Anti-Leishmanial Activity of Novel Homo- and Heteroleptic Bismuth(iii) Thiocarboxylates
Philip C. Andrews A E , Peter C. Junk B , Lukasz Kedzierski C D and Roshani M. Peiris AA School of Chemistry, Monash University, PO Box 23, Melbourne, Vic. 3800, Australia.
B School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Qld 4811, Australia.
C Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Vic. 3052, Australia.
D Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, Vic. 3010, Australia.
E Corresponding author. Email: phil.andrews@monash.edu
Australian Journal of Chemistry 66(10) 1297-1305 https://doi.org/10.1071/CH13374
Submitted: 18 July 2013 Accepted: 12 August 2013 Published: 10 September 2013
Abstract
Two new thiocarboxylic acids, p-bromothiobenzoic BTA and thionaphthoic acid TNA, and five new homo- and heteroleptic bismuth(iii) compounds derived from thiocarboxylic acids: [Bi{S(C=O)C6H4Br}3] 1, [PhBi{S(C=O)C6H4Br}2] 2, [Bi{S(C=O)C10H7}3] 3, [PhBi{S(C=O)C10H7}2] 4, and [Ph2Bi{S(C=O)C10H7}] 5 were synthesised and fully characterised. The solid-state structure of complex [PhBi{S(C=O)C6H4Br}2] 2 was confirmed by X-ray crystallography. In complex 2, the two thiocarboxylate ligands are coordinated to the bismuth(iii) centre in a didentate fashion, forming a distorted octahedral geometry in which the phenyl group and the lone pair are oriented axial to the plane formed by the two thiocarboxylate ligands. Long-range Bi–S interactions (3.54 Å) link these monomeric units to form a one-dimensional polymer. These compounds, in addition to six previously synthesised complexes: [Bi{SC(=O)C6H5}3] 6, [PhBi{SC(=O)C6H5}2] 7, [Ph2Bi{SC(=O)C6H5}] 8, [Bi{SC(=O)C6H4NO2}3] 9, [PhBi{SC(=O)C6H4NO2}2] 10, and [PhBi{SC(=O)C6H4SO3}] 11, and the thiocarboxylic acids themselves, were assessed for their in vitro activity against Leishmania major promastigotes, and for general toxicity against human fibroblast cells. The thiocarboxylic acids, with the exception of thiobenzoic acid and sulfothiobenzoic acid, were toxic to both L. major parasites and the mammalian cells at high concentrations of 50–100 μM. The bismuth(iii) thiocarboxylate derivatives proved to be more active than the corresponding acids. Among these, the heteroleptic phenyl-substituted bismuth(iii) complexes 2, 4, 5, and 7 were highly active, showing IC50 (half maximal inhibitory concentration) values ranging from 0.39 to 4.69 μM, and a clear ligand dependence on activity.
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