RESUMO
Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.
Assuntos
Compostos de Aminobifenil/síntese química , Antimaláricos/síntese química , Carbazóis/síntese química , Naftalenos/síntese química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Compostos de Aminobifenil/química , Compostos de Aminobifenil/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Di-Hidro-Orotato Desidrogenase , Desenho de Fármacos , Humanos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Naftalenos/química , Naftalenos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Plasmodium falciparum/efeitos dos fármacos , Mutação Puntual , Ligação ProteicaRESUMO
The synthesis of novel substituted 3-aralkylthiomethylimidazo[1,2-b]pyridazines is reported. All of the synthesized compounds are devoid of antiviral activity against the replication of human immunodeficiency virus. However, compounds 6-chloro-8-methyl-3-phenethylthioimidazo[1,2-b]pyridazine and 6-chloro-2-methyl-3-phenethylthioimidazo[1,2-b]pyridazine are potent inhibitors of the replication of human cytomegalovirus in vitro, while compounds 6-chloro-2-methyl-3-benzylthiomethylimidazo[1,2-b]pyridazine and 6-chloro-2-methyl-3-phenethyl-thioimidazo[1,2-b]pyridazineare inhibitors of the replication of varicella-zoster virus. The results presented here suggest that compound 10 should be considered as a new lead in the development of antiviral agents.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Herpesvirus Humano 3/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Antivirais/química , Antivirais/toxicidade , Linhagem Celular , Citomegalovirus/fisiologia , Desenho de Fármacos , HIV/efeitos dos fármacos , Herpesvirus Humano 3/fisiologia , Humanos , Imidazóis/química , Concentração Inibidora 50 , Estrutura Molecular , Piridazinas/química , Piridazinas/toxicidade , Replicação Viral/efeitos dos fármacosRESUMO
The synthesis of various 2-substituted imidazo[1,2-a]pyridine bearing a thioether side chain in position 3 was reported. The new compounds were characterized by 1H and 13C NMR spectra. A conformational study was obtained by X-ray crystallographic analysis for 2-biphen-4-ylimidazopyridine 7. The antiviral activity against human cytomegalovirus (HCMV) was investigated. It was strongly influenced by the nature of C-2 substituent.
