2. Academic Validation
  3. Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase

Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase

  • Bioorg Med Chem. 2017 Aug 15;25(16):4433-4443. doi: 10.1016/j.bmc.2017.06.029.
Melissa M Cadelis 1,  Marie-Lise Bourguet-Kondracki 2,  Joëlle Dubois 3,  Marcel Kaiser 4,  Jean Michel Brunel 5,  David Barker 6,  Brent R Copp 6
Affiliations

Affiliations

  • 1 School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: mcad006@aucklanduni.ac.nz.
  • 2 Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France.
  • 3 Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France.
  • 4 Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box CH-4002, Basel, Switzerland; The University of Basel, CH-4003 Basel, Switzerland.
  • 5 Aix-Marseille Université, Centre de Recherches en Cancérologie de Marseille (CRCM), CNRS, UMR7258, 13385 Marseille, France.
  • 6 School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 28666857 DOI: 10.1016/j.bmc.2017.06.029
Abstract

Marine meroterpenoids, thiaplidiaquinones A and B and their respective non-natural dioxothiazine regioisomers have been shown to inhibit mammalian and protozoal farnesyltransferase (FTase) with the regioisomers exhibiting activity in the nanomolar range. In order to explore the structure-activity relationship (SAR) of this class of Marine natural products, analogues of thiaplidiaquinones A and B and their regioisomers were synthesised, with variation in the number of isoprene units present in their side chains to afford prenyl and farnesyl analogues. The previously reported geranyl series of compounds were found to be the most potent FTase inhibitors closely followed by the novel farnesyl series. The prenyl series exhibited the most potent anti-plasmodial activity but the series was also the most cytotoxic. Overall, the farnesyl series exhibited moderate anti-plasmodial activity with one analogue, 14 also exhibiting low cytotoxicity, identifying it as a scaffold worthy of further exploration.

Keywords

Anti-plasmodial; Biomimetic; FTase inhibitor; Natural product; Thiaplidiaquinone.

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