Trends in activity related to structure have been observed for other complexes of a similar structure. The following trend of the activity of the complexes was concluded to be: o-Tol > p-Tol > o-OMe > m-OMe > p-OMe. From the amastigote invasion assay it was found that a trend existed for not only the functional group on the phenyl ring of the ligand, but its position on the ring. Complex S4, proved to be the least effective anti-leishmanial, with complex S9, proving to be the best candidate. A % infection range of 7.75–40.5% was observed, indicating the complexes exhibited moderate to mild activity at 10 μM. Similar to the α-hydroxy carboxylates a varying degree of activity was observed for the complexes. 90,91ĭue to a high degree of selectivity, the remaining antimony complexes, S4, S6– S9, were assessed for their anti-amastigote activity. Unfortunately, the selectivity's of these NHC gold(I) complexes were limited, with a significant range of activity observed against the murine macrophage controls (IC 50: 0.23–7.08 μM, 90 0.66–33.4 μM 91). have exhibited excellent anti-leishmanial activity against both forms of the parasite (IC 50 amastigote: 1.41–4.25 μM, 90 0.19–11.1 μM 91). 87–89 Gold complexes synthesized by Zhang et al. Other metals/metal complexes have been explored as anti-leishmanials in recent years, with gold, zinc and ruthenium providing a potential alternative to the current group 15 metallodrugs. 84 However, no cytotoxic studies on these compounds have been reported or the activity against the amastigotes determined, therefore the possibility of these complexes presenting as potential lead compounds is uncertain. presenting with an IC 50 range of 0.028–7.49 μM. Other tris-aryl Sb(V) complexes described in the literature have been observed to exhibit a greater degree of activity, with tris-aryl Sb(V) cinnamates reported by Mustaq et al. By repeating the assay at a higher concentration gradient, the actual value could be accurately determined. All antimony complexes, except for S10′, are likely to have indices greater than what was calculated as no activity was observed at the highest fixed concentration of 100 μM. Though the selectivity indices of the bismuth complexes were found to be in a therapeutic range, their instability and solubility issues meant there was little value in evaluating then in the amastigote assay. a Values would be greater than calculated due to ≥ 100 μM activity. Selectivity index = (IC 50: fibroblasts/IC 50: parasite). Several of our previous complexes have shown to be active with substantially quicker decay rates. With a half-life of 5.2 h, the complexes are well within a therapeutic time-frame. major and human fibroblasts was conducted regardless. Though the bismuth complexes were known to be unstable in culture media, an analysis of their activity against both L. Unsurprisingly, the antimony complexes exhibited no change over a 12-h period. Though this decay happened at a more rapid rate that the α-hydroxy complexes, a half-life of 5.2 h was calculated, along with the zero-order rate constant of 59.5 μM/h (based on an initial concentration of 500 μM). Similar to the α-hydroxy acetates, the bismuth complex was found to once again exhibit a linear decay in the culture media ( R 2 = 0.9923) ( Fig. Example complexes of the p-tolylacetate, B13 and S6 were placed into the culture media in an NMR tube and monitored by 1H NMR spectroscopy over a period of 24 h. 82 After the initial stability studies in d 6-DMSO, the stability of the complex in culture media was determined. This was confirmed by 1H NMR spectrum of the complex in d 6-DMSO. Similar to the cyclometallates previously isolated, re-arrangement occurs in DMSO and therefore the biologically active form of the complex is the mono-hydroxido. major variant was conducted.Ĭomplex S10′ was isolated as a pure solid via extraction using a 50:50 H 2O:DMSO mixture.
tropica strain of Leishmania, (IC 50: 0.58 and 0.67 μg/mL, respectively) 83 therefore, due to the physiological difference between species, testing on the L. 78 Complexes S7 and S9 had underwent previous anti-leishmanial testing against the L.
We had previously examined complexes S5 and S11 for their anti-leishmanial activity. 14 of the bismuth and antimony acetate complexes were screened for their anti-leishmanial activity. Solid-state structures of 15 of the complexes were determined by single-crystal X-ray diffraction and were found to exhibit analogous coordination geometry to the previously synthesized triphenyl mandelates. Of these 17 complexes, 13 were found to be novel.
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