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Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty

2019; Elsevier BV; Volume: 29; Issue: 19 Linguagem: Inglês

10.1016/j.bmcl.2019.08.014

1464-3405

Jonathan M. Large, Kristian Birchall, Nathalie Bouloc, Andy Merritt, Ela Smiljanic-Hurley, Denise J. Tsagris, Mary C. Wheldon, Keith H. Ansell, P.J. Coombs, Catherine Kettleborough, David Whalley, Lindsay B. Stewart, Paul W. Bowyer, David A. Baker, Simon A. Osborne,

Phenothiazines and Benzothiazines Synthesis and Activities

Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles.