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

Abstract

Background: The 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.

Methods: A 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.

Results: The 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.

Conclusions: A 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.

Figure 1

Structure of mefloquine and synthesis of 4-position library. The structure of mefloquine is indicated (1). The intermediate scaffold 4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (3) was synthesized from bis(trifluoromethyl)quinolin-4-ol (2) by the addition of POBr₃, at 75°C - 150°C for 2 h with 91% yield. The resulting 4-bromo-2,8-bis(trifluoromethyl) quinoline was dissolved in tetrahydrofuran, cooled to -78°C and subjected to n-butyllithium. N,N-dimethylformamide was subsequently added to afford 2,8-bis(trifluoromethyl)quinoline-4-carbaldehyde. Utilization of Corey's dimethylsulfonium methylide provided racemic epoxide (3). The epoxide (3) can also be purchased commercially from Bioblocks (San Diego, California). The quinoline scaffold (3) was diversified at the 4-position in a single step with commercially available nucleophiles.

Figure 2

Structures and IC90s of the most potent quinoline methanols. IC90s are against the mefloquine resistant Pf C2A strain.

Figure 3

Structures and key biological data for diamine quinoline methanols. The P. falciparum IC90 and RAW macrophage LC50 data for mefloquine are presented as the mean +/- standard deviation. The LC50 values are against the macrophage cell line. Papp/recovery refers to the apparent permeability in the apical direction across MDR1-transfected MDCK cell monolayers (units in 10^-6 cm/s) and the % recovery for each compound at the end of the experiment.