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

Authors:
Open Access
Publisher website
Google Scholar
Abstract
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, (IC 50 = 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.
Funding Information
  • Bill and Melinda Gates Foundation
  • Medicines for Malaria Venture

This publication has 21 references indexed in Scilit: