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

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

  • ACS Med Chem Lett. 2013 Dec 27;5(2):178-82. doi: 10.1021/ml400447v.
Rebecca H Pouwer 1,  Sophie M Deydier 1,  Phuc Van Le 1,  Brett D Schwartz 1,  Nicole C Franken 1,  Rohan A Davis 1,  Mark J Coster 1,  Susan A Charman 2,  Michael D Edstein 3,  Tina S Skinner-Adams 1,  Katherine T Andrews 1,  Ian D Jenkins 1,  Ronald J Quinn 1
Affiliations

Affiliations

  • 1 Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
  • 2 Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, VIC 3052, Australia.
  • 3 Australian Army Malaria Institute , Brisbane, QLD 4051, Australia.
PMID: 24900794 DOI: 10.1021/ml400447v
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.

Keywords

Malaria; natural products; total synthesis.

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