Structure–activity effects in the anti-leishmanial activity of di-alkyl gallium quinolin-8-olates

Abstract

Six (G1–G6) novel organogallium complexes of the general formula [Ga(R)₂quin] (where R = Et, ⁱPr, ⁿBu, ^tBu, ^sBu and hexyl; quin = quinolin-8-olate, C₉H₆NO) have been synthesised and fully characterised. Single crystal X-ray diffraction shows the complexes adopt a five-coordinate geometry through dimerisation. Complexes G1–G5 were analytically pure and could undergo further biological analysis. [Ga(hex)₂quin] G6 could not be satisfactorily purified and was excluded from biological assays. ¹H NMR spectroscopy indicated the complexes are stable to hydrolysis over 24 hours in ‘wet’ d₆-DMSO. Complexes G1–G5 were assessed for their anti-leishmanial activity towards three separate strains: L. major, L. amazonensis and L. donovani, with varied results toward the promastigote form. G1 and G2 were found to be the most selective with little to no toxicity towards mammalian cell lines. Amastigote invasion assays on the three strains showed that [Ga(ⁿBu)₂quin] G3 and [Ga(^tBu)₂quin] G4 gave the best all round anti-parasitic activity with percentage infection ranges of 1.50–3.00% and 3.25–7.50% respectively, with G3 out-performing the drug control amphotericin B in all three assays. The activity was found to correlate with lipophilicity and water solubility, with the most effective G3 proving the most lipophilic and least water soluble.