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

Abstract

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 <i>Plasmodium falciparum</i>. The most active compound <b>5c</b> 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 <b>7</b>), and its antimalarial activity was re-evaluated. Compound <b>7</b> exhibited optimized antimalarial properties (<i>P. falciparum</i> 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.