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. 2019 Dec 16;11(1):98-101.
doi: 10.1039/c9md00511k. eCollection 2020 Jan 1.

Discovery of isoxazolyl-based inhibitors of Plasmodium falciparum cGMP-dependent protein kinase

Shams Ul Mahmood  1 , Huimin Cheng  1 , Sreedhar R Tummalapalli  1 , Ramappa Chakrasali  1 , Rammohan R Yadav Bheemanaboina  1 , Tamara Kreiss  1 , Agnieska Chojnowski  1 , Tyler Eck  1 , John J Siekierka  1 , David P Rotella  1
Affiliations

Discovery of isoxazolyl-based inhibitors of Plasmodium falciparum cGMP-dependent protein kinase

Shams Ul Mahmood et al. RSC Med Chem. .

Abstract

The cGMP-dependent protein kinase in Plasmodium falciparum (PfPKG) plays multiple roles in the life cycle of the parasite. As a result, this enzyme is a potential target for new antimalarial agents. Existing inhbitors, while potent and active in malaria models are not optimal. This communication describes initial optimization of a structurally distinct class of PfPKG inhibitors.

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Figures

Fig. 1
Fig. 1. PfPKG inhibitors.
Fig. 2
Fig. 2. Isoxazole based PfPKG leads.
Scheme 1
Scheme 1. Synthesis of initial isoxazole PfKG inhibitors.
Scheme 2
Scheme 2. Synthesis of isoxazole amine and chlorophenyl PfPKG inhibitors.
Scheme 3
Scheme 3. Synthesis of pyrrolidine amide PfPKG inhibitors.
Scheme 4
Scheme 4. Synthesis of tertiary amine and sulphonamide PfPKG inhibitors.
Scheme 5
Scheme 5. Diamine linker variations.
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