2. Academic Validation
  3. Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction

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.
Rosa Adam 1,  Pablo Bilbao-Ramos 2,  Sonia López-Molina 1,  Belén Abarca 3,  Rafael Ballesteros 4,  M Eugenia González-Rosende 5,  M Auxiliadora Dea-Ayuela 6,  Gloria Alzuet-Piña 7
Affiliations

Affiliations

  • 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: Belen.Abarca@uv.es.
  • 4 Departament de Química Orgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain. Electronic address: Rafael.Ballesteros@uv.es.
  • 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: Gloria.Alzuet@uv.es.
PMID: 24953952 DOI: 10.1016/j.bmc.2014.05.069
Abstract

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.

Keywords

BSA binding; DNA interaction; Leishmanicidal activity; Triazolopyridyl ketones.

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