Total Synthesis of Thiaplakortone A: Derivatives as Metabolically Stable Leads for the Treatment of Malaria

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 sh...

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Published inACS medicinal chemistry letters Vol. 5; no. 2; pp. 178 - 182
Main Authors Pouwer, Rebecca H, Deydier, Sophie M, Le, Phuc Van, Schwartz, Brett D, Franken, Nicole C, Davis, Rohan A, Coster, Mark J, Charman, Susan A, Edstein, Michael D, Skinner-Adams, Tina S, Andrews, Katherine T, Jenkins, Ian D, Quinn, Ronald J
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.02.2014
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Malaria
natural products
total synthesis
NATURAL-PRODUCTS
DRUG DISCOVERY
MEFLOQUINE
STRATEGIES
RESISTANCE
ANTIMALARIAL ACTIVITY
THERAPEUTIC TARGETS
BIOSYNTHETIC-ENZYMES
INHIBITORS
ALKALOIDS
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Summary: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.
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ISSN:1948-5875
1948-5875
DOI:10.1021/ml400447v