Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors
- Bioorg Med Chem. 2016 Jul 15;24(14):3102-7. doi: 10.1016/j.bmc.2016.05.024.
- 1. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
- 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. Université de Toulouse, PHARMA-DEV, UMR 152 IRD-UPS, UPS, 118 Route de Narbonne, F-31062 Toulouse Cedex 9, France.
- 5. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: [email protected].
Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure-activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed.