Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols

Abstract

BackgroundThe clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier.MethodsA library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed.ResultsThe most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs). The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability.ConclusionsA drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified.

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

“…Previously, only the activity of a racemic mixture of compound 1 has been described [7]. It was reported to have an IC 90 of 32 nmol/L on P. falciparum strain TM90C2A, resistant to CQ and MQ.…”

Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics

“…For example, the result of the optimisation of AQ-tert-butyl isoquine-does not generate undesirable products when metabolised ( [191]; Fig. 1d), and attempts are underway to design analogues of MQ that do not cross the blood-brain barrier, and which cause fewer adverse side effects [192].…”

Characterization of in vivo metabolites of WR319691, a novel compound with activity against Plasmodium falciparum

“…Moreover, it cannot completely explain the efficacy outcome since we have observed superior efficacy in other quinoline methanols which have demonstrably less microsomal stability (e.g. WR308278) (Milner et al 2010b). It is likely that WR319691 also exhibits lower relative bioavailability than MQ, which would need to be addressed in a new series of analogs.…”

“…We employed a primary in vitro testing cascade involving in vitro susceptibility screening against two drug-resistant strains of P. falciparum (mefloquine resistant D6 and multiple drug resistant C235) and a MDCK permeability assay which we showed previously to be reasonably predictive of maximum brain levels in vivo (Milner et al 2010b). Potential late leads were selected on the basis of exhibiting IC90 s \ 100 ng/ml against at least one strain of Pf together with an apparent permeability \ 7.4 9 1-E-6 cm/s in the A-B direction across MDCK monolayers.…”