Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction
- Bioorg Med Chem. 2014 Aug 1;22(15):4018-27. doi: 10.1016/j.bmc.2014.05.069.
- 1. Departament de Química Orgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain.
- 2. Departamento de Parasitología, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
- 3. Departament de Química Orgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain. Electronic address: [email protected].
- 4. Departament de Química Orgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain. Electronic address: [email protected].
- 5. Departamento de Farmacia, Universidad CEU Cardenal Herrera, Avda. Seminario s/n, 46113 Moncada (Valencia), Spain.
- 6. Departamento de Parasitología, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; Departamento de Farmacia, Universidad CEU Cardenal Herrera, Avda. Seminario s/n, 46113 Moncada (Valencia), Spain.
- 7. Departament de Química Inorgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain. Electronic address: [email protected].
A new series of triazolopyridyl pyridyl ketones has been synthetized by regioselective lithiation of the corresponding [1,2,3]triazolo[1,5-a]pyridine at 7 position followed by reaction with different electrophiles. The in vitro antileishmanial activity of these compounds was evaluated against Leishmaniainfantum, Leishmaniabraziliensis, Leishmaniaguyanensis and Leishmaniaamazonensis. 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 × 10(5)M(-1) (6) and 3.26 × 10(5)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 × 10(4)M(-1) (6) and 1.9 × 10(4)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.