Neil R. Norcross, Caroline Wilson, Beatriz Baragaña, Irene Hallyburton, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Daniel Fletcher, Robert Sinden, Michael Delves, Andrea Ruecker, Sandra Duffy, Stephan Meister, Yevgeniya Antonova-Koch, Benigno Crespo, Cristina de Cózar, Laura Sanz Francisco, Javier Gamo ,Vicky M. Avery, Julie A. Frearson, David W. Gray, Alan H. Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul A. Willis, Kevin D. Read, Ian Gilbert.
In this paper we describe the optimisation of a phenotypic hit against Plasmodium falciparum, based on an aminoacetamide scaffold. This led to a compound (28) with low nanomolar antimalarial activity against the intraerythrocytic stages of the malaria parasite and was inactive in a mammalian cell counter screen up to 50 μM. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimise the aqueous solubility and microsomal stability to a point where the aminoacetamides were suitable for in vivo pharmacokinetic and efficacy studies, 28 displayed excellent antimalarial potency and selectivity and therefore, could serve as a suitable chemical tool for drug target identification.