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Design, synthesis and anthelmintic activity of 7-keto-sempervirol analogues.

Abstract：

:The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC50 = 19.1 μM) and Fasciola hepatica (IC50 = 17.7 μM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fascioliasis, respectively. Here, we aimed to increase the potency of 7-keto-sempervirol by total synthesis of 30 structural analogues. Subsequent screening of these new diterpenoids against juvenile and adult lifecycle stages of both parasites as well as the human HepG2 liver cell line and the bovine MDBK kidney cell line revealed structure-activity relationship trends. The most active analogue, 7d, displayed improved dual anthelmintic activity over 7-keto-sempervirol (IC50 ≈ 6 μM for larval blood flukes; IC50 ≈ 3 μM for juvenile liver flukes) and moderate selectivity (SI ≈ 4-5 for blood flukes, 8-13 for liver flukes compared to HepG2 and MDBK cells, respectively). Phenotypic studies using scanning electron microscopy revealed substantial tegumental alterations in both helminth species, supporting the hypothesis that the parasite surface is one of the main targets of this family of molecules. Further modifications of 7d could lead to greater potency and selectivity metrics resulting in a new class of broad-spectrum anthelmintic.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Crusco A,Bordoni C,Chakroborty A,Whatley KCL,Whiteland H,Westwell AD,Hoffmann KF

doi

10.1016/j.ejmech.2018.04.032

subject

Has Abstract

pub_date

2018-05-25 00:00:00

pages

87-100

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30366-0

journal_volume

152

pub_type

杂志文章

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