Synthesis and structure-activity relationships of antimalarial 4-oxo-3-carboxyl quinolones

Abstract

Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development.

Figure 1

Reference compounds

Figure 2

Determination of quinolone/quinoline tautomerism of compound 7 in DMSO by NOE.

Figure 3

Activity and physicochemical property summary sorted by therapeutic index. Antimalarial activity is represented as the EC₅₀ value in green, with darker squares indicating higher potency. Cytotoxicity data is represented as the percentage cell death relative to untreated control at a fixed 27.5 μM screening concentration in orange, with lighter squares indicating more cell death. The therapeutic index is represented as a ratio of the cytotoxicity value in HEK 293 cells to the EC₅₀ in the K1 strain in blue, with darker squares indicating higher potency (LD₅₀ in HEK 293 cells applied to estimate the therapeutic index.). Permeability (PAMPA) at pH 7.4 is represented in purple, with darker squares indicating higher permeability. Solubility is represented in yellow, with darker squares indicating higher solubility.

Scheme 1. Synthesis of 4(1H)-quinolones

^a Reagents and conditions: a) EtOH, 130 °C, 3 h; b) Ph₂O, reflux, 4–6 h; c) 5% Pd/C, H₂, MeOH, rt, overnight; d) POCl₃, 1,4-dioxane, 120 °C, 1 h; e) m-chloroperbenzoic acid, CHCl₃, rt, 4 h; f) POBr₃, CHCl₃, rt, 1 h. g) 3,4-methylenedioxyphenyl boronic acid, Pd(PPh₃)₄, CsCO₃, 1,4-dioxane/H₂O, 75 °C, 3 h; h) AcOH/H₂O (4:1), 120 °C, 1 h.

Scheme 2. Synthesis of 3-carboxylic acid and 3-carboxylic amide quinolones

^a Reagents and conditions: a) NaOH (1 N, aqueous), 130 °C, overnight; b) KOH (1 N, aqueous), 75 °C, overnight; c) N,N′-carbonyldiimidazole, DMF, 65 °C, 2.5 h, NH₄OH (aqueous), rt, overnight.

Scheme 3. Synthesis of 4-methoxy and 4-methylamino derivatives

^a Reagents and conditions: a) NaOMe, MeOH/THF, 85 °C, 30 min; b) MeNH₂ (2 N in MeOH), THF, 85 °C, 30 min.

Scheme 4. Reduction of 4-chloroquinolines 19

^a Reagents and conditions: a) 5% Pd/C, H₂, Et₃N, MeOH/THF, rt, overnight; b) DIBAL, THF, 0 °C to rt. 7 h; c) LiAlH₄, THF, −42 °C, 1 h, rt, overnight; d) NaH (60% dispersion on mineral oil), EtI, THF, overnight.

Scheme 5. Exploring the 2-aryl group

^a Reagents and conditions: a) ArB(OH)₂, Pd(PPh₃)₄, CsCO₃, 1,4-dioxane/H₂O, 75 °C, 3 h; b) AcOH/H₂O (4:1), 120 °C, 1 h.