Back to the future: lessons learned in modern target-based and whole-cell lead optimization of antimalarials

Abstract

Antimalarial drug discovery has historically benefited from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. However over the past two decades there has been a shift in the pharmaceutical industry to move away from whole-cell screening to target-based approaches. As part of a Wellcome Trust and Medicines for Malaria Venture (MMV) funded consortium to discover new blood-stage antimalarials, we used both approaches to identify new antimalarial chemotypes, two of which have progressed beyond the lead optimization phase and display excellent in vivo efficacy in mice. These two advanced series were identified through a cell-based optimization devoid of target information and in this review we summarize the advantages of this approach versus a target-based optimization. Although the each lead optimization required slightly different medicinal chemistry strategies, we observed some common issues across the different the scaffolds which could be applied to other cell based lead optimization programs.

Fig. (1)

Substituted benzamides derived from a kinase pharmacophore.

Fig. (2)

Optimization path for imidazolopyrimidine kinase library hit.

Fig. (3)

Summary of hit to lead for the imidazolopiperazines series.

Fig. (4)

The activity of the spiroindolone hit and its stereoisomers.