Abstract
Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.
Highlights
Malaria is an endemic human disease caused by the parasite plasmodium which uses the female Anopheles mosquito as a vector for transmition
To a previous described series (Krake et al 2017), the initial hit 12 was discovered through high throughput screen (HTS) and constitutes a trisubstituted quinoline with excellent anti-plasmodial activity (IC50 Pf NF54 = 22 nM). (Figure 2) this quinoline-based compound showed other interesting properties such as low cytotoxicity (IC50 THP1 > 50 μM; IC50 Hep G2 > 10 μM), minimal hERG inhibition (IC50 hERG = 23 μM) and good permeability in Caco2 cells (34 . 10-6 cm/s at pH = 6.5), a high logD led to metabolically instability and low solubility
A moderate rate of killing was observed for 12 (Figure 2), which is uncommon for quinoline antimalarials and may indicate a different mode of action compared to marketed quinolines
Summary
Malaria is an endemic human disease caused by the parasite plasmodium which uses the female Anopheles mosquito as a vector for transmition. Resistance to artemisinbased combination therapies (WHO 2016), the best available treatment nowadays, continues to develop, requiring the discovery of new medicines to treat this life threatening infection. Despite these issues, global efforts between public and private sectors, academia and NGO’s (non-governamental organization) have been able to reduce the number of deaths and endemic regions. Since 2000, a 20% decline in the number of infected people and a 50% decline in deaths were observed along with 16% retraction of areas where this disease is present (WHO 2016)
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