RESUMO
Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
Assuntos
Antimaláricos/farmacologia , Astemizol/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Astemizol/síntese química , Astemizol/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/crescimento & desenvolvimento , Relação Estrutura-Atividade , Regulador Transcricional ERG/antagonistas & inibidores , Regulador Transcricional ERG/metabolismoRESUMO
Astemizole, a H1R antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors. The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low (pK i from 4.4 to 5.6). Three representative compounds were docked into the histamine H1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H4 receptor, a H1/H4-pharmacophore hypothesis was developed.
Assuntos
Astemizol/farmacologia , Indóis/farmacologia , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos/efeitos dos fármacos , Animais , Astemizol/síntese química , Astemizol/química , Feminino , Cobaias , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Piperazinas/síntese química , Piperazinas/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H4 , Células Sf9 , SpodopteraRESUMO
O(2) in, H(2)O out: Various diamines and related bisnucleophiles readily undergo oxidative isocyanide insertion with Pd(OAc)(2) (1 mol %) as the catalyst and O(2) as the terminal oxidant to give a diverse array of medicinally relevant N heterocycles. The utility of this highly sustainable method is demonstrated by a formal synthesis of the antihistamines astemizole and norastemizole.