RESUMO
Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Cisteína Endopeptidases/química , Peptídeos/química , Peptídeos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos , Cisteína Endopeptidases/metabolismo , Células HEK293 , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The total synthesis and stereochemical assignment of gallinamide A, an antimalarial depsipeptide of cyanobacterial origin, is described. Synthesis of the four possible N-terminal diastereoisomers of gallinamide A (including the natural product symplostatin 4) was achieved using a divergent strategy from a common imide fragment. The natural product and corresponding diastereoisomers were synthesized in 30-33% overall yield in a longest linear sequence of 8 steps. Comparative NMR spectroscopic studies of the four synthetic diastereoisomers with the isolated natural product demonstrated that gallinamide A possesses a dimethylated L-isoleucyl residue at the N-terminus. As such, we have shown that gallinamide A is structurally and stereochemically identical to symplostatin 4. Gallinamide A and its N-terminal diastereoisomers were also shown to possess significant antimalarial activity with IC(50) values in the nanomolar range against the 3D7 strain of Plasmodium falciparum.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Produtos Biológicos/síntese química , Peptídeos/síntese química , Plasmodium falciparum/química , Antimaláricos/química , Peptídeos Catiônicos Antimicrobianos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Peptídeos/química , Peptídeos/farmacologia , EstereoisomerismoRESUMO
The first total synthesis of symplostatin 4, a marine cyanobacterium-derived natural product, is described. Notable features of the route include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings. Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED(50) of 74 nM against Plasmodium falciparum, strain 3D7).