Synthesis and Structure–Activity Relationships of the Novel Antimalarials 5-Pyridinyl-4(1H)-Pyridones

Abstract

Malaria is still one of the most prevalent parasitic infections in the world, with half of the world's population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1 H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1 H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.

A Comprehensive Review of 4(1H)-Quinolones and 4(1H)-Pyridones for the Development of an Effective Antimalarial

“…Another observation was that replacing the proximal phenyl ring with a pyridine ring maintains the activity and improves pharmacokinetic profiles. This demonstrates the potential of analogues of 13 in hopes of improving pharmacokinetic and toxicology profiles of 4(1H)pyridones [34].…”

Recent Advances of Pyridinone in Medicinal Chemistry

“…In 2018, the same group ( Bueno et al, 2018 ) performed the follow-up exploration starting from the previously developed antagonists 96 . A series of novel “hybrid” polar 4(1 H )-pyridinone derivatives ( 97 ) were obtained by introducing pyridine rings into lipophilic side chains or attaching polar moieties such as hydroxymethyl group to the 4(1 H )-pyridinone cores.…”

“…Heart failure ( Bueno et al, 2018 ) is considered to be the major cause of death in patients with cardiac disease. Among therapeutic targets strengthening myocardial contraction, phosphodiesterase-3 (PDE3) is a validated one that could increase calcium influx in cardiac myocytes and trigger positive inotropic effects, and agents such as milrinone and amrinone have been approved for clinical use ( Thompson et al, 2007 ).…”

Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

“…Octanedioic acid was A second hybrid, for which the ATQ moiety of 4 was replaced by the GW844520 unit, was prepared according to a similar sequence (Scheme 2). GW844520 ( 7) 37 was first prepared via a Suzuki-Miyaura cross-coupling reaction between 3-chloro-5-iodo-2,6-dimethylpyridin-4(1H)-one 5 38 and boronic acid 6, 37 under microwave conditions. Compound 7 was then treated with sodium hydride and the resulting pyridinolate intermediate was reacted with the acyl chloride of compound 3, to give hybrid 8 with a yield of 30 %.…”