RESUMEN
Malaria is a tropical parasitic disease threatening populations in tropical and sub-tropical areas. Resistance to antimalarial drugs has spread all over the world in the past 50 years, thus new drugs are urgently needed. Plasmodione (benzylmenadione series) has been identified as a potent antimalarial early lead drug, acting through a redox bioactivation on asexual and young sexual blood stages. To investigate its metabolism, a series of plasmodione-based tools, including a fully 13C-labelled lead drug and putative metabolites, have been designed and synthesized for drug metabolism investigation. Furthermore, with the help of UHPLC-MS/MS, two of the drug metabolites have been identified from urine of drug-treated mice.
Asunto(s)
Antimaláricos/síntesis química , Vitamina K 3/análogos & derivados , Vitamina K 3/síntesis química , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacología , Isótopos de Carbono , Resistencia a Múltiples Medicamentos , Humanos , Marcaje Isotópico , Ratones , Oxidación-Reducción , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Vitamina K 3/metabolismo , Vitamina K 3/farmacologíaRESUMEN
In the context of the investigation of drug-induced oxidative stress in parasitic cells, electrochemical properties of a focused library of polysubstituted menadione derivatives were studied by cyclic voltammetry. These values were used, together with compatible measurements from literature (quinones and related compounds), to build and evaluate a predictive structure-redox potential model (quantitative structure-property relationship, QSPR). Able to provide an online evaluation (through Web interface) of the oxidant character of quinones, the model is aimed to help chemists targeting their synthetic efforts towards analogues of desired redox properties.
RESUMEN
Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The Ag(II)-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO(3) and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of ß-hematin.