RESUMO
Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.
Assuntos
Antimaláricos/farmacologia , Ácido Pantotênico/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ácido Pantotênico/síntese química , Ácido Pantotênico/química , Ácido Pantotênico/farmacologia , Testes de Sensibilidade Parasitária , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Plasmodium falciparum/enzimologia , Relação Estrutura-AtividadeRESUMO
The fast and efficient syntheses of pantothenic acid and the antiparasitic agent CJ-15,801 have been achieved starting from a common imide unit through the selective manipulation of enamide intermediates.
Assuntos
Imidas/química , Ácido Pantotênico/análogos & derivados , Ácido Pantotênico/síntese química , Conformação Molecular , Estrutura Molecular , Ácido Pantotênico/química , Ácido Pantotênico/farmacologia , Plasmodium falciparum/efeitos dos fármacos , EstereoisomerismoRESUMO
[reaction: see text] A fast, flexible, and efficient approach for the stereocontrolled synthesis of enamides has been developed starting from lactams and amides through the use of imides. This new approach provides access to enamide systems not easily or currently accessible through other approaches.