Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Crusco, Alessandra, Bordoni, Cinzia, Chakroborty, Anand, Whatley, Kezia C.L., Whiteland, Helen, Westwell, Andrew D. and Hoffmann, Karl F. 2018. Design, synthesis and anthelmintic activity of 7-keto-sempervirol analogues. European Journal of Medicinal Chemistry 152 , pp. 87-100. 10.1016/j.ejmech.2018.04.032

[img]
Preview
PDF - Accepted Post-Print Version
Download (3MB) | Preview

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 18 April 2018
Date of Acceptance: 15 April 2018
Last Modified: 28 Jun 2019 02:11
URI: http://orca-mwe.cf.ac.uk/id/eprint/110783

Citation Data

Cited 2 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics