Synthesis and Structure–Activity Relationships of the Novel Antimalarials 5‑Pyridinyl-4(1<i>H</i>)‑Pyridones

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 <i>Plasmodium</i> strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4­(1<i>H</i>)-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<i>H</i>)-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

Case Study of Small Molecules As Antimalarials: 2‑Amino-1-phenylethanol (APE) Derivatives

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4–0.5 μM are able to show in vivo activity

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (<b>1</b>), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as <b>19</b> with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (<b>1</b>), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as <b>19</b> with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile