N-Substituted Bridged Azaozonides as Promising Antimalarial Agents.

Forty-five aminoperoxides belonging to bridged azaozonides, bridged N-substituted azaozonides, and tricyclic aminoperoxides were evaluated for in vitro antimalarial activity against Plasmodium falciparum (3D7) and for cytotoxicity against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines, as well as human liver (HepG2) and lung (A549) cancer cell lines. Seven N-substituted azaozonides exhibited high antimalarial activity against the chloroquine-sensitive 3D7 strain of P. falciparum, with IC50 < 1 μM. The lead compound 22 showed IC50 = 0.07 μM and selectivity index of 1428. Most aminoperoxides were generally non-cytotoxic to both normal and cancer liver and lung cells. Only two azaozonides exhibited moderate cytotoxicity on HepG2 cell line (2: IC50 = 4.12 μM, 40: 9.95 μM), while one azaozonide 2 had an IC50 = 5.56 μM against A549 cell line. From this small library of 45 aminoperoxides, compound 22 was found to have antimalarial activity comparable to artemisinin and chloroquine used in medical practice. These findings provide a new source for developing antimalarial agents through structural modification of aminoperoxide compounds.