nitd-609 and Malaria

Malaria is an endemic disease, prevalent in tropical and subtropical regions which cost half of million deaths annually. The eradication of malaria is one of the global health priority nevertheless, current therapeutic efforts seem to be insufficient due to the emergence of drug resistance towards most of the available drugs, even first-line treatment ACT, unavailability of the vaccine, and lack of drugs with a new mechanism of action. Intensification of antimalarial research in recent years has resulted into the development of single dose multistage therapeutic agents which has advantage of overcoming the antimalarial drug resistance. The present review explored the current progress in the development of new promising antimalarials against prominent target proteins that have the potential to be a clinical candidate. Here, we also reviewed different aspects of drug resistance and highlighted new drug candidates that are currently in a clinical trial or clinical development, along with a few other molecules with excellent antimalarial activity overs ACTs. The summarized scientific value of previous approaches and structural features of antimalarials related to the activity are highlighted that will be helpful for the development of next-generation antimalarials.

Topics: Animals; Antimalarials; Drug Development; Drug Resistance; Humans; Malaria; Molecular Targeted Therapy; Plasmodium; Protozoan Proteins; Small Molecule Libraries

Malaria is a devastating disease caused by

Topics: Antimalarials; Drug Discovery; Humans; Malaria; Molecular Structure; Plasmodium

Malaria is a life threatening disease caused by microscopic parasites called Plasmodium that are transmitted to human beings by mosquitoes. Single celled Eukaryotic plasmodium parasite is responsible to cause malaria in human beings and is transmitted by bite of Anopheles species mosquitoes. Resurgence of malaria towards the end of 20th Century is due to failure of its eradication completely. Parasite recurrence occurs due to high densities of parasite, low immunity and non opimized drug concentration. The ineffective eradications strategies were due to indefinable complex life cycle of Plasmodium and emergence of drugs resistant strains of Plasmodium falciparum (Pf) including Artemisinin and Artemisinin based combination therapy (ACT). The vector of the disease i.e. mosquitoes became resistive towards Pyrethroids, which are only class of insecticides recommended for vector control. Artemisinin based combination therapy gained acceptance as an effective approach to counter the spread of disease resistance to chloroquine, sulfadoxine, pyrimethamine and other anti malarial drugs. Understanding the underlying molecular basis of the pathogenesis led to the development of some new diagnostic, drugs and insecticides. Reports on the use of new combination therapies reduced the burden of disease worldwide. Some of the new combination therapies are in clinical stage of development that have efficacy against drug resistant parasites and the potential to use in single dose regimens to improve compliance. The current review represents the recent anti-malarial research carried out globally especially in the class of synthesis of small molecule and natural product derivatives as potent anti-malarial drugs. The review also covers the advancement in the anti-malarial vaccine development although goal for vaccine development still remains elusive.

Topics: Animals; Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria; Plasmodium falciparum

Malaria is caused by the Plasmodium parasite and is a major health problem leading to many deaths worldwide. Lack of a vaccine and increasing drug resistance highlights the need for new antimalarial drugs with novel targets. Antiplasmodial activity of spiroindolones was discovered through whole-cell, phenotypic screening methods. Optimization of the lead spiroindolone improved both potency and pharmacokinetic properties leading to drug candidate NITD609 which has produced encouraging results in clinical trials. Spiroindolones inhibit PfATP4, a P-type Na(+)-ATPase in the plasma membrane of the parasite, causing a fatal disruption of its sodium homeostasis. Other diverse compounds from the Malaria Box appear to target PfATP4 warranting further research into its structure and binding with NITD609 and other potential antimalarial drugs.

Topics: Adenosine Triphosphatases; Animals; Antimalarials; Cation Transport Proteins; Half-Life; Humans; Indoles; Malaria; Microsomes, Liver; Plasmodium falciparum; Protozoan Proteins; Spiro Compounds

The burden of malaria has been considerably reduced over recent years. However, to achieve disease elimination, drug discovery for the next generation needs to focus on blocking disease transmission and on targeting the liver-stage forms of the parasite. Properties of the 'ideal' new antimalarial drug and the key scientific and technological advances that have led to recent progress in antimalarial drug discovery are reviewed. Using these advances, Novartis has built a robust pipeline of next-generation antimalarials. The preclinical and clinical development of two candidate drugs: KAE609 and KAF156, provide a framework for the path to breakthrough treatments that could be taking us a step closer to the vision of malaria elimination.

Topics: Animals; Antimalarials; Drug Design; Drug Discovery; Humans; Imidazoles; Indoles; Malaria; Piperazines; Spiro Compounds

This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria.

Topics: Animals; Antimalarials; Drug Discovery; Humans; Liver; Liver Transplantation; Malaria; Molecular Structure

Spiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intracellular Na. A genetically engineered P. falciparum Dd2 strain (Dd2. Sublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts, whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, a substantial alteration (≥ fourfold) in the abundances of carbohydrate metabolites in the presence of either compound was found. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol.. The results of this study suggest that malaria parasites activate protein kinases via phospholipid-dependent signalling in response to the ionic perturbation induced by the Na

Topics: Animals; Antimalarials; Malaria; Malaria, Falciparum; Parasites; Phospholipids; Plasmodium falciparum

Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC

Topics: Animals; Antimalarials; Folic Acid Antagonists; Humans; Malaria; Malaria, Falciparum; Mice; Oxindoles; Plasmodium falciparum

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Antimalarials; Cations; Humans; Malaria; Malaria, Falciparum; Parasites; Plasmodium falciparum; Plasmodium knowlesi

Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.

Topics: Animals; Disease Models, Animal; Drug Discovery; Drug Stability; ERG1 Potassium Channel; Humans; Imidazoles; Malaria; Mice; Plasmodium falciparum; Pyridines; Solubility; Structure-Activity Relationship; Tissue Distribution; Water

KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. After oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Among the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1,2-acyl shift to form a ring expansion metabolite M37. The in vitro metabolism of KAE609 in hepatocytes was investigated to understand this novel biotransformation. The metabolism of KAE609 was qualitatively similar across the species studied; thus, further investigation was conducted using human recombinant cytochrome P450 enzymes. The ring expansion reaction was found to be primarily catalyzed by cytochrome P450 (CYP) 3A4 yielding M37. M37 was subsequently oxidized to M18 by CYP3A4 and hydroxylated to M23 primarily by CYP1A2. Interestingly, M37 was colorless, whereas M18 and M23 showed orange yellow color. The source of the color of M18 and M23 was attributed to their extended conjugated system of double bonds in the structures.

Topics: Animals; Bile; Biotransformation; Cytochrome P-450 Enzyme System; Dogs; Feces; Hepatocytes; Humans; Hydroxylation; Indoles; Malaria; Male; Rats; Rats, Wistar; Spiro Compounds

KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [(14)C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta.

Topics: Administration, Oral; Adult; Body Fluids; Carbon Radioisotopes; Feces; Healthy Volunteers; Humans; Hydroxylation; Indoles; Malaria; Male; Metabolic Networks and Pathways; Middle Aged; Oxidation-Reduction; Spiro Compounds

To achieve malarial elimination, we must employ interventions that reduce the exposure of human populations to infectious mosquitoes. To this end, numerous antimalarial drugs are under assessment in a variety of transmission-blocking assays which fail to measure the single crucial criteria of a successful intervention, namely impact on case incidence within a vertebrate population (reduction in reproductive number/effect size). Consequently, any reduction in new infections due to drug treatment (and how this may be influenced by differing transmission settings) is not currently examined, limiting the translation of any findings. We describe the use of a laboratory population model to assess how individual antimalarial drugs can impact the number of secondary Plasmodium berghei infections over a cycle of transmission. We examine the impact of multiple clinical and preclinical drugs on both insect and vertebrate populations at multiple transmission settings. Both primaquine (>6 mg/kg of body weight) and NITD609 (8.1 mg/kg) have significant impacts across multiple transmission settings, but artemether and lumefantrine (57 and 11.8 mg/kg), OZ439 (6.5 mg/kg), and primaquine (<1.25 mg/kg) demonstrated potent efficacy only at lower-transmission settings. While directly demonstrating the impact of antimalarial drug treatment on vertebrate populations, we additionally calculate effect size for each treatment, allowing for head-to-head comparison of the potential impact of individual drugs within epidemiologically relevant settings, supporting their usage within elimination campaigns.

Topics: Adamantane; Animals; Anopheles; Antimalarials; Artemether; Artemisinins; Ethanolamines; Female; Fluorenes; Indoles; Insect Vectors; Lumefantrine; Malaria; Mice; Peroxides; Plasmodium berghei; Primaquine; Spiro Compounds

Topics: Antimalarials; Clinical Trials, Phase II as Topic; Humans; Indoles; Malaria; Phenotype; Spiro Compounds

The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Topics: Animals; Antimalarials; Carbolines; Cell Line; Crystallography, X-Ray; Humans; In Vitro Techniques; Indoles; Malaria; Mice; Microsomes, Liver; Molecular Structure; Plasmodium berghei; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

Topics: Adenosine Triphosphatases; Animals; Antimalarials; Cell Line; Drug Discovery; Drug Resistance; Erythrocytes; Female; Genes, Protozoan; Humans; Indoles; Malaria; Male; Mice; Models, Molecular; Mutant Proteins; Mutation; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; Protein Synthesis Inhibitors; Protozoan Proteins; Rats; Rats, Wistar; Spiro Compounds

Topics: Adenosine Triphosphatases; Animals; Antimalarials; Drug Approval; Drug Discovery; Drug Resistance; Erythrocytes; Genes, Protozoan; Humans; Indoles; Malaria; Parasitic Sensitivity Tests; Plasmodium; Protein Synthesis Inhibitors; Protozoan Proteins; Spiro Compounds