Antiplasmodial Activity and Pharmacokinetic Profiling of Cryptolepine and 2,7‐Dibromocryptolepine With a View to Informing the Design of Novel Antimalarial Cryptolepine Analogues

The roots of the climbing shrub Cryptolepis sanguinolenta are traditionally used in West Africa for the treatment of malaria. The principal constituent, cryptolepine (1), has been shown to have antimalarial activity but there are concerns regarding its toxicity on account of its DNA-intercalating property. The synthetic analogue, 2,7-dibromocryptolepine, (2) does not intercalate into DNA and is markedly more active than the parent against Plasmodium sp. in vitro and in vivo. The aim of this study was to carry out a pre-clinical assessment of 1 and 2, and if appropriate, carry out in vivo pharmacokinetic studies. Cryptolepine (1) and 2,7-dibromocryptolepine (2), were evaluated in a range of in vitro assays in line with those recommended by Medicines for Malaria Venture (MMV) for the profiling of a Validated Hit Compound (https://www.mmv.org/frontrunner-templates). In vitro profiling of 1 and 2 showed that 2 is superior to 1 with respect to antiplasmodial activities, and the parasite rate of kill (fast for 2, in contrast with modest for 1); however 2 exhibited potent inhibition of the hERG potassium channel, (IC₅₀ = 1.0 µM compared with 7.8 µM for 1), raising concerns that 2 may be cardiotoxic, so that 2 was not selected for in vivo pharmacokinetic profiling. The studies of cryptolepine (1) pharmacokinetics in the rat revealed a second peak, especially with oral administration, indicating that enterohepatic circulation following biliary excretion may be taking place. This study complements previous pharmacokinetic data of 1 and presents novel data on 2,7-dibromocryptolepine (2) that will inform the development of cryptolepine analogues as potential antimalarial agents.