4 research outputs found
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