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Projeto de investigação
Discovery of novel Quinolone-based antimalarials using the Winterfeldt chemistry
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Discovery of novel antimalarials using the witkop-winterfeldt and indole chemistries
Publication . Silva, Gustavo Da; Moreira, Rui Ferreira Alves; Silva, Artur Manuel Soares da
Despite excellent drug discovery programs and unprecedent commitment to eliminate malaria, this protozoan disease remains a major cause of mortality and morbidity worldwide, and specially in developing nations. Apart from socio-economic issues, drug-resistance seems to be the major causing factor for the malaria incidence in these countries.
This project aimed to disclose new leads that are active against drug-resistant malaria parasites, acting as multi-stage antimalarials with new mechanisms of action (MoA). A common synthetic strategy was explored to prepare new chemical entities (NCE) and structurally related heterocycles, which included the synthesis of indoles, quinolones and spiroindolones.
A library of pyrroloquinolones was prepared based on the Winterfeldt chemistry. The Winterfeldt precursors were usually prepared based on Pictet-Spengler reactions, followed by N-acylation or N-alkylation. A pyrroloquinolone lead was disclosed from this small library, with nanomolar antimalarial activity, against blood-stage and liver stage parasites. The lead compound revealed to be a DHODH and cytochrome bc1 inhibitor, targeting two components of the plasmodial mitochondrial electron transport chain, and favorable pharmacokinetic properties. The lead compound also revealed to be stable (absence of putative hydroxylated metabolites), after incubation with human and mouse liver microsomes.
A secondary library of polyfunctionalized indoles was prepared via A3 coupling of aldehydes, amines and alkynes. The exploratory project that aimed for the diversity-oriented synthesis of novel pyrroloquinoles yielded a synthetic intermediate with low sub-micromolar antimalarial activity against drug-sensitive and drug-resistant blood stage malaria parasites with unknown MoA, which has an inhibitory activity comparable to the most potent indole antimalarials known. The lead compound from this library enabled systemic exposure after oral administration and limited aqueous kinetic solubility.
A tertiary library of spiroindolones was also prepared, using previously prepared Winterfeldt precursors. The extension of this preliminary strategy of repurposing tetrahydro-ß-carbolines as synthetic intermediates for oxidative rearrangement yielded unprecedented antimalarial spiroindolones with nanomolar activity against drug-sensitive and drug-resistant blood-stage malaria parasites.
This project was a contribution for the development of three small libraries of synthetically related N-containing heterocycles, with promising antimalarial activity.
Facile access to structurally diverse antimalarial indoles using a one‐pot A3 coupling and domino cyclization approach
Publication . Silva, Gustavo Da; Luz, André F. S.; Duarte, Denise; Fontinha, Diana; Silva, Vera L. M.; Almeida Paz, Filipe A.; Madureira, Ana Margarida; Simões, Sandra; Prudêncio, Miguel; Nogueira, Fátima; Silva, Artur M. S.; Moreira, Rui
A multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
OE
Número da atribuição
SFRH/BD/103412/2014