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

ACS Omega
Camila de Souza BarbosaGustavo Henrique Ribeiro Viana

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.

References

Aug 20, 1976·Science·W Trager, J B Jensen
Apr 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·D E GoldbergG B Henderson
Dec 13, 2000·Mutation Research·K Mortelmans, E Zeiger
May 23, 2002·Antimicrobial Agents and Chemotherapy·Harald NoedlChansuda Wongsrichanalai
Apr 5, 2007·Nature Protocols·Peggy L Olive, Judit P Banáth
Jun 5, 2007·Nature Protocols·Michael Fenech
Jun 4, 2011·Genetics and Molecular Biology·Cristiano C GomesFabio V Santos
Jun 15, 2011·Chemical Biology & Drug Design·Flaviane F HilárioFernando de Pilla Varotti
Jul 23, 2013·Angewandte Chemie·Theresa LiangTobias Ritter
Jul 22, 2014·Angewandte Chemie·K C Nicolaou
Aug 5, 2014·Marine Drugs·Alessandra Mirtes Marques Neves GonçalvesGustavo Henrique Ribeiro Viana
Jun 10, 2015·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Rodrigo Pinheiro AraldiRita de Cassia Stocco
Jun 27, 2015·European Journal of Medicinal Chemistry·Vanessa Silva GontijoRossimiriam Pereira Freitas
Jul 23, 2015·Journal of Medicinal Chemistry·Eric P GillisNicholas A Meanwell
Oct 6, 2015·Nature Reviews. Drug Discovery·Kei KatsunoB T Slingsby
Jan 20, 2016·Drug Discovery Today·Tina S Skinner-AdamsKatherine T Andrews
Mar 10, 2016·Journal of Chemical Information and Modeling·Renato Márcio Ribeiro VianaClebio Soares Nascimento
Jun 16, 2016·Nature Communications·Victoria C CoreyElizabeth A Winzeler
Jun 16, 2016·Chemistry : a European Journal·Debangsu SilSankar Prasad Rath
Nov 26, 2016·European Journal of Medicinal Chemistry·Mitali MishraSushil Kumar Kashaw
Dec 13, 2016·Trends in Parasitology·Irene N NkumamaFaith H A Osier
Jan 15, 2017·Malaria Journal·Jeremy N BurrowsTimothy N C Wells

❮ Previous
Next ❯

Citations

Dec 2, 2020·Materials Science & Engineering. C, Materials for Biological Applications·Renata Bem Dos SantosSandra Elisa Haas
Feb 9, 2021·Mutation Research. Genetic Toxicology and Environmental Mutagenesis·Júlia Teixeira de OliveiraFabio Vieira Dos Santos
May 20, 2021·Chemical Biology & Drug Design·Shiyang Zhou, Gangliang Huang

❮ Previous
Next ❯

Methods Mentioned

BETA
ELISA
chemical treatment
electrophoresis
confection
column chromatography

Software Mentioned

Gaussian
SALANAL
Origin
OriginPro

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

© 2022 Meta ULC. All rights reserved