3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance

Abstract

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331, exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596, a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598, a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

Keywords: antimalarial drug; next-generation ELQs; oral prophylaxis; structure−activity relationships.

Figure 1

Structures of coenzyme Q_8–9, endochin, ELQ-300, ELQ-331, ELQ-596, and ELQ-598.

Scheme 1. Synthesis of ELQ-596

Reaction (a): POCl₃, methylene chloride (DCM), reflux, 93%; (b): Pd(dppf)Cl₂, bis(pinacolato)diboron, KOAc, DMF, 80 °C, 71%; (c): Pd(dppf)Cl₂, K₂CO₃, DMF, 80 °C, 71%; (d): KOAc, AcOH, 120 °C, 85%.

Scheme 2. Two Different Approaches to the Chemical Synthesis of 3-Biaryl-ELQs Substituted in the Quinolone Core or Biaryl Side Chain

Scheme 3. Synthesis of β-Keto Esters 9a and 9b

Reaction (a): (4-(trifluoromethoxy)phenyl) boronic acid, Pd(dppf)Cl₂, K₂CO₃, DMF, 80 °C, 58%; (b): LiHMDS, Ac₂O, and THF, −20 °C to RT over 20–72 h; (c) 10% p-TsOH and AcOH, 100 °C over 2–16 h, 89–100%.

Scheme 4. Synthesis of a Series of 3-Biaryl-ELQs with Variable Substitution of the Benzenoid Ring (X, Y, and Z) from β-Ketoester 9b

Reaction (a): 10% p-TsOH, benzene, reflux, 24–72 h; (b): Dowtherm A, 250 °C, 5 min, 28–37%.

Scheme 5. Synthesis of 3-(4-Bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline 14 from β-Ketoester 9a

Reaction (a): 10% p-TsOH, benzene, reflux, 21 h; (b): Dowtherm A, 250 °C, 5 min, 50%; POCl₃, reflux, 45 min, 100%.

Scheme 6. Synthesis of a Series of 3-Biaryl-ELQs with Structural Variation at the Terminal Benzene Ring

Reaction (a): Pd(dppf)Cl₂, K₂CO₃, DMF, 80 °C, 11–67%; (b): KOAc, AcOH, 16–24 h, 36–87%, (c): Pd(dppf)Cl₂, BPin₂, KOAc, DMF, 80 °C, 46%.

Scheme 7. Synthesis of Alkoxy Carbonate Prodrug ELQ-598

Reaction: (a) chloromethyl ethyl carbonate, TBAI, K₂CO₃, and DMF, 60 °C, 24 h, 73%.

Figure 2

Mean ELQ-596 and ELQ-598 plasma concentration–time profiles after dosing with a single dose ELQ-598: (A) 10 mg/kg PO dose and (B) 0.3 mg/kg IV dose.

Figure 3

Docked complex of ELQ-596 at Qi site of the P. falciparum cytochrome b subunit of the cyt bc₁ complex. (A, B) The cytochrome b subunit is represented as ribbons and colored green, heme is represented in the stick model and colored orange, ELQ-596 is colored by atom type (C: cyan, O: red, N: blue, Cl: dark green), and interacting residues are colored gray and labeled. The distance of interaction is shown in yellow dotted lines (C) Schematic mapping of ELQ-596 interactions with the cytochrome b subunit is shown with scheme legend below generated using Molecular Operating Environment (MOE).

Figure 4

Structures of ELQ-300, ELQ-307, and ELQ-596. Arrows show the rotational flexibility of selected ELQs with and without the ethereal oxygen atom in the 3-position side chain.

Figure 5

This is an overlay of the ORTEP (Oak Ridge Thermal Ellipsoid Plot) diagrams of ELQ-331 (bold lines) and ELQ598 (dashed lines). Ellipsoids are drawn at the 30% probability level. These structures were generated from X-ray diffraction patterns of ELQ-331 and ELQ-598 crystals. The image shows that the quinoline core nucleus remains a constant structural feature of both molecules whereas the rigid biaryl ring system of ELQ-598 projects into chemical space not occupied by the angular diphenylether side chain of ELQ-331.