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Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

ABSTRACT: Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are "Rule-of-5" compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.

SUBMITTER: Pouwer RH

PROVIDER: S-EPMC4027726 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

Pouwer Rebecca H RH Deydier Sophie M SM Le Phuc Van PV Schwartz Brett D BD Franken Nicole C NC Davis Rohan A RA Coster Mark J MJ Charman Susan A SA Edstein Michael D MD Skinner-Adams Tina S TS Andrews Katherine T KT Jenkins Ian D ID Quinn Ronald J RJ

ACS medicinal chemistry letters 20131227 2

Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compound ...[more]

PMID: 24900794

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