Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Bioorganic and Medicinal Chemistry Année : 2017

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

Résumé

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 pre-nyl 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.
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Dates et versions

hal-01789378 , version 1 (22-05-2018)

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Melissa Cadelis, Marie-Lise Bourguet-Kondracki, Joëlle Dubois, Marcel Kaiser, Jean Michel Brunel, et al.. Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase. Bioorganic and Medicinal Chemistry, 2017, 25 (16), pp.4433 - 4443. ⟨10.1016/j.bmc.2017.06.029⟩. ⟨hal-01789378⟩
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