Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum

Abstract

Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN.

Figure 1

Chemical structures of active antimalarial drugs.

Figure 2

Stereoisomeric Cinchona alkaloids.

Figure 3

Structures and yields of Cinchona alkaloid derivatives synthesized by the Heck reaction.

Figure 4

Plot of β-hematin inhibitory IC₅₀ vs. antiplasmodial IC₅₀. Black symbols correspond to BHIA IC₅₀ at pH 5.6 and antiplasmodial IC₅₀ against HB3. Grey symbols correspond to BHIA IC₅₀ at pH 5.2 and antiplasmodial IC₅₀ against Dd2. The IC₅₀ value for QN at pH 5.2 is omitted for clarity. QN series derivatives that were not active antiplasmodial agents (and therefore do not have an antiplasmodial IC₅₀) are also not included.