title: 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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Pouwer
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Deydier
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Phuc Van
authors.initials: PV
authors.lastname: Le
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Schwartz
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Franken
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Coster
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Australian Army Malaria Institute , Brisbane, QLD 4051, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Edstein
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Jenkins
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Quinn
keywords: Malaria; natural products; total synthesis