Development of a new generation of 4-aminoquinoline antimalarial compounds using predictive pharmacokinetic and toxicology models

Abstract

Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability. Yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMET prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC(50) values of 5.6 and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (for CQ, IC(50) = 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials.

Figure 1

Structures of 4-aminoquinolines compounds used to profile the ADMET properties for the series.

Figure 2

Relative percentages of metabolites for 8 (A) and 10 (B) identified by LC/MS after incubation with pooled human microsomes.

Figure 3

Inhibition of CYP2D6 enzyme activity by the test articles. Graph shows the amount of the metabolite 1′-OH-bufuralol produced in the presence of each test article (1 μM) as a percentage of control (no drug). Values <70% indicate significant inhibition.

Figure 4

Cytotoxic effects of the compounds on isolated rat hepatocytes. (a) MTT assay, (b) LDH assay

Figure 5

Plasma drug concentration in male CD-1 mice after a single oral dose at 50 mg/kg.

Scheme 1

Synthesis of side chain substituted secondary amines. Reagents and Conditions: (a) RCHO (4 eq.), MeOH, 16 h.; (b) NaBH₄ (4 eq.), MeOH, 2 h.