Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ.The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.Mefloquine (MQ) is a quinoline methanol derivative with a high schizontocide activity against Plasmodium species. This molecule possesses two asymmetric carbon atoms (Figure 1) and a long half-life (circa 14 days) [1,2]. The latter propriety can be seen as a therapeutic advantage as a lower rate of relapses has been reported for anti-malarials with long half-lives [3]. Additionally, it also allows a weekly administration, making MQ a good candidate for long-term prophylactic treatments through improved compliance [4]. Despite an overall acceptable tolerability, dose-related neuropsychiatric adverse effects can occur [4,5], therefore, contraindicating MQ in individuals with a history of epilepsy or psychiatric disease. The opening of the piperidine ring at the 4-position of the quinoline scaffold was reported to yield molecules with a better potency and a lesser neurotoxicity than that of MQ [6]. The same team recently described a series of MQ non-piperidine analogs displaying a lower penetrat