Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors

作者：Cadelis Melissa M; Bourguet Kondracki Marie Lise; Dubois Joelle; Valentin Alexis; Barker David; Copp Brent R^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(14): 3102-3107.

DOI：10.1016/j.bmc.2016.05.024

• Tecomaquinone I
• Natural product
• Dimerization
• FTase inhibitor
• Anti-plasmodial

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 +/- 0.004 mu M) 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 +/- 0.20 mu M. 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.

• 出版日期2016-7-15