Parallel synthesis and antimalarial screening of a 4-aminoquinoline library

Abstract

Due to growing problems with drug resistance, there is an outstanding need for new, cost-effective drugs for the treatment of malaria. The 4-aminoquinolines have provided a number of useful antimalarials, and Plasmodium falciparum, the causative organism for the most deadly form of human malaria, is generally slow to develop resistance to these drugs. Therefore, diverse screening libraries of quinolines continue to be useful for antimalarial drug discovery. We report herein the development of an efficient method for producing libraries of 4-aminoquinolines variant in the side chain portion of the molecule. The effects of these substitutions were evaluated by screening this library for activity against P. falciparum, revealing four potent compounds active against drug-resistant strains.

Figure 1

Structure of 7-chloro-4-aminoquinoline library 1.

Figure 2

Structures of aldehyde diversity element 5{1-24}. Boxed elements represent the base structure used for R₂. All elements were used for R₁.

Figure 3

Histogram of purities of product library 1{2,13;1–24} after purification by reversed-phase HPLC. Purity was assessed by analytical HPLC analysis monitored at 220 nm on a reversed-phase C18 column (Column Engineering, ReliaSil C18 BDX, 5 μM).

Figure 4

Relative activity of library 1{2,13;1–24} against Plasmodium falciparum 3D7 in cultured human erythrocytes. Substituents for R₁ are arrayed on the X-axis, broken into groups representing the general structural class of substituents. Substituents for R₂ are shown on the Y-axis. Grayscale shade represents the percent of parasite growth at 30 nm drug concentration relative to untreated cultures. “−“ refers to cultures treated with no drug. “− −“ refers to cultures treated with 30 nM negative control compound 4-amino-7-chloroquinoline. “+” refers to cultures treated with 30 nM Chloroquine. The structures of two representative active compounds are shown above the graphic.

Scheme 1

Synthesis of 4-amino-7-chloroquinoline library 1{1-24;2,13}. a) 1,3-diaminopropane (neat), reflux, 2 h, 83% yield; b) R₁CHO (5{1-24}, 4 eq.), MeOH, rt, 24 h; c) NaBH₄ (5 eq.), rt., 1 h; d) R₂CHO (5{2,13}, 4 eq.), MeOH, rt, 24 h; e) NaBH₄ (5 eq.), rt, 1 h.

SYNOPSIS TOC Due to growing problems with drug resistance, there is an outstanding need for new, cost-effective drugs for the treatment of malaria. The 4-aminoquinolines have provided a number of useful antimalarials and Plasmodium falciparum, the causative organism for the most deadly form of human malaria, is generally slow to develop resistance to these drugs. Therefore, diverse screening libraries of quinolines continue to be useful for antimalarial drug discovery. We report herein the development of an efficient method for the production of libraries of 4-aminoquinolines variant in the substitutions of the sidechain portion of the molecule and the results of screening this library for activity against P. falciparum.