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 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.

Synthesis, and antimalarial and antibacterial activities of marine alkaloids

“…In the process of screening the activity of natural products, the 3‐alkylpyridine marine alkaloids and their analogues were found to have antimalarial activity. On this basis, Camila de Souza Barbosa et al (Barbosa et al., 2017) further modified the structure of the lead compound and designed a new type of 3‐alkylpyridine marine alkaloid analogues. To improve antimalarial activity, selectivity, and safety, they selected different lengths of alkyl chains and the types of functional groups attached to the ends of the chains to further investigate the structure–activity relationships (SARs) of the designed compounds.…”

Evaluation of Antiplasmodial Activity in Silico and in Vitro of N-Acylhydrazone Derivatives

“…The use in silico approaches has become increasingly frequent in malaria, mainly as a tool that helps to describe the mechanism of action and reaction of antimalarials [26,27,28,29,30]. Knowledge about these mechanisms helps to predict possible unwanted interactions with other targets, in addition to guiding research aimed at structurally altering existing drugs, against which the parasite is already resistant in order to make them effective again [11,31].…”