RESUMO
A 43-member 1,2-dioxolane library was synthesized by coupling a 1,2-dioxolane-3-acetic acid derivative to a range of amines. Ten compounds had EC(50)s30nM against Plasmodium falciparum 3D7 and Dd2 strains, and another 15 compounds had EC(50)s50nM against both 3D7 and Dd2. The library was then subjected to a range of in vitro DMPK assays, which revealed that side chains with a heteroatom were required for favorable solubility, LogD and membrane permeability. CYP450 inhibition was isoform dependent, with 2C19 and 3A4 particularly susceptible, and the majority of compounds tested against rat and human microsomes were metabolized rapidly.
Assuntos
Antimaláricos/síntese química , Antimaláricos/metabolismo , Inibidores das Enzimas do Citocromo P-450 , Dioxolanos/síntese química , Dioxolanos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Dioxolanos/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Bibliotecas de Moléculas PequenasRESUMO
A focused quinazolinone natural product-templated library was designed and synthesized. Compounds from this privileged structure-based library were identified as antimitotic agents acting through destabilization of tubulin polymerization. The results suggested that 2 could be a privileged substructure.