Discovery and optimisation studies of antimalarial phenotypic hits

Eur J Med Chem. 2015 Oct 20:103:530-8. doi: 10.1016/j.ejmech.2015.08.044.

Alka Mital ¹, Dinakaran Murugesan ¹, Marcel Kaiser ², Clive Yeates ³, Ian H Gilbert ⁴

Affiliations

1 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
2 Swiss Tropical and Public Health Institute, Postfach, Socinstrasse 57, 4002 Basel, Switzerland; University Basel, Petersplatz 1, 4003 Basel, Switzerland.
3 InPharma Consultancy, Herts, UK.
4 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK. Electronic address: i.h.gilbert@dundee.ac.uk.

PMID: 26408453 DOI: 10.1016/j.ejmech.2015.08.044

Abstract

There is an urgent need for the development of new antimalarial compounds. As a result of a phenotypic screen, several compounds with potent activity against the parasite Plasmodium falciparum were identified. Characterization of these compounds is discussed, along with approaches to optimise the physicochemical properties. The in vitro antimalarial activity of these compounds against P. falciparum K1 had EC50 values in the range of 0.09-29 μM, and generally good selectivity (typically >100-fold) compared to a mammalian cell line (L6). One example showed no significant activity against a rodent model of malaria, and more work is needed to optimise these compounds.

Keywords

Malaria; Medicinal chemistry; Phenotypic hit; Plasmodium falciparum.

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