RESUMO
CsOH- or Ag(2)O-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n-dihaloalkanes (n = 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in moderate yields. Subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8 in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro[7.11]nonadecane 4a has considerable potential as a new, inexpensive, and potent antimalarial drug.
Assuntos
Antimaláricos/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos de Espiro/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Césio , Ciclização , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Hidróxidos , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Óxidos , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Compostos de Prata , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Monoozonolyses of dienes 2 in methanol gave in each case the corresponding unsaturated alpha-methoxy hydroperoxides 3. Capture of 2-alkyl-substituted cyclohexanone oxides by methanol was highly diastereoselective, thereby providing exclusively the hydroperoxides derived from attack by methanol from the less hindered face of the carbonyl oxide intermediates. Halonium ion-mediated reactions of the hydroperoxides 3 gave the novel methoxy- or hydroxy-migrated products, together with the expected halogen-substituted 1, 2-dioxanes and/or 1,2-dioxepanes, the composition of the product mixture being a function of the halogenating agent utilized and the structure of 3.
Assuntos
Acetais/síntese química , Antimaláricos/síntese química , Dioxanos/síntese química , Peróxidos/síntese química , Acetais/química , Antimaláricos/química , Ciclização , Dioxanos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Metanol/metabolismo , Modelos Moleculares , Peróxidos/químicaRESUMO
Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) 3 and 4 were designed as metabolically stable analogues of the dimethyl-substituted dispiro-1, 2,4,5-tetraoxane prototype WR 148999 (2). For a positive control we selected the sterically unhindered tetraoxane 5 (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecane), devoid of any substituents. Tetraoxanes 3 and 4 were completely inactive in contrast to tetraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes possess sufficient steric hindrance about the tetraoxane ring due to the two additional axial methyl groups to prevent their activation to presumed parasiticidal carbon radicals by inhibiting electron transfer from heme or other iron(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both spirocyclohexyl rings are in a chair conformation and the bond lengths and angles are all quite normal except for the C1-C2 bond which is slightly lengthened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 reveals that molecular mechanics (MMX and MM3) and 3-21G calculations each gave accurate structural parameters such as bond lengths, bond angles, and dihedral angles. In contrast, semiempirical methods such as AM1 gave poor results.
