Modulating aryl substitution: Does it play a role in the anti-leishmanial activity of a series of tetra-aryl Sb(V) fluorinated carboxylates?

Abstract

Eight tetra-arylantimony carboxylates of the general formula Ar₄SbOC(O)R with Ar = Ph (a), p-Tol (b), R = C₆F₅ (1), CH₂CF₃ (2), CF₂Br (3), CF₂CF₂CF₃ (4) have been synthesised and characterised. Two of them (2b, 3b) are structurally novel. All structures were analytically characterised by FT-IR, ¹H, ¹³C NMR spectroscopy. Previously synthesised structures were also analysed by X-ray diffraction and their solid-state structures authenticated. The solid-state structures exhibited a typical trigonal-bipyramidal geometry at the antimony centre, with the carboxylic oxygen and one of the aryl group carbons occupying axial positions with the remaining three aryl groups in the equatorial plane. All complexes were screened for their anti-leishmanial activity and cytotoxicity towards mammalian macrophages. No anti-leishmanial testing on tetra-arylantimony carboxylates have been previously performed. It was observed that the tetra-phenylantimony analogues are far more effective in comparison to the tetra-(p-tolyl)antimony complexes, with IC₅₀ values in the ranges of 2.90-7.75 μM and 64.97-124.71 μM, respectively, for the promastigote assay, and 70.87-76.28 μM, 9.08-10.18 μM for the macrophages. Interestingly, the dose-response curve for tetra-phenylantimony carboxylates is a standard sigmoid curve, while for all tetra-(p-tolyl)antimony complexes it has an unusual inverted U-shape, indicating they are effective only at a low dose. All tetra-phenylantimony carboxylates were assessed for their anti-amastigote activity and showed promising results: 1.00% ± 1.44 (1a), 5,25% ± 1.72 (2a), 20.75% ± 8.46 (3a), 5.75% ± 1.62 (4a) at 10 μM.

Keywords: Anti-leishmanial activity; Carboxylates; Cytotoxicity; Leishmania; Leishmaniasis; Tetra-arylantimony.