title: Discovery and optimisation studies of antimalarial phenotypic hits.
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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors.forename: Alka
authors.initials: A
authors.lastname: Mital
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors.forename: Dinakaran
authors.initials: D
authors.lastname: Murugesan
authors.affiliation: Swiss Tropical and Public Health Institute, Postfach, Socinstrasse 57, 4002 Basel, Switzerland; University Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: InPharma Consultancy, Herts, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Yeates
authors.affiliation: 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.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008288:Malaria / Q000469:parasitology; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials
keywords: Malaria; Medicinal chemistry; Phenotypic hit; Plasmodium falciparum