Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction |
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Institution: | 1. Department of Chemical and Biomedical Engineering, Florida State University, FAMU-FSU College of Engineering, 2525 Pottsdamer Street, Tallahassee, FL 32310, United States;2. Department of Biology and Marine Biology, University of North Carolina Wilmington, 601 South College Road, Wilmington, NC 28403-5915, United States |
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Abstract: | A new series of triazolopyridyl pyridyl ketones has been synthetized by regioselective lithiation of the corresponding 1,2,3]triazolo1,5-a]pyridine at 7 position followed by reaction with different electrophiles. The in vitro antileishmanial activity of these compounds was evaluated against Leishmania infantum, Leishmania braziliensis, Leishmania guyanensis and Leishmania amazonensis. Compounds 6 and 7 were found to be the most active leishmanicidal agents. Both of them showed activities at micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 99.8–26.8 μM), without cytotoxicity on J774 macrophage cells. These two compounds were also tested in vivo in a murine model of acute infection by L. infantum. The triazolopyridine derivative 6 was effective against both spleen and liver parasites forms, while 7 was inactive against liver parasites. Mechanistic aspects of the antileishmanial activity were investigated by means of DNA binding studies (UV-titration and viscosimetry). Results have revealed that these active ligands are able to interact strongly with DNA Kb = 1.14 × 105 M?1 (6) and 3.26 × 105 M?1 (7)]. Moreover, a DNA groove binding has been proposed for both 6 and 7. To provide more insight on the mode of action of compounds 6 and 7 under biological conditions, their interaction with bovine serum albumin (BSA) was monitored by fluorescence titrations and UV–visible spectroscopy. The quenching constants and binding parameters were determined. Triazolopyridine ketones 6 and 7 have exhibited significant affinity towards BSA Kb = 2.5 × 104 M?1 (6) and 1.9 × 104 M?1 (7)]. Finally, to identify the binding location of compounds 6 and 7 on the BSA, competitive binding experiments were carried out, using warfarin, a characteristic marker for site I, and ibuprofen as one for site II. Results derived from these studies have indicated that both compounds interact at BSA site I and, to a lesser extent, at site II. |
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Keywords: | Triazolopyridyl ketones Leishmanicidal activity DNA interaction BSA binding |
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