Expanding the toolbox of chemical tools to target malaria parasites with azaindoles
Autor(a) principal: | |
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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 |
Resumo: | 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. |
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Expanding the toolbox of chemical tools to target malaria parasites with azaindolesMalariaN-heterocyclesPd-catalyzed reactionsdockingbiological evaluationDomínio/Área Científica::Engenharia e Tecnologia::Engenharia QuímicaMalaria 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.Malária é uma das doenças infeciosas letais que mais afeta a população mundial. De acordo com a organização mundial de saúde (OMS), existiram 228 milhões de casos e 405.000 mortes associadas a esta doença originária do mosquito e causada por parasitas protozoários Plasmodium. O desenvolvimento de novas terapias para combater o impacto da malaria tem sido particularmente desafiante, devido ao aparecimento de novas resistências generalizadas. O desenvolvimento de novos fármacos com atividade antimalárica, consiste agora na identificação de novos quimiotipos com diversos modos de ação inovadores para atuar nas diferentes fases da vida do parasita. Recentemente, um conjunto de composto contendo o núcleo de indole apresentaram potente atividade antimalárica e estes representam uma nova classe com interesse químico e biológico. Azaindoles, que são bioisoteres do indole, e os seus derivados apresentam uma atividade biológica significativa e o uso deste tipo de esqueleto-base tem contribuído para o aparecimento de novos agentes terapêuticos. Neste trabalho é descrita a síntese de nove azaindoles a partir de amino-orto-halopiridinas, de modo a explorar novos possíveis alvos terapêuticos com atividade antimalária. Este procedimento consistiu numa reação de etapa única envolvendo N-arilação catalisada por paládio, seguido de reação de Sonogashira e subsequente ciclização. A actividade biológica dos azaindoles sintetizados foi avaliada in vitro contra Plasmodium falciparum. Os resultados obtidos indicaram que quatro dos nove novos compostos apresentaram atividade contra a malária. Para identificar o binding mode e a proteína mais favorável foram usados algoritmos de machine learning para analisar as bases de dados, resultando na identificação da CGMP-dependent protein kinase como alvo promissor. Os estudos de docking estão concordantes com a bioatividade obtida, sugerindo um elevado potencial para as moléculas testadas como agentes antimaláricos.Marques, Maria ManuelMoreira, RuiRUNCunha, José Carlos Ferreira da2022-01-212025-01-01T00:00:00Z2022-01-21T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/133287enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:11:56Zoai:run.unl.pt:10362/133287Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:47:45.404624Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
title |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
spellingShingle |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles Cunha, José Carlos Ferreira da Malaria N-heterocycles Pd-catalyzed reactions docking biological evaluation Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química |
title_short |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
title_full |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
title_fullStr |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
title_full_unstemmed |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
title_sort |
Expanding the toolbox of chemical tools to target malaria parasites with azaindoles |
author |
Cunha, José Carlos Ferreira da |
author_facet |
Cunha, José Carlos Ferreira da |
author_role |
author |
dc.contributor.none.fl_str_mv |
Marques, Maria Manuel Moreira, Rui RUN |
dc.contributor.author.fl_str_mv |
Cunha, José Carlos Ferreira da |
dc.subject.por.fl_str_mv |
Malaria N-heterocycles Pd-catalyzed reactions docking biological evaluation Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química |
topic |
Malaria N-heterocycles Pd-catalyzed reactions docking biological evaluation Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química |
description |
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. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-01-21 2022-01-21T00:00:00Z 2025-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
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publishedVersion |
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http://hdl.handle.net/10362/133287 |
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http://hdl.handle.net/10362/133287 |
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eng |
language |
eng |
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info:eu-repo/semantics/embargoedAccess |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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