RESUMO
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Aminopiridinas/uso terapêutico , Antimaláricos/uso terapêutico , Sulfonas/uso terapêutico , Aminopiridinas/farmacologia , Animais , Antimaláricos/farmacologia , Feminino , Malária/tratamento farmacológico , Malária/enzimologia , Masculino , Camundongos , Camundongos SCID , Testes de Sensibilidade Parasitária , Plasmodium/efeitos dos fármacos , Plasmodium/patogenicidade , Sulfonas/farmacologiaRESUMO
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.
RESUMO
Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Malária/tratamento farmacológico , Malária/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , 1-Fosfatidilinositol 4-Quinase/química , 1-Fosfatidilinositol 4-Quinase/genética , 1-Fosfatidilinositol 4-Quinase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Citocinese/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Ácidos Graxos/metabolismo , Feminino , Hepatócitos/parasitologia , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Macaca mulatta , Masculino , Modelos Biológicos , Modelos Moleculares , Fosfatos de Fosfatidilinositol/metabolismo , Plasmodium/classificação , Plasmodium/crescimento & desenvolvimento , Pirazóis/metabolismo , Pirazóis/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Reprodutibilidade dos Testes , Esquizontes/citologia , Esquizontes/efeitos dos fármacos , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, we show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. Our data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited.
Assuntos
Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Fungos/química , Isocumarinas/farmacologia , Lisina-tRNA Ligase/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Antimaláricos/isolamento & purificação , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Isocumarinas/isolamento & purificação , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidoresRESUMO
The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol (2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C(7b) quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon global deprotection, hopeahainol A (3). The latter was converted under basic conditions to hopeanol (2), whereas the reverse transformation, previously suggested as a step in the biosynthesis of hopeahainol A (3), was not observed under a variety of conditions. Biological evaluation of the synthesized compounds confirmed the reported acetylcholinesterase inhibitory activity of hopeahainol A (3) but not the reported cytotoxic potencies of hopeanol (2).
Assuntos
Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Inibidores da Colinesterase/síntese química , Flavonoides/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Fenóis/síntese química , Estilbenos/química , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Flavonoides/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fenóis/farmacologia , Polifenóis , ResveratrolRESUMO
Total syntheses of the highly selective antiproliferative natural products cortistatins A (1) and J (5) in their naturally occurring enantiomeric forms are described. The modular and convergent strategy employed relies on an intramolecular oxa-Michael addition/aldol/dehydration cascade reaction to cast the ABCD ring framework of the molecule and both Sonogashira and Suzuki-Miyaura coupling reactions to assemble the necessary building blocks into the required heptacyclic skeleton. A divergent approach from a late-stage epoxy ketone leads to both target molecules in a stereoselective manner. The developed synthetic technologies were applied to the construction of several analogues of the cortistatins which were biologically evaluated and compared to the natural products with regards to their antiproliferative activities against a variety of cancer cells. Analogues 8 and 81, lacking both the dimethylamino and hydroxyl groups of cortistatin A, were found to exhibit comparable biological activity as the parent compound, leading to the conclusion that such functionalities are not essential for biological activity.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Compostos Policíclicos/síntese química , Compostos Policíclicos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Isoquinolinas/químicaRESUMO
Molecular design and chemical synthesis of several palmerolide A analogues allowed the first structure activity relationships (SARs) of this newly discovered marine antitumor agent. From several analogues synthesized and tested (ent- 1, 5- 14, 21- 26, 50, 51), compounds 25 (with a phenyl substituent on the side chain) and 51 (lacking the C-7 hydroxyl group) were the most interesting, exhibiting approximately a 10-fold increase in potency and equipotency, respectively, to the natural product. These findings point the way to more focused structure activity relationship studies.