Methyl-substituted dispiro-1,2,4,5-tetraoxanes: Correlations of structuralstudies with antimalarial activity

Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxa dispiro[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 t etraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes posses s sufficient steric hindrance about the tetraoxane ring due to the two addi tional axial methyl groups to prevent their activation to presumed parasiti cidal carbon radicals by inhibiting electron transfer from heme or other ir on(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both sp irocyclohexyl rings are in a chair conformation and the bond lengths and an gles are all quite normal except for the C1-C2 bond which is slightly lengt hened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 r eveals 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 r esults.