An investigation of the antileishmanial properties of semi-synthetic saponins

Anderson, O.; Beckett, J.; Briggs, C.C.; Natrass, L.A.; Cranston, C.F.; Wilkinson, E.J.; Owen, J.H.; Williams, R.M.; Loukaidis, A.; Bouillon, M.E.; Pritchard, D.; Lahmann, M.; Baird, M.S.; Denny, P.W.

doi:10.1039/d0md00123f

An investigation of the antileishmanial properties of semi-synthetic saponins

Anderson, O.; Beckett, J.; Briggs, C.C.; Natrass, L.A.; Cranston, C.F.; Wilkinson, E.J.; Owen, J.H.; Williams, R.M.; Loukaidis, A.; Bouillon, M.E.; Pritchard, D.; Lahmann, M.; Baird, M.S.; Denny, P.W.

Authors

O. Anderson

J. Beckett

C.C. Briggs

L.A. Natrass

C.F. Cranston

E.J. Wilkinson

J.H. Owen

R.M. Williams

A. Loukaidis

M.E. Bouillon

D. Pritchard

M. Lahmann

M.S. Baird

Professor Paul Denny p.w.denny@durham.ac.uk
Professor

Abstract

Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the, Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive efforts have recently been made to discover new leads from small molecule synthetic compound libraries held by industry; however, the number of new chemical entities identified and entering development as anti-leishmanials has been very low. This has led to increased interest in the possibility of discovering naturally derived compounds with potent antileishmanial activity which may be developed towards clinical applications. Plant-derived triterpenoid and steroidal saponins have long been considered as anti-microbials and here we describe an investigation of a library of 137 natural (9) and semi-synthetic saponins (128) for activity against Leishmania mexicana, a causative agent of cutaneous leishmaniasis. The triterpenoid sapogenin, hederagenin, readily obtained in large quantities from Hedera helix (common ivy), was converted into a range of 128 derivatives. These semi-synthetic compounds, as well as saponins isolated from ivy, were examined with a phenotypic screening approach to identify potent and selective anti-leishmanial hits. This led to the identification of 12 compounds, including the natural saponin gypsogenin, demonstrating high potency (ED50 < 10.5 μM) against axenic L. mexicana amastigotes, the mammalian pathogenic form. One of these, hederagenin disuccinate, was sufficiently non-toxic to the macrophage host cell to facilitate further analyses, selectivity index (SI) > 10. Whilst this was not active in an infected cell model, the anti-leishmanial properties of hederagenin-derivatives have been demonstrated, and the possibility of improving the selectivity of natural hederagenin through chemical modification has been established.

Citation

Anderson, O., Beckett, J., Briggs, C., Natrass, L., Cranston, C., Wilkinson, E., …Denny, P. (2020). An investigation of the antileishmanial properties of semi-synthetic saponins. RSC Medicinal Chemistry, 11(7), 833-842. https://doi.org/10.1039/d0md00123f

Journal Article Type	Article
Acceptance Date	May 21, 2020
Online Publication Date	Jun 9, 2020
Publication Date	Jul 1, 2020
Deposit Date	May 2, 2020
Publicly Available Date	Jun 10, 2020
Journal	RSC medicinal chemistry.
Publisher	Royal Society of Chemistry
Peer Reviewed	Peer Reviewed
Volume	11
Issue	7
Pages	833-842
DOI	https://doi.org/10.1039/d0md00123f