Expanding the toolbox of chemical tools to target malaria parasites with azaindoles

• Autor(a) principal: Cunha, José Carlos Ferreira da
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/133287
• topic: Malaria; N-heterocycles; Pd-catalyzed reactions; docking; biological evaluation; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

Malaria remains one of most lethal infectious diseases in the world. According to WHO, there were 228 million cases and 405,000 deaths in 2018 related to this mosquito-borne dis-ease caused by Plasmodium protozoan parasites. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Identifying new chemo-types with novel modes of action against different stages of the parasite lifecycle are now recognized as the defining traits of modern antimalarial drug discovery. Recently a set of indoles was found to present potent antimalarial activity and that represent a novel entry in the toolbox of chemical tools to target malaria parasites. Azaindoles, which are bioisosteres of the indoles, and their derivatives, exhibit significant biological activities, and the use of this framework has contributed to the generation of new therapeutic agents. This work describes the synthesis of nine novel azaindoles from available amino-ortho-halopyridines to expand the toolbox of modern antimalarial drugs. This procedure involved a palladium-catalyzed N-arylation followed by a Sonogashira reaction and sub-sequent cyclization in a one-pot manner. The acquired azaindoles were tested for their bioactivity in an in vitro activity screening against Plasmodium falciparum and it was found that four out of nine azaindoles showed activity against the Plasmodium strain. To identify the binding mode and the favored binding proteins we applied machine learning algorithms to analyze the existing databases, which acknowledged the CGMP-dependent protein kinase as one of the most feasible targets. The subsequent docking studies on the promising protein are in agreement with the obtained bioactivity and indicate a high potential application of the new molecules as antimalarial agents.