RESUMEN
Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.
Asunto(s)
Aminoquinolinas/síntesis química , Antimaláricos/síntesis química , Clotrimazol/análogos & derivados , Clotrimazol/síntesis química , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Transporte Biológico , Línea Celular , Cloroquina/farmacocinética , Cloroquina/farmacología , Clotrimazol/farmacocinética , Clotrimazol/farmacología , Resistencia a Medicamentos , Femenino , Semivida , Hemoproteínas/antagonistas & inhibidores , Hemoproteínas/biosíntesis , Humanos , Malaria/tratamiento farmacológico , Malaria/parasitología , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/fisiología , Ratones , Modelos Moleculares , Mutación , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Piperazinas/síntesis química , Piperazinas/farmacocinética , Piperazinas/farmacología , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/genética , Proteínas Protozoarias/fisiología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Presión Ventricular/efectos de los fármacos , Xenopus laevisRESUMEN
Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
Asunto(s)
Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Antipsicóticos/química , Antipsicóticos/clasificación , Sitios de Unión , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Ratones , Modelos Moleculares , Estructura Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.
Asunto(s)
Aminoquinolinas/farmacología , Antimaláricos/farmacología , Clotrimazol/farmacología , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Línea Celular , Clotrimazol/química , Clotrimazol/farmacocinética , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Plasmodium/efectos de los fármacos , Ratas , Especificidad de la Especie , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
The design, synthesis, and antiplasmodial activity of antimalarial heterodimers based on the 1,4-bis(3-aminopropyl)piperazine linker is reported. In this series key structural elements derived from quinoline antimalarials were coupled to fragments capable of coordinating metal ions. Biological evaluation included determination of activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. Some of the novel compounds presented high activity in vitro against chloroquine-resistant strains, more potent than chloroquine and clotrimazole. Computational studies revealed that the activity is likely due to the ability of the compounds to assume a multisite iron coordinating geometry.