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Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines.

ABSTRACT: Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.

SUBMITTER: Large JM

PROVIDER: S-EPMC6355318 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines.

Large Jonathan M JM Birchall Kristian K Bouloc Nathalie S NS Merritt Andy T AT Smiljanic-Hurley Ela E Tsagris Denise J DJ Wheldon Mary C MC Ansell Keith H KH Coombs Peter J PJ Kettleborough Catherine A CA Whalley David D Stewart Lindsay B LB Bowyer Paul W PW Baker David A DA Osborne Simon A SA

Bioorganic & medicinal chemistry letters 20181120 3

Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis p ...[more]

PMID: 30553738

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