RESUMO
Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Malária/transmissão , Plasmodium falciparum/efeitos dos fármacos , Animais , Descoberta de Drogas , Feminino , Células Germinativas/efeitos dos fármacos , Células Hep G2 , Humanos , Malária/tratamento farmacológico , Malária/prevenção & controle , Masculino , Camundongos , Plasmodium falciparum/citologia , Relação Estrutura-AtividadeRESUMO
A straightforward synthesis of α-substituted acrylonitriles is described using 4-cyano-3-oxotetrahydro-thiophene (c-THT) as an acrylonitrile surrogate. This unprecedented two-step sequence featuring a palladium-catalyzed allylic alkylation (Pd-AA) and a retro-Dieckmann fragmentation provides a general entry into diversely substituted 1,4-dienes.