Spirofused Tetrahydroisoquinoline-Oxindole Hybrids (Spiroquindolones) as Potential Multitarget Antimalarial Agents: Preliminary Hit Optimization and Efficacy Evaluation in Mice

Abstract

Previous studies suggest that 3′,5′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones (DSIIQs [spiroquindolones]) are multitarget antiplasmodial agents that combine the actions of spiroindolone and naphthylisoquinoline antimalarial agents. In this study, 12 analogues of compound (±)-5 (moxiquindole), the prototypical spiroquindolone, were synthesized and tested for antiplasmodial activity. Compound (±)-11 (a mixture of compounds 11a and 11b), the most potent analogue, displayed low-nanomolar activity against P. falciparum chloroquine-sensitive 3D7 strain (50% inhibitory concentration [IC 50 ] for 3D7 = 21 ± 02 nM) and was active against all major erythrocytic stages of the parasite life cycle (ring, trophozoite, and schizont); it also inhibited hemoglobin metabolism and caused extensive vacuolation in parasites. In drug-resistant parasites, compound (±)-11 exhibited potent activity (IC 50 for Dd2 = 58.34 ± 2.04 nM) against the P. falciparum multidrug-resistant Dd2 strain, and both compounds (±)-5 and (±)-11 displayed significant cross-resistance against the P. falciparum ATP4 mutant parasite Dd2 SJ733 but not against the Dd2 KAE609 strain.