Abstract
Malaria caused by Plasmodium falciparum is responsible for approximately 80% of the incidence and 90% of deaths which occur in the World Health Organization (WHO) African region, with children and pregnant women having the highest incidence. P. falciparum has developed resistance, and therefore new effective candidate antimalarial drugs need to be developed. Previous studies identified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates; therefore, derivatives of these compounds were synthesized in order to improve their desired properties and pharmacokinetic (PK) properties of the derivatives were investigated in a mouse model which was dosed orally and intravenously. Collected blood samples were analyzed using liquid chromatography coupled to mass spectrometer (LC-MS/MS). The mean peak plasma level of 1.9 μM was obtained at 1 hour for compound 1 and 3.3 μM at 0.5 hours for compound 2. A decline in concentration was observed with a half-life of 2.53 and 0.87 hours for compound 1 in mice dosed orally and intravenously, respectively. For compound 2 a half-life of 2.96 and 0.68 hours was recorded. The bioavailability was 69% and 59.7% for compound 1 and compound 2, respectively.
Highlights
Malaria is a disease caused by parasites from the genus Plasmodium and is transmitted to a human host when a vector, an infected female Anopheles mosquito, bites the host [1]
P. falciparum and P. vivax are responsible for most malaria infections, which has become one of the major public health problems in many regions of Africa, Asia, and Latin America [2]
Recent studies by Gonzalez Cabrera et al [5] and Younis et al [6, 7] identified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates based on in vivo efficacy data obtained from a P. berghei infected mouse model
Summary
Malaria is a disease caused by parasites from the genus Plasmodium and is transmitted to a human host when a vector, an infected female Anopheles mosquito, bites the host [1]. Recent studies by Gonzalez Cabrera et al [5] and Younis et al [6, 7] identified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates based on in vivo efficacy data obtained from a P. berghei infected mouse model These compounds were identified from an image-based high-throughput screening of a BioFocus DPI SoftFocus kinase library of promising selective in vitro antiplasmodial hits. A number of active compounds with varying aryl groups at positions 3 and 5 of the aminopyridine core were identified and analogues were synthesized in order to explore the structure-activity relationship (SAR) around aryl substitution Some of these analogues showed good oral bioavailability in a pharmacokinetic study performed in rats, identifying them as potential clinical candidates [6]. This led to the synthesis of new derivatives of 3,5-diaryl-2aminopyridines with the aim of overcoming liabilities such as the human Ether-a-go-go-Related Gene (hERG) activity, which was identified in an earlier study as a property that is not ideal for a clinical candidate [5, 6]
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