RESUMO
Thirty-three N-acyl 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. For these ozonides, weak base functional groups were not required for high antimalarial potency against Plasmodium falciparum in vitro, but were necessary for high antimalarial efficacy in Plasmodium berghei-infected mice. A wide range of LogP/D(pH)(7.4) values were tolerated, although more lipophilic ozonides tended to be less metabolically stable.
Assuntos
Antimaláricos/síntese química , Compostos Heterocíclicos/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Camundongos , Plasmodium falciparum/efeitos dos fármacos , RatosRESUMO
Fourteen spiro- and dispiro-1,2-dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperoxyketals and -acetals derived from ozonolysis of alkenes. The 1,2-dioxolanes were either inactive or orders of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-dioxolane 3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms that permits rapid beta-scission reactions (or H shifts) to form primary or secondary carbon-centered radicals rather than further reduction of the initially formed Fe(III) complexed oxy radicals.
Assuntos
Antimaláricos/síntese química , Dioxolanos/síntese química , Compostos Ferrosos/química , Peróxidos/síntese química , Compostos de Espiro/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Resistência a Medicamentos , Malária/tratamento farmacológico , Camundongos , Oxirredução , Peróxidos/química , Peróxidos/farmacologia , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
With an aim to identify a dispiro-1,2,4-trioxolane with high oral activity and good physicochemical properties, 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL. The oral efficacies of two of these were superior to artesunate and comparable to artemether. The attractive chemical simplicity of these compounds is balanced only by an apparent metabolic susceptibility.
Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Piperidinas/farmacologia , Aminas/química , Aminas/farmacocinética , Aminas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Humanos , Camundongos , Microssomos Hepáticos/fisiologia , Piperidinas/química , Piperidinas/farmacocinética , Plasmodium berghei/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Ureia/química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
Based on the structures of several lipophilic trioxolane antimalarial prototypes, we set out to determine which functional groups were associated with good antimalarial profiles and identify more polar (lower LogP/LogD) lead compounds with good physicochemical properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles.