Orally Bioavailable 6-Chloro-7-methoxy-4(1H)-quinolones Efficacious against Multiple Stages of Plasmodium

Abstract

The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure–activity and structure–property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

Metal-Free Arylation of Ethyl Acetoacetate with Hypervalent Diaryliodonium Salts: An Immediate Access to Diverse 3-Aryl-4(1H)-Quinolones

“…: >300°C (decomp); Analytic data matches with the previously reported. 23 1 H NMR (500 MHz, DMSO) δ 11.75 (s, 1H), 8.00 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 3.96 (s, 3H), 2.22 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 173.2, 156.9, 146.9, 140.4, 139.6, 131.9, 127.1 (q, J = 31.6 Hz), 126.1, 124.6 (q, J = 3.6 Hz), 124.5 (q, J = 271.9 Hz), 119.4, 118.7, 118.3, 99.5, 56.4, 18.9.…”

Antibiotics in malaria therapy: which antibiotics except tetracyclines and macrolides may be used against malaria?

“…Recently, new substituted compounds based on endochin with a 4(1 H )-quinolone scaffold displayed activity against multi-drug resistant P. falciparum isolates at low nanomolar range. They targeted the Plasmodium bc 1 complex without cross-resistance with atovaquone, demonstrated erythrocytic and exoerythrocytic activity and transmission blocking, and improved metabolic stability in the presence of cytochrome P450 [69–74]. Some of these analogues (quinolone-3-diarylethers) were also highly active against Plasmodium vivax isolates [75].…”

Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities

“…6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.…”

“…6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.Our attention is drawn to decoquinate (DQ, 1) that has been used for many years in veterinary medicine largely coadministered with poultry feed for treatment of coccidiosis wherein it displays negligible toxicity. 13,14 It is also used against other apicomplexan infections in animals 15 and is highly active in a murine model against Toxoplasma gondii.…”