Inherent Flexibility vis-à-vis Structural Rigidity in Chemically Stable Antimalarial Dispiro N-Sulfonylpiperidine Tetraoxanes

Abstract

Structurally diverse and chemically stable tetraoxanes were formed by peroxidation of N-sulfonylpiperidones. X-ray analysis revealed that the crystal structures possess central spiro-2,5-disubstituted tetraoxane rings trans fused to 6-membered piperidine and cyclohexylidene substituents in classical chair conformations. The more flexible cycloheptane ring exhibited pseudorotation between chair and twist chair conformation. The two sulfonyl oxygen atoms act as hydrogen-bonding acceptors and participate in hydrogen bonding. Docking calculations showed that the tetraoxanes are aligned parallel to the plane of the porphyrin ring of heme so that the iron can attack the O−O bond to initiate redox-mediated reaction to render nanomolar antimalarial potency to these compounds against P. falciparum 3D7. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim