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Target-Guided Synthesis and Antiplasmodial Evaluation of a New Fluorinated 3‑Alkylpyridine Marine Alkaloid Analog

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journal contribution
posted on 21.11.2017, 13:40 by Camila de Souza Barbosa, Daniel Silqueira Martins Guimarães, Alessandra Mirtes Marques Neves Gonçalves, Maria Cristina da Silva Barbosa, Marília Ladeira Alves e Costa, Clébio Soares Nascimento Júnior, Luciana Guimarães, Renato Márcio Ribeiro-Viana, Fabio Vieira dos Santos, Cristiana Ferreira Alves de Brito, Fernando de Pilla Varotti, Gustavo Henrique Ribeiro Viana
The need to develop new alternatives for antimalarial treatment is urgent. Herein, we report the synthesis and antimalarial evaluation of a small library of synthetic 3-alkylpyridine marine alkaloid (3-APA) analogs. First, the compounds were evaluated in vitro against Plasmodium falciparum. The most active compound 5c was selected for optimization of its antimalarial properties. An in silico approach was used based on pure ab initio electronic structure prediction, and the results indicated that a substitution of the hydroxyl group by a fluorine atom could favor a more stable complex with heme at a molecular ratio of 2:1 (heme/3-APA halogenated). A new fluorinated 3-APA analog was synthesized (compound 7), and its antimalarial activity was re-evaluated. Compound 7 exhibited optimized antimalarial properties (P. falciparum IC50 = 2.5 μM), low genotoxicity, capacity to form a more stable heme/3-APA complex at a molecular ratio of 2:1, and conformity to RO5. The new compound, therefore, has great potential as a new lead antimalarial agent.

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