1354745-52-0Relevant articles and documents
Scalable Multigram Syntheses of Antimalarial 4(1H)-Quinolones ELQ-300 and P4Q-391
Namelikonda, Niranjan K.,Monastyrskyi, Andrii,Manetsch, Roman
, p. 3328 - 3334 (2017)
Antimalarial compounds ELQ-300 and P4Q-391 are highly potent against the blood and the liver stages of the Plasmodium parasite and also possess potent transmission-blocking activity. Gram amounts of these two compounds were required for extensive assessment of in vivo efficacy, pharmacokinetics, and safety. Several deficiencies existed in the original synthetic routes of ELQ-300 and P4Q-391 including reliance on toxic heavy-metal reagents, harsh reaction conditions, and several low-yielding steps. Herein, we report the development of two alternative syntheses, which are reliable, high yielding, scalable, and have the potential to become a route of choice at process scale.
New Scalable Synthetic Routes to ELQ-300, ELQ-316, and Other Antiparasitic Quinolones
Pou, Sovitj,Dodean, Rozalia A.,Frueh, Lisa,Liebman, Katherine M.,Gallagher, Rory T.,Jin, Haihong,Jacobs, Robert T.,Nilsen, Aaron,Stuart, David R.,Doggett, J. Stone,Riscoe, Michael K.,Winter, Rolf W.
, p. 1841 - 1852 (2021/08/24)
The endochin-like quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised, which would lower costs and be amenable to large-scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial-scale production, is relatively short (five reaction steps), does not require palladium, chromatographic separation, or protecting group chemistry, and may be performed without high vacuum distillation.
Discovery, synthesis, and optimization of antimalarial 4(1 H)-quinolone-3-diarylethers
Nilsen, Aaron,Miley, Galen P.,Forquer, Isaac P.,Mather, Michael W.,Katneni, Kasiram,Li, Yuexin,Pou, Sovitj,Pershing, April M.,Stickles, Allison M.,Ryan, Eileen,Kelly, Jane Xu,Doggett, J. Stone,White, Karen L.,Hinrichs, David J.,Winter, Rolf W.,Charman, Susan A.,Zakharov, Lev N.,Bathurst, Ian,Burrows, Jeremy N.,Vaidya, Akhil B.,Riscoe, Michael K.
, p. 3818 - 3834 (2014/05/20)
The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
