Class Of Antimalarials Research Articles

Candidate Selection and Preclinical Evaluation of N-tert-Butyl Isoquine (GSK369796), An Affordable and Effective 4-Aminoquinoline Antimalarial for the 21st Century

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.

Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials

Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.

New antimalarial and cytotoxic 4-nerolidylcatechol derivatives

4-Nerolidylcatechol ( 1) was isolated from cultivated Pothomorphe peltata root on a multigram scale using straight-forward solvent extraction-column chromatography. New semi-synthetic derivatives of 1 were prepared and tested in vitro against multidrug-resistant Plasmodium falciparum K1 strain. Mono- O-methyl, mono- O-benzyl, O, O-dibenzyl and O, O-dibenzoyl derivatives 2– 8 exhibited IC 50 in the 0.67–22.52 μM range. Mono- O-methyl ethers 6 and 7 inhibited the in vitro growth of human tumor cell lines HCT-8 (colon carcinoma), SF-295 (central nervous system), LH-60 (human myeloblastic leukemia) and MDA/MB-435 (melanoma). In general, derivatives 2– 8 are more stable to light, air and pH at ambient temperatures than their labile, natural precursor 1. These derivatives provide leads for the development of a novel class of antimalarial drugs with enhanced chemical and pharmacological properties.

Depsipeptides from Microorganisms: A New Class of Antimalarials

Depsipeptides are a large group of natural products produced by fungi, actinomycetes, cyanobacteria, higher plants and marine organisms. This family of compounds is known to exhibit a wide range of biological activities, and thanks to the progress of isolation techniques and the advances of methods for structure determination, the numbers of depsipeptides having both unique structures and attractive biological activities are increasing. Many of these compounds have shown a wide range of biological activities, and some are in clinical use or have entered human clinical trials as antibiotic or anticancer agents. However, only a handful of them have been evaluated for their antimalarial activity. This paper aims to review the recent advances in depsipeptides as potential antimalarial compounds.

A liquid chromatography–mass spectrometry assay for simultaneous determination of two antimalarial thiazolium compounds in human and rat matrices

A new class of antimalarial drugs targeting phospholipid metabolism of the malarial parasite is now in development. In the strategy of this development, two mono-thiazolium salts, T1 and T2, need to be monitored. A liquid chromatography–mass spectrometry (LC–MS) method has been developed and validated according to FDA guidelines for simultaneous determination of T1 and T2 in plasma, whole blood and red blood cells (RBCs) from human and rat. The sample-pre-treatment procedure involved solid phase extraction after protein precipitation. Chromatography was carried out on a Zorbax eclipse XDB C8 column and mass spectrometric analysis was performed using an Agilent 1100 quadrupole mass spectrometer working with an electrospray ionization source. LC–MS data were acquired in single ion monitoring mode at m/ z 312, 326 and 227 for T1, T2 and the internal standard (T3), respectively. The drug/internal standard peak area ratios were linked via a quadratic relationship to concentrations (human and rat plasma: 2.25–900 μg/l; human blood and rat RBCs: 4.5–900 μg/kg). Precision was below 14.5% for T1 and below 13% for T2. Accuracy was 92.6–111% for T1 and 95.6–108% for T2. Extraction recoveries were ≥85% in plasma and ≥53% in blood and RBCs. For T1 and T2, the lower limits of quantitation were 2.25 μg/l in plasma, and 4.5 μg/kg in whole blood and RBCs. Stability tests under various conditions were also investigated. This highly specific and sensitive method was useful to analyse samples from pharmacokinetic studies carried out in rat and would also be useful in clinical trials at a later stage.

Antimalarial Drugs – What is in Use and What is in the Pipeline

Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.

Characterization of a novel class of antimalarials and its applicability to plasmodial target identification

Candidate drugs related to the lead compound propafenone are highly effective inhibitors of P. falciparum growth with 50% inhibitory concentrations (IC(50)s) in the sub-micromolar range. The parental compound propafenone is a cardiac sodium channel blocker which is in clinical use for the treatment of ventricular arrhythmia. An in house library of more than 400 compounds with systematically varied structures is available for 2D and 3D quantitative structure activity relationship studies. In a first step selected compounds were evaluated for their antimalarial activity using the histidine-rich protein 2 drug sensitivity assay. Propafenone analogues contain an inherently photoactive aryl-carbonyl substructure, which allows their use in photolabeling studies. Labelling efficiency is increased for compounds in which the phenylpropiophenone core structure is replaced by a benzophenone substructure. However, the phenylpropiophenone substructure represents part of the pharmacophore of the compounds. Benzophenone-type analogues show IC(50) values that are higher than their congeneric phenylpropiophenones. Nevertheless, one of the photoligands shows an IC(50) value in the low micro-molar range. Use of this photoligand is thus expected to allow identification of candidate targets by mass spectrometry following two dimensional separation of the plasmodial proteome. The Malaria Genome Project has advanced our understanding of parasite biology and development of novel drugs can mount on data made available by the recently completed sequencing effort of P. falciparum. The lead compound propafenone is a registered drug and this compound class might therefore have a major potential as an antimalarial drug, either alone, or in combination with conventional antimalarials.

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

Efficacy of sulfadoxine-pyrimethamine, amodiaquine, and sulfadoxine-pyrimethamine–amodiaquine combination for the treatment of uncomplicated falciparum malaria in the urban and suburban areas of Brazzaville (Congo)

Congo-Brazzaville has recently adopted artesunate-amodiaquine as the first-line antimalarial drug to replace chloroquine. Before the implementation of this new strategy, we conducted several clinical studies to assess the therapeutic efficacy of former, classical first-line antimalarial drugs in the city of Brazzaville, in which reside about 30% of the Congolese population. From 2003 to 2005, non-randomised trials were conducted to evaluate the efficacy of sulfadoxine-pyrimethamine (SP) ( n = 97 patients), amodiaquine (AQ) ( n = 62 patients), and the combination of sulfadoxine-pyrimethamine–amodiaquine ( n = 54 patients) in children aged between 6 months and 5 years with uncomplicated malaria using the 2003 WHO guidelines during the 28-day follow-up period. After excluding new infections by PCR, the proportion of treatment failure on day 28 was 30.2% (95% confidence interval, 19.2–43.0%) for sulfadoxine-pyrimethamine, 34.8% (95% confidence interval, 21.4–50.2%) for amodiaquine, and 14.2% (95% confidence interval, 5.9–27.2%) for sulfadoxine-pyrimethamine + amodiaquine combination. Treatment with sulfadoxine-pyrimethamine was associated with an increase of gametocyte charge. These results suggest that neither sulfadoxine-pyrimethamine nor amodiaquine is efficacious as monotherapy and that their combination may not remain effective in the coming years. Based on our results, the implementation of artemisinin-based combination therapy appears to be urgent in the country.

Sulfadoxine-Pyrimethamine, Chlorproguanil-Dapsone, or Chloroquine for the Treatment of Plasmodium vivax Malaria in Afghanistan and Pakistan

In areas where Plasmodium falciparum and Plasmodium vivax coexist and treatments for the 2 species differ, misdiagnosis can lead to poor outcomes in either disease. A unified therapy effective against both species would reduce reliance on species-specific diagnosis, which in many areas is difficult to maintain. The antifolates are an important and affordable antimalarial class to which it is often assumed P vivax malaria is intrinsically resistant. To test the relative efficacy and safety of 2 antifolate drugs against P vivax malaria and compare each with chloroquine. An open-label randomized controlled trial comparing chloroquine, sulfadoxine-pyrimethamine, and chlorproguanil-dapsone for the treatment of P vivax malaria was conducted in eastern Afghanistan and northwestern Pakistan, areas in which P vivax malaria predominates. A total of 20,410 patients older than 3 years were screened; 767 patients (315 in Pakistan and 452 in Afghanistan) with confirmed P vivax malaria were enrolled and followed up daily for 4 days, then weekly for 28 days, between March 2004 and June 2006. Complete clearance of parasites with no recrudescence by day 14. Secondary outcomes included being parasite-free by day 28, clinical failure, and anemia. By day 14, only 1 patient in the sulfadoxine-pyrimethamine group had parasites. By day 28, failure rates were found in 2 of 153 patients (1.3%) in the chloroquine group, 5 of 290 patients (1.7%) in the sulfadoxine-pyrimethamine group, and 27 of 272 patients (9.9%) in the chlorproguanil-dapsone group. Chlorproguanil-dapsone was less effective than sulfadoxine-pyrimethamine (adjusted odds ratio [OR], 6.4; 95% confidence interval [CI], 2.4-17.0; P<.001) and chloroquine (adjusted OR, 8.4; 95% CI, 2.0-36.5; P = .004). Chloroquine and sulfadoxine-pyrimethamine were equivalent in efficacy at day 28 (adjusted OR, 1.3; 95% CI, 0.3-7.0; P = .73). Chloroquine cleared gametocytes and asexual parasites more rapidly than sulfadoxine-pyrimethamine or chlorproguanil-dapsone did. All drugs were well tolerated. Although chloroquine remains the drug of choice, antifolates are effective against P vivax malaria in South Asia. These drugs may be appropriate for unified treatment where species-specific diagnosis is unavailable, most likely in combination with other drugs. clinicaltrials.gov Identifier: NCT00158561.

Divergent Strategy for the Synthesis of α-Aryl-Substituted Fosmidomycin Analogues

Fosmidomycin is the first representative of a new class of antimalarial drugs acting through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway for the synthesis of isoprenoids. This work describes a divergent strategy for the synthesis of a series of alpha-aryl-substituted fosmidomycin analogues, featuring a palladium-catalyzed Stille coupling as the key step. An alpha-(4-cyanophenyl)fosmidomycin analogue emerged as the most potent analogue in the present series. Its antimalarial activity clearly surpasses that of the reference compound fosmidomycin.

EFFECT OF ARTEMISININ-BASED TREATMENT POLICY ON CONSUMPTION PATTERN OF ANTIMALARIALS

The purpose of this study was to observe the effect of the 2004 national artemisinin-based malaria treatment policy on consumption pattern of antimalarials. The study was undertaken at the University of Ilorin Teaching Hospital (UITH), Nigeria. Prescription and sales data at our pharmacy outlets were gathered from January to December 2004 and compared with similar data for 2005 after policy introduction in January 2005. Total consumption of antimalarials in 2004 was 23,404 doses, made up of artemisinin-containing medications (ACMs; 18.5%); sulphadoxine-pyrimethamine (SP; 7.1%); chloroquine (CQ; 72.85%); and quinine (QUI; 1.6%), compared with 26,383 doses in 2005, made up of ACMs (50.00%); SP (22.7%); CQ (27.3%); and QUI (0%). Z-tests indicate that these differences in proportions were significant (P < 0.001) for ACMs and SP (increased) and decreased for CQ and QUI. The comparative retail price per dose of these medications was in the order: ACMs > QUI > SP > CQ. These data show increased use of antimalarials, with ACMs overtaking CQ as the dominant antimalarial class purchased from the pharmacies operated by the hospital in the first year of policy implementation. This suggests that cost alone may not be the overriding determinant of specific antimalarial consumption.

Drug Development Papers in PLoS Medicine: How We Try to Spot a Winner

Drug Development Papers in PLoS Medicine: How We Try to Spot a Winner

Decreased availability of antimalarials in the private sector following the policy change from chloroquine to sulphadoxine-pyrimethamine in the Kilombero Valley, Tanzania

BackgroundMalaria control strategies emphasize the need for prompt and effective treatment of malaria episodes. To increase treatment efficacy, Tanzania changed its first-line treatment from chloroquine to sulphadoxine-pyrimethamine (SP) in 2001. The effect of this policy change on the availability of antimalarials was studied in rural south-eastern Tanzania.MethodsIn 2001 and 2004, the study area was searched for commercial outlets selling drugs and their stocks were recorded. Household information was obtained from the local Demographic Surveillance System.ResultsFrom 2001 to 2004, the number of general shops stocking drugs increased by 15% and the number of drug stores nearly doubled. However, the proportion of general shops stocking antimalarials dropped markedly, resulting in an almost 50% decrease of antimalarial selling outlets. This led to more households being located farther from a treatment source. In 2004, five out of 25 studied villages with a total population of 13,506 (18%) had neither a health facility, nor a shop as source of malaria treatment.ConclusionWhile the change to SP resulted in a higher treatment efficacy, it also led to a decreased antimalarial availability in the study area. Although there was no apparent impact on overall antimalarial use, the decline in access may have disproportionately affected the poorest and most remote groups. In view of the imminent policy change to artemisinin-based combination therapy these issues need to be addressed urgently if the benefits of this new class of antimalarials are to be extended to the whole population.

Quinones and Malaria

The intensive usage and the efficacy of quinoline and artemisinin antimalarials have led scientists to focus mainly on these two families of compounds resulting in the other classes of antimalarial drugs being ignored. Recently atovaquone, a hydroxy-naphtoquinone derivative, was reported as an effective antimalarial drug against the multidrugresistant parasite with a novel drug mechanism. This discovery, which emerged from earlier studies, opened a new approach for the design of new quinone antimalarials. Other well known anthraquinone antibiotics such as tetracycline and doxycycline have been in use in malaria prophylaxis for more than three decades. This review aims to explore the background to the discovery of existing quinone antimalarials, and the advance in the chemistry and biochemistry of synthetic and naturally occurring quinones with antimalarial activity. Reactions and metabolism of antimalarial quinones in animals and men are considered, focusing on compounds that are or have been used to treat human malaria, with an emphasis on the relationship between metabolism and biological effects. Keywords: Quinones, malaria, metabolism and biological effects

Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets. The Plasmodium falciparum methionine aminopeptidase 1b (PfMetAP1b), one of four MetAP proteins encoded in the P. falciparum genome, was cloned, overexpressed, purified, and used to screen a 175,000-compound library for inhibitors. A family of structurally related inhibitors containing a 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activity studies led to the identification of a potent PfMetAP1b inhibitor, XC11, with an IC(50) of 112 nM. XC11 was highly selective for PfMetAP1b and did not exhibit significant cytotoxicity against primary human fibroblasts. Most importantly, XC11 inhibited the proliferation of P. falciparum strains 3D7 [chloroquine (CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and is active in mouse malaria models for both CQ-sensitive and CQ-resistant strains. These results suggest that PfMetAP1b is a promising target and XC11 is an important lead compound for the development of novel antimalarial drugs.

NEW ANTIMALARIAL TARGET IS FOUND

SCIENTISTS HAVE FOUND A compound that potently inhibits a novel target protein in the malaria parasite, including forms of the parasite resistant to the classic antimalarial drug chloroquine. The compound could portend a new class of agents to fight malaria. Malaria, an infection caused by the protozoan Plasmodium falciparum and transmitted by mosquitoes, causes high fever, body aches, and often death, particularly among children. Despite decades of effort to eradicate the disease, it still kills more than 1 million people per year, mostly in Africa. Current medications can't adequately address the problems posed by malaria worldwide, and new treatments that are more effective, cheaper, and easier to distribute are urgently needed. One problem is that few targets for antimalarial drugs are known. Now, pharmacology professor Jun O. Liu of Johns Hopkins University School of Medicine and coworkers have identified a methionine aminopeptidase (MetAP) enzyme from P. falciparum as a new molecular target for mala...

Should New Antimalarial Drugs Be Subsidized?

We use analytical and numerical models to explain and quantify the welfare effects of subsidies for artemisinin combination treatments (ACTs), a valuable new class of antimalarial drugs. There are two (second-best) efficiency rationales for such subsidies: by expanding drug use, they reduce infection transmission from one individual to another, and they slow the evolution of drug resistance by deterring use of substitute monotherapy drugs for which resistance emerges more rapidly than for ACTs. Our analysis merges epidemiological models of malaria transmission among individuals and mosquitoes, evolution of drug resistance, and economic models of the demand for alternative drugs; parameter values for the simulations are representative of malaria prevalence in sub-Saharan Africa. We find that large subsidies for ACT are welfare improving across many plausible scenarios for malaria transmission, drug-demand elasticities, and evolution of drug resistance; the benefits of the policy are often several times larger than the costs.

3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold

With annual death tolls in the millions and emerging resistance to existing drugs, novel therapies are needed against malaria. Wiesner et al. recently developed a novel class of antimalarials derived from farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. The compounds displayed a wide range of activity, including submicromolar, against the multi-drug resistant Plasmodium falciparum strain Dd2. In order to investigate quantitatively the local physicochemical properties involved in the interaction between drug and biotarget, we used the 3D-QSAR methods CoMFA and CoMSIA to study some of the series, including the screened lead compound 2,5-bis-acylaminobenzophenone, 28 cinnamic acid derivatives, 29 N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides, and 34 N-(4-substituted-amino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. We found that steric, electrostatic, and hydrophobic properties of substituent groups play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact. We built several highly predictive 3D-QSAR models, including a CoMSIA one composed of steric, electrostatic, and hydrophobic fields, with r 2 = 0.94, q 2 = 0.63, and r pred 2 = 0.63 . The results provide insight for optimization of this class of antimalarials for better activity and may prove helpful for further lead optimization.