Synthesis and Structure–Activity Relationships of the Novel Antimalarials 5‑Pyridinyl-4(1H)‑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 con...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-04, Vol.61 (8), p.3422-3435 |
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| creator | Bueno, José M Calderon, Félix Chicharro, Jesús De la Rosa, Juan C Díaz, Beatriz Fernández, Jorge Fiandor, José M Fraile, María T García, Mercedes Herreros, Esperanza García-Pérez, Adolfo Lorenzo, Milagros Mallo, Araceli Puente, Margarita Saadeddin, Anas Ferrer, Santiago Angulo-Barturen, Iñigo Burrows, Jeremy N León, María L |
| description | 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(1H)-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(1H)-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. |
| doi_str_mv | 10.1021/acs.jmedchem.7b01256 |
| format | Article |
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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(1H)-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(1H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. 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Med. Chem</addtitle><date>2018-04-26</date><risdate>2018</risdate><volume>61</volume><issue>8</issue><spage>3422</spage><epage>3435</epage><pages>3422-3435</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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(1H)-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(1H)-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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>29589932</pmid><doi>10.1021/acs.jmedchem.7b01256</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-5411-0382</orcidid><orcidid>https://orcid.org/0000-0003-0486-6883</orcidid><orcidid>https://orcid.org/0000-0003-0498-9066</orcidid><oa>free_for_read</oa></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - pharmacokinetics Antimalarials - pharmacology Female Mice Molecular Structure Parasitic Sensitivity Tests Plasmodium falciparum - drug effects Plasmodium yoelii - drug effects Pyridones - chemical synthesis Pyridones - chemistry Pyridones - pharmacokinetics Pyridones - pharmacology Structure-Activity Relationship |
| title | Synthesis and Structure–Activity Relationships of the Novel Antimalarials 5‑Pyridinyl-4(1H)‑Pyridones |
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