))(IC(50)= 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED(50) activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.
PLoS One. 2012 ;7 (4):e35019 22514702
Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence "transmission blocking" assay.
Joël Lelièvre, Maria Jesus Almela, Sonia Lozano, Celia Miguel, Virginia Franco, Didier Leroy, Esperanza Herreros
GlaxoSmithKline R&D, Tres Cantos Medicine Development Campus, Malaria Discovery Performance Unit, Madrid, Spain. Joel.firstname.lastname@example.org
BACKGROUND Current anti-malarial drugs have been selected on the basis of their activity against the symptom-causing asexual blood stage of the parasite. Which of these drugs also target gametocytes, in the sexual stage responsible for disease transmission, remains unknown. Blocking transmission is one of the main strategies in the eradication agenda and requires the identification of new molecules that are active against gametocytes. However, to date, the main limitation for measuring the effect of molecules against mature gametocytes on a large scale is the lack of a standardized and reliable method. Here we provide an efficient method to produce and purify mature gametocytes in vitro. Based on this new procedure, we developed a robust, affordable, and sensitive ATP bioluminescence-based assay. We then assessed the activity of 17 gold-standard anti-malarial drugs on Plasmodium late stage gametocytes. METHODS AND FINDINGS Difficulties in producing large amounts of gametocytes have limited progress in the development of malaria transmission blocking assays. We improved the method established by Ifediba and Vanderberg to obtain viable, mature gametocytes en masse, whatever the strain used. We designed an assay to determine the activity of antimalarial drugs based on the intracellular ATP content of purified stage IV-V gametocytes after 48 h of drug exposure in 96/384-well microplates. Measurements of drug activity on asexual stages and cytotoxicity on HepG2 cells were also obtained to estimate the specificity of the active drugs. CONCLUSIONS The work described here represents another significant step towards determination of the activity of new molecules on mature gametocytes of any strain with an automated assay suitable for medium/high-throughput screening. Considering that the biology of the forms involved in the sexual and asexual stages is very different, a screen of our 2 million-compound library may allow us to discover novel anti-malarial drugs to target gametocyte-specific metabolic pathways.
Antimalarial drugs and their useful therapeutic lives: rational drug design lessons from pleiotropic action of quinolines and artemisinins.
Department of Infectious Diseases, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu 431-3192, Japan. email@example.com
Efforts to develop an effective malarial vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Unfortunately, Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to classical antimalarials, necessitating a search for new chemotherapeutics preferably with novel modes of action. Today, rational drug discovery strategy is gaining new impetus as knowledge of malaria parasite biology expands, aided by the parasite genome database and improved bioinformatics tools. Drug development is a laborious, time consuming and costly process, and thus the "useful therapeutic lives"(UTLs) of new drugs should be commensurate with the resources invested in their development. Historical evidence on development and evolution of resistance to classical antimalarial drugs shows that the mode of action of a drug influences its UTL. Drugs that target single and specific targets such as antimalarial antifolates and atovaquone (ATQ) are rendered ineffective within a short time of their clinical use, unlike drugs with pleiotropic action such as chloroquine (CQ) and artemisinins (ART) with long UTLs. Unfortunately, almost all new targets currently being explored for development of novel drugs belong to the "specific target" other than the "multiple target" category, and is plausible that such drugs will have short UTLs. This review relates the pleiotropic action of CQ and ART with their long UTLs, and discusses their relevance in rational drug development strategies. Novel targets with potential to yield drugs with long UTLs are also explored.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
The quinoline scaffold is prevalent in a variety of pharmacologically active synthetic and natural compounds. The discovery of chloroquine, the most famous drug containing this scaffold resulted in control and eradication of malaria for decades. The other known antimalarial drugs from the quinoline family include: quinine, amodiaquine, piperaquine, primaquine, and mefloquine. The drugs from this group mostly act during the blood stages of the parasite's life cycle but some like primaquine targets the tissue stages. This review provides a comprehensive literature compilation concerning the study of quinolines and also other heterocycles structurally similar to quinoline scaffold in the treatment of malaria. This review covers advances made in the last ten years and it is subdivided into eight sub-headings. It consists of discussion on the biological activities, structure-activity relationship, and potential biochemical pathways of 4-aminoquinolines, 4-anilinoquinolines, 8-aminoquinolines, quinolines from nature, quinolones, isoquinolines and tetrahydroquinolines, ring-modified quinolines, and miscellaneous quinolines.
Department of Pharmacology and Therapeutics, Centre for Drug Safety Science, School of Biomedical Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, UK.
Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.
Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and development.
Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University, Pathumtanee, Thailand. firstname.lastname@example.org
Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to currently used antimalarials, and the lack of affordable new drugs are the limiting factors in the fight against malaria. In addition, other problems with some existing agents include unfavorable pharmacokinetic properties and adverse effects/toxicity. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. In recent years, major advances have been made in the pharmacology of several antimalarial drugs both in pharmacokinetics and pharmacodynamics aspects. These include the design, development, and optimization of appropriate dosage regimens of antimalarials, basic knowledge in metabolic pathways of key antimalarials, as well as the elucidation of mechanisms of action and resistance of antimalarials. Pharmacologists have been working in close collaboration with scientists in other disciplines of science/biomedical sciences for more understanding on the biology of the parasite, host, in order to exploit rational design of drugs. Multiple general approaches to the identification of new antimalarials are being pursued at this time. All should be implemented in parallel with focus on the rational development of new agents directed against newly identified parasite targets. With major advances in our understanding of malaria parasite biology coupled with the completion of the malaria genome, has presented exciting opportunities for target-based antimalarial drug discovery.
In vivo and in vitro efficacy of amodiaquine against Plasmodium falciparum in an area of continued use of 4-aminoquinolines in East Africa.
Philip Sasi, Abdi Abdulrahaman, Leah Mwai, Steven Muriithi, Judith Straimer, Elise Schieck, Anja Rippert, Mahfudh Bashraheil, Amina Salim, Judith Peshu, Ken Awuondo, Brett Lowe, Munir Pirmohamed, Peter Winstanley, Steve Ward, Alexis Nzila, Steffen Borrmann
Kenya Medical Research Institute, Center for Geographic Medicine Research-Coast, Kilifi, Kenya.
In light of reports of increasing resistance of parasites to amodiaquine in African countries in which Plasmodium falciparum is endemic as well as the paucity of recent in vitro sensitivity data, we assessed the in vivo and in vitro sensitivity to amodiaquine of P. falciparum isolates from 128 pediatric outpatients (0.5-10 years old) in Pingilikani, Kilifi District, Kenya, who were treated with amodiaquine (10 mg/kg/day for 3 days). The polymerase chain reaction-corrected parasitological cure rate on day 28 (by Kaplan-Meier analysis) was 82%(95% confidence interval [CI], 74%-88%). Twenty-six percent (17/66) of tested pretreatment P. falciparum field isolates had 50% in vitro growth inhibition at concentrations of N-desethyl-amodiaquine (DEAQ)-the major biologically active metabolite of amodiaquine-above the proposed resistance threshold of 60 nmol/L, but baseline median DEAQ 50% inhibitory concentration values were not associated with subsequent risk of asexual parasite recrudescence (29 nmol/L [95% CI, 23-170 nmol/L] and 34 nmol/L [95% CI, 30-46 nmol/L] for patients with and those without recrudescences, respectively). The median absolute neutrophil count dropped by 1.3 X 10(3) cells/microL (95% CI,-1.7 X 10(3) to -0.7 X 10(3) cells/microL) between days 0 and 28. The high prevalence of in vitro and in vivo resistance precludes the use of amodiaquine on its own as second-line treatment. These findings also suggest that the value of amodiaquine combinations as first- or second-line treatment in areas with similar patterns of 4-aminoquinoline resistance should be reassessed.
UNICEF/UNDP/WB/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland. email@example.com
With the elimination of malaria now considered a realistic goal, it would be useful for scientists and policy makers to have an inventory of the arsenal of antimalarials, current and prospective, that could help make this goal a reality. In order to provide an overview of antimalarial projects in recent clinical development, we review here the global portfolio of antimalarial drugs in clinical phases of development complemented by projects in the preclinical and early discovery phases. The portfolio is discussed in terms of the novelty of the new molecules and their potential health impact in terms of addressing the requirements for the control and eventual eradication of malaria.
Recent developments in the design and synthesis of hybrid molecules basedon aminoquinoline ring and their antiplasmodial evaluation.
Laboratorio de Química Orgánica y Biomolecular, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia.
A short history of hybrid molecules based on aminoquinolines gave interesting and important information useful for organic and medicinal chemistry, which are deeply involved in the design and development of new antimalarial agents. The highlights in the preparation of aminoquinoline antimalarials, their protocols and antiplasmodial activity and, specially, the development on hybridization approaches are represented.
UMR CNRS 8161 - Universités de Lille I & II - Institut Pasteur de Lille, 1 rue du Professeur Calmette, B.P. 447, 59021 Lille cedex, France.
Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development.
Comparative preclinical drug metabolism and pharmacokinetic evaluation of novel 4-aminoquinoline anti-malarials.
Charles B Davis, Ramesh Bambal, Ganesh S Moorthy, Erin Hugger, Hong Xiang, Brian Kevin Park, Allison E Shone, Paul M O'Neill, Stephen A Ward
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Drug Discovery, 1250 South Collegeville Rd, Collegeville, Pennsylvania 19426, USA. firstname.lastname@example.org
The disposition of three 4-aminoquinoline leads, namely isoquine (ISO), des-ethyl isoquine (DEI) and N-tert-butyl isoquine (NTBI), were studied in a range of in vivo and in vitro assays to assist in selecting an appropriate candidate for further development. Analogous to amodiaquine (ADQ), ISO undergoes oxidative N-dealkylation to form DEI in vivo. Blood clearance of DEI was as much as 10-fold lower than that of ISO in animals and after oral administration, metabolite exposure exceeded that of parent by as much as 14-fold. Replacement of the N-ethyl with an N-tert-butyl substituent substantially reduced N-dealkylation as blood clearance of NTBI was approximately 2 to 3-fold lower than DEI in mouse, rat, dog and monkey. Mean NTBI oral bioavailability was generally higher than the other leads (>/=68%). Blood cell association was substantial for NTBI, particularly in dog and monkey, where blood to plasma concentration ratios >4 were observed. Human plasma protein binding was similar for NTBI, DEI, and des-ethyl amodiaquine (DEA). Allometric scaling predicted human blood clearance (CL) for NTBI to be low ( approximately 12% liver blood flow). All the 4-aminoquinolines inhibited recombinant human cytochrome P450 2D6 with similar potency; DEI also inhibited 1A2. On balance, NTBI appeared the most promising lead to progress towards full development.
Other papers by authors:
Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.
Paul M O'Neill, B Kevin Park, Alison E Shone, James L Maggs, Phillip Roberts, Paul A Stocks, Giancarlo A Biagini, Patrick G Bray, Peter Gibbons, Neil Berry, Peter A Winstanley, Amira Mukhtar, Richard Bonar-Law, Stephen Hindley, Ramesh B Bambal, Charles B Davis, Martin Bates, Timothy K Hart, Stephanie L Gresham, Ron M Lawrence, Richard A Brigandi, Federico M Gomez-delas-Heras, Domingo V Gargallo, Stephen A Ward
Department of Chemistry, University of Liverpool, Liverpool, United Kingdom. email@example.com
N-tert-Butyl isoquine (4)(GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine.
Paul M O'Neill, Alison E Shone, Deborah Stanford, Gemma Nixon, Eghbaleh Asadollahy, B Kevin Park, James L Maggs, Phil Roberts, Paul A Stocks, Giancarlo Biagini, Patrick G Bray, Jill Davies, Neil Berry, Charlotte Hall, Karen Rimmer, Peter A Winstanley, Stephen Hindley, Ramesh B Bambal, Charles B Davis, Martin Bates, Stephanie L Gresham, Richard A Brigandi, Federico M Gomez-de-Las-Heras, Domingo V Gargallo, Silvia Parapini, Livia Vivas, Hollie Lander, Donatella Taramelli, Stephen A Ward
Department of Chemistry, University of Liverpool, Liverpool, UK.
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.
Stephen Hindley, Stephen A Ward, Richard C Storr, Natalie L Searle, Patrick G Bray, B Kevin Park, Jill Davies, Paul M O'Neill
Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK.
The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.
Michael Jones, Amy E Mercer, Paul A Stocks, Louise J I La Pensée, Rick Cosstick, B Kevin Park, Miriam E Kennedy, Ivo Piantanida, Stephen A Ward, Jill Davies, Patrick G Bray, Sarah L Rawe, Jonathan Baird, Tafadzwa Charidza, Omar Janneh, Paul M O'Neill
Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK.
Artemisinin-acridine hybrids were prepared and evaluated for their in vitro activity against tumour cell lines and a chloroquine sensitive strain of Plasmodium falciparum. They showed a 2-4-fold increase in activity against HL60, MDA-MB-231 and MCF-7 cells in comparison with dihydroartemisinin (DHA) and moderate antimalarial activity. Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle.
Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs.
Paul A Stocks, Patrick G Bray, Victoria E Barton, Mohammed Al-Helal, Michael Jones, Nuna C Araujo, Peter Gibbons, Stephen A Ward, Ruth H Hughes, Giancarlo A Biagini, Jill Davies, Richard Amewu, Amy E Mercer, Gemma Ellis, Paul M O'Neill
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX.
Patrick G Bray, Mathirut Mungthin, Ian M Hastings, Giancarlo A Biagini, Dauda K Saidu, Viswanathan Lakshmanan, David J Johnson, Ruth H Hughes, Paul A Stocks, Paul M O'Neill, David A Fidock, David C Warhurst, Stephen A Ward
Department of Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. firstname.lastname@example.org
It is accepted that resistance of Plasmodium falciparum to chloroquine (CQ) is caused primarily by mutations in the pfcrt gene. However, a consensus has not yet been reached on the mechanism by which resistance is achieved. CQ-resistant (CQR) parasite lines accumulate less CQ than do CQ-sensitive (CQS) parasites. The CQR phenotype is complex with a component of reduced energy-dependent CQ uptake and an additional component that resembles energy-dependent CQ efflux. Here we show that the required energy input is in the form of the proton electrochemical gradient across the digestive vacuole (DV) membrane. Collapsing the DV proton gradient (or starving the parasites of glucose) results in similar levels of CQ accumulation in CQS and CQR lines. Under these conditions the accumulation of CQ is stimulated in CQR parasite lines but is reduced in CQS lines. Energy deprivation has no effect on the rate of CQ efflux from CQR lines implying that mutant PfCRT does not function as an efflux pump or active carrier. Using pfcrt-modified parasite lines we show that the entire CQ susceptibility phenotype is switched by the single K76T amino acid change in PfCRT. The efflux of CQ in CQR lines is not directly coupled to the energy supply, consistent with a model in which mutant PfCRT functions as a gated channel or pore, allowing charged CQ species to leak out of the DV.
Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore.
Paul M O'Neill, Amira Mukhtar, Stephen A Ward, Jamie F Bickley, Jill Davies, Mario D Bachi, Paul A Stocks
Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, UK. email@example.com
[reaction: see text] Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates alpha-hydroxyperoxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.
Paul M O'Neill, Paul A Stocks, Matthew D Pugh, Nuna C Araujo, Edward E Korshin, Jamie F Bickley, Stephen A Ward, Patrick G Bray, Erica Pasini, Jill Davies, Edite Verissimo, Mario D Bachi
Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK. firstname.lastname@example.org
Novel short chain chloroquine analogues retain activity against chloroquine resistant K1 Plasmodium falciparum.
Department of Chemistry, The University of Liverpool, United Kingdom.
A series of short chain chloroquine (CQ) derivatives have been synthesized in one step from readily available starting materials. The diethylamine function of CQ is replaced by shorter alkylamine groups (4-9) containing secondary or tertiary terminal nitrogens. Some of these derivatives are significantly more potent than CQ against a CQ resistant strain of Plasmodium falciparum in vitro. We conclude that the ability to accumulate at higher concentrations within the food vacuole of the parasite is an important parameter that dictates their potency against CQ sensitive and the chloroquine resistant K1 P. falciparum.
The molecular basis of folate salvage in Plasmodium falciparum: characterization of two folate transporters.
J Enrique Salcedo-Sora, Edwin Ochong, Susan Beveridge, David Johnson, Alexis Nzila, Giancarlo A Biagini, Paul A Stocks, Paul M O'Neill, Sanjeev Krishna, Patrick G Bray, Stephen A Ward
Molecular and Biochemical Parasitology Group, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
Tetrahydrofolates are essential cofactors for DNA synthesis and methionine metabolism. Malaria parasites are capable both of synthesizing tetrahydrofolates and precursors de novo and of salvaging them from the environment. The biosynthetic route has been studied in some detail over decades, whereas the molecular mechanisms that underpin the salvage pathway lag behind. Here we identify two functional folate transporters (named PfFT1 and PfFT2) and delineate unexpected substrate preferences of the folate salvage pathway in Plasmodium falciparum. Both proteins are localized in the plasma membrane and internal membranes of the parasite intra-erythrocytic stages. Transport substrates include folic acid, folinic acid, the folate precursor p-amino benzoic acid (pABA), and the human folate catabolite pABAG(n). Intriguingly, the major circulating plasma folate, 5-methyltetrahydrofolate, was a poor substrate for transport via PfFT2 and was not transported by PfFT1. Transport of all folates studied was inhibited by probenecid and methotrexate. Growth rescue in Escherichia coli and antifolate antagonism experiments in P. falciparum indicate that functional salvage of 5-methyltetrahydrofolate is detectable but trivial. In fact pABA was the only effective salvage substrate at normal physiological levels. Because pABA is neither synthesized nor required by the human host, pABA metabolism may offer opportunities for chemotherapeutic intervention.
Latest similar papers:
Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models.
Sunetra Ray, Peter B Madrid, Paul Catz, Susanna E Levalley, Michael J Furniss, Linda L Rausch, R Kiplin Guy, Joseph L Derisi, Lalitha V Iyer, Carol E Green, Jon C Mirsalis
SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025.
Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability. Yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMET prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC(50) values of 5.6 and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (for CQ, IC(50)= 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials.
Synthesis of novel thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline as potent antimalarials.
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India.
In search of new 4-aminoquinolines which are not recognized by CQR mechanism, thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities. Thiourea derivative 3 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro model with an IC(50) of 6.07ng/mL and also showed an in vivo suppression of 99.27% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.
Replacement of the 4'-hydroxy group of amodiaquine and amopyroquine by aromatic and aliphatic substituents: synthesis and antimalarial activity.
Emilia Păunescu, Sophie Susplugas, Emmanuelle Boll, Richard Varga, Elisabeth Mouray, Ion Grosu, Philippe Grellier, Patricia Melnyk
UMR CNRS - Universités de Lille I & II - IPL, France.
The prophylactic administration of amodiaquine (AQ), a 4-aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone-imine, an electrophilic metabolite. Replacement of the 4'-hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4'-position were synthesized using Csp(2)-Csp(2) and Csp(2)-Csp(3) 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 IC(50) values in the range of 7-200 nM. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit beta-hematin formation in vitro. A detailed investigation of the structure-activity relationships for these new compounds was carried out; the 4'-methyl compound showed interesting in vivo antimalarial activity.
Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, School of Pharmacy, University of Mississippi, University, Mississippi 386771, USA.
In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn(2+) complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC(50)s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [(3)H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose,<or=1.1 mg/kg when given orally); no apparent toxicity has been observed up to the highest dose tested (3 x 30 mg/kg). The bisquinoline inhibits in vitro hemozoin (beta-hematin) formation with an IC(50) of 1.1 microM, which is about 10-fold more potent than chloroquine (IC(50) 9.5 microM). Overall, this article describes the discovery of a new class of cyclen 4-aminoquinoline analogs as potent antimalarial drugs.
Clive Yeates, John Batchelor, Edward Capon, Neil Cheesman, Mitch Fry, Alan Hudson, Mary Pudney, Helen Trimming, James Woolven, José Bueno, Jesús Chicharro, Esther Fernández, José Fiandor, Domingo Gargallo-Viola, Federico Gómez de Las Heras, Esperanza Herreros, María León
A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC 50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED 50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc 1 complex.
Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum.
Wolfgang Friebolin, Beate Jannack, Nicole Wenzel, Julien Furrer, Thomas Oeser, Cecilia P Sanchez, Michael Lanzer, Vanessa Yardley, Katja Becker, Elisabeth Davioud-Charvet
Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems providing a steady glutathione flux. As a future generation of dual drugs, 18 naphthoquinones and phenols (or their reduced forms) containing three different linkers between the 4-aminoquinoline core and the redox active component were synthesized. Their antimalarial effects have been characterized in parasite assays using chloroquine-sensitive and -resistant strains of Plasmodium, alone or in drug combination, and in the Plasmodium berghei rodent model. In particular, two tertiary amides 34 and 36 showed potent antimalarial activity in the low nanomolar range against CQ-resistant parasites. The ability to compete both for (Fe (III))protoporphyrin and for chloroquine transporter was determined. The data are consistent with the presence of a carrier for uptake of the short chloroquine analogue 2 but not for the potent antimalarial amide 34, suggesting a mode of action distinct from chloroquine mechanism.
Application of multicomponent reactions to antimalarial drug discovery. Part 3: discovery of aminoxazole 4-aminoquinolines with potent antiplasmodial activity in vitro.
Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
The synthesis and antimalarial activity of a novel series of first generation 4-aminoquinoline-containing 2,4,5-trisubstituted aminoxazoles against two strains of the Plasmodium falciparum parasite in vitro is described. A number of compounds significantly more potent than the standard drug chloroquine were identified.
In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border.
ABSTRACT: BACKGROUND: On the borders of Thailand, Plasmodium falciparum has become resistant to nearly all available drugs, and there is an urgent need to find new antimalarial drugs or drug combinations. Ferroquine (SSR97193) is a new 4-aminoquinoline antimalarial active against chloroquine resistant and sensitive P. falciparum strains in vivo and in vitro. This antimalarial organic iron complex (a ferrocenyl group has been associated with chloroquine) is meant to use the affinity of Plasmodium for iron to increase the probability for encountering the anti-malarial molecule. The aim of the present study was to investigate the activity of ferroquine against P. falciparum isolates from an area with a known high multi-drug resistance rate. METHODS: Parasite isolates were obtained from patients with acute falciparum malaria attending the clinics of SMRU. In vitro cultures of these isolates were set-up in the SMRU-laboratory on pre-dosed drug plates, and grown in culture for 42 hours. Parasite growth was assessed by the double-site enzyme-linked pLDH immunodetection (DELI) assay. RESULTS: Sixty-five P. falciparum isolates were successfully grown in culture. The ferroquine mean IC50 (95% CI) was 9.3 nM (95% C.I.: 8.7 - 10.0). The mean IC50 value for the principal metabolite of ferroquin, SR97213A, was 37.0 nM (95% C.I.: 34.3 - 39.9), which is four times less active than ferroquine. The isolates in this study were highly multi-drug resistant but ferroquine was more active than chloroquine, quinine, mefloquine and piperaquine. Only artesunate was more active than ferroquine. Weak but significant correlations were found between ferroquine and its principal metabolite (r2 = 0.4288), chloroquine (r2 = 0.1107) and lumefantrine (r2 = 0.2364). CONCLUSION: The results presented in this study demonstrate that the new ferroquine compound SSR97193 has high anti-malarial activity in vitro against multi-drug resistant P. falciparum.
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA.
Amodiaquine (AQ) and tebuquine are 4-aminoquinoline antimalarials with Mannich base side chain and are highly effective against chloroquine (CQ)-resistant strains of Plasmodium falciparum. Clinical use of AQ has been severely restricted due to hepatoxicity and agranulocytosis side effects associated with its long term use. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of the observed AQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogues and their Nomega-oxides with hydroxy group meta to the amino rather than in para position of the aniline moiety were prepared. The new Mannich bases are highly active against both CQ-sensitive (D6) and -resistant (W2 and TM91C235) clones of P. falciparum with IC50 in the range of 0.3-120 ng/mL. New compounds are1000-fold less toxic (IC50 = 0.7-6 microg/mL) to mouse macrophage cell line than to parasite cell lines. Mono-Mannich bases are more active than bis-Mannich bases. Mono-Mannich base 1a (IC50 = 0.3 ng/mL) is 20-fold more active than the corresponding trifluoromethyl analogue 1b. No appreciable difference in either toxicity or efficacy were observed between the new Mannich bases (m-hydroxyaniline derivatives) 1a or 2a and the corresponding p-hydroxyaniline derivatives.
Françoise Benoit-Vical, Joël Lelièvre, Antoine Berry, Caroline Deymier, Odile Dechy-Cabaret, Jérôme Cazelles, Christophe Loup, Anne Robert, Jean-François Magnaval, Bernard Meunier
Laboratoire de Chimie de Coordination du CNRS, 31077 Toulouse cedex 4, France; Service de Parasitologie-Mycologie, Centre Hospitalier Universitaire Rangueil, 31059 Toulouse cedex 9, France; Palumed SA., Prologue Biotech, BP 28262, 31682 Labège cedex, France.
Malaria is the third cause of diseases by infection in the World. The search for new antimalarial chemotherapy has become increasingly urgent due to the parasite resistance to classical drugs. Trioxaquines(R) are synthetic hybrid molecules containing a trioxane motif (responsible for the artemisinin antimalarial activity) linked to an aminoquinoline entity (known for the chloroquine antiplasmodial properties). These trioxaquines are highly potent on young erythrocytic stages of Plasmodium falciparum, and exhibit efficient antimalarial activity in vitro on chloroquine-sensitive or -resistant strains of P. falciparum (IC50 = 4-32 nM) and are also active in vivo against P. vinckei and P. yoelii in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in mice model. Moreover, DU1302 exhibits a potent activity on gametocytes, the mosquito-transmissible forms, as killing gametocytes is essential to limit the spread of malaria. The easy chemical synthesis of this trioxaquine prototype should be considered as an additional advantage and would make them affordable without perturbations in drug supply.