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1.
ACS Med Chem Lett ; 5(8): 947-50, 2014 Aug 14.
Article in English | MEDLINE | ID: mdl-25147620

ABSTRACT

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.

2.
Antimicrob Agents Chemother ; 58(9): 5060-7, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24913172

ABSTRACT

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.


Subject(s)
Antimalarials/pharmacology , Imidazoles/pharmacology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/transmission , Piperazines/pharmacology , Animals , Inhibitory Concentration 50 , Mice , Mice, Inbred ICR , Plasmodium falciparum/drug effects , Sporozoites/drug effects
3.
Antimicrob Agents Chemother ; 58(3): 1586-95, 2014.
Article in English | MEDLINE | ID: mdl-24366744

ABSTRACT

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 µM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 µM, and PQ, 0.84 µM; for developing liver stages, KAI407, 0.64 µM, and PQ, 0.37 µM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure.


Subject(s)
Antimalarials/pharmacology , Imidazoles/pharmacology , Malaria/drug therapy , Plasmodium cynomolgi/drug effects , Pyrazines/pharmacology , Animals , Antimalarials/therapeutic use , Drug Evaluation, Preclinical/methods , Female , Hepatocytes/parasitology , Imidazoles/therapeutic use , In Vitro Techniques , Liver/parasitology , Macaca mulatta/parasitology , Malaria/parasitology , Malaria/prevention & control , Mice , Mice, Inbred ICR , Pyrazines/therapeutic use , Sporozoites/drug effects
4.
J Med Chem ; 55(9): 4244-73, 2012 May 10.
Article in English | MEDLINE | ID: mdl-22524250

ABSTRACT

On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.


Subject(s)
Antimalarials/pharmacology , Imidazoles/pharmacology , Malaria, Falciparum/drug therapy , Piperazines/pharmacology , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Biological Availability , Caco-2 Cells , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Malaria, Falciparum/parasitology , Mice , Mice, Inbred BALB C , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Plasmodium falciparum/metabolism , Rats , Rats, Wistar , Structure-Activity Relationship
5.
Science ; 334(6061): 1372-7, 2011 Dec 09.
Article in English | MEDLINE | ID: mdl-22096101

ABSTRACT

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.


Subject(s)
Antimalarials/pharmacology , Drug Discovery , Imidazoles/pharmacology , Liver/parasitology , Malaria/drug therapy , Piperazines/pharmacology , Plasmodium/drug effects , Animals , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Cell Line, Tumor , Drug Evaluation, Preclinical , Drug Resistance , Erythrocytes/parasitology , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Malaria/parasitology , Malaria/prevention & control , Mice , Mice, Inbred BALB C , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Plasmodium/cytology , Plasmodium/growth & development , Plasmodium/physiology , Plasmodium berghei/cytology , Plasmodium berghei/drug effects , Plasmodium berghei/growth & development , Plasmodium berghei/physiology , Plasmodium falciparum/cytology , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Plasmodium falciparum/physiology , Plasmodium yoelii/cytology , Plasmodium yoelii/drug effects , Plasmodium yoelii/growth & development , Plasmodium yoelii/physiology , Polymorphism, Single Nucleotide , Protozoan Proteins/chemistry , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Random Allocation , Small Molecule Libraries , Sporozoites/drug effects , Sporozoites/growth & development
6.
J Med Chem ; 54(14): 5116-30, 2011 Jul 28.
Article in English | MEDLINE | ID: mdl-21644570

ABSTRACT

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.


Subject(s)
Antimalarials/chemical synthesis , Imidazoles/chemical synthesis , Piperazines/chemical synthesis , Amino Acids/chemical synthesis , Amino Acids/chemistry , Amino Acids/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Cell Line , Drug Resistance , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Malaria/drug therapy , Mice , Mice, Inbred BALB C , Piperazines/chemistry , Piperazines/pharmacology , Plasmodium berghei , Plasmodium falciparum/drug effects , Rats , Structure-Activity Relationship
7.
Mol Biochem Parasitol ; 175(1): 21-9, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20813141

ABSTRACT

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC(50) values below 1.25µM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.


Subject(s)
Antimalarials/pharmacology , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays , Plasmodium falciparum/drug effects , Antimalarials/isolation & purification , Enzyme Inhibitors/isolation & purification , Enzymes/metabolism , Inhibitory Concentration 50 , Plasmodium falciparum/growth & development , Protozoan Proteins/antagonists & inhibitors
8.
Proc Natl Acad Sci U S A ; 107(46): 20045-50, 2010 Nov 16.
Article in English | MEDLINE | ID: mdl-21037109

ABSTRACT

Plasmodium vivax causes 25-40% of malaria cases worldwide, yet research on this human malaria parasite has been neglected. Nevertheless, the recent publication of the P. vivax reference genome now allows genomics and systems biology approaches to be applied to this pathogen. We show here that whole-genome analysis of the parasite can be achieved directly from ex vivo-isolated parasites, without the need for in vitro propagation. A single isolate of P. vivax obtained from a febrile patient with clinical malaria from Peru was subjected to whole-genome sequencing (30× coverage). This analysis revealed over 18,261 single-nucleotide polymorphisms (SNPs), 6,257 of which were further validated using a tiling microarray. Within core chromosomal genes we find that one SNP per every 985 bases of coding sequence distinguishes this recent Peruvian isolate, designated IQ07, from the reference Salvador I strain obtained in 1972. This full-genome sequence of an uncultured P. vivax isolate shows that the same regions with low numbers of aligned sequencing reads are also highly variable by genomic microarray analysis. Finally, we show that the genes containing the largest ratio of nonsynonymous-to-synonymous SNPs include two AP2 transcription factors and the P. vivax multidrug resistance-associated protein (PvMRP1), an ABC transporter shown to be associated with quinoline and antifolate tolerance in Plasmodium falciparum. This analysis provides a data set for comparative analysis with important potential for identifying markers for global parasite diversity and drug resistance mapping studies.


Subject(s)
Drug Resistance/genetics , Genes, Protozoan/genetics , Oligonucleotide Array Sequence Analysis/methods , Plasmodium vivax/genetics , Selection, Genetic , Sequence Analysis, DNA/methods , Erythrocytes/parasitology , Gene Expression Regulation , Humans , Leukocytes/parasitology , Malaria Vaccines/immunology , Multigene Family/genetics , Mutation/genetics , Peru , Plasmodium vivax/immunology , Plasmodium vivax/isolation & purification , Polymorphism, Genetic , Sequence Alignment , Transcription Factors/genetics
9.
Bioorg Med Chem Lett ; 19(24): 6970-4, 2009 Dec 15.
Article in English | MEDLINE | ID: mdl-19879133

ABSTRACT

Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered a known pan-kinase inhibitor scaffold as a hit. Further optimization of this series led us to a novel benzamide scaffold which was devoid of human kinase activity while retaining its antiplasmodial activity. The evolution of this compound series leading to optimized candidates with good cellular potency against multiple strains as well as decent in vivo profile is described in this Letter.


Subject(s)
Antimalarials/chemistry , Benzamides/chemistry , Enzyme Inhibitors/chemistry , Phosphotransferases/antagonists & inhibitors , Plasmodium falciparum/enzymology , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Directed Molecular Evolution , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Mice , Plasmodium falciparum/drug effects
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