title: Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction.
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.
authors: Departament de Química Orgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain.
authors: Rosa
authors: R
authors: Adam
authors: Departamento de Parasitología, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors: Pablo
authors: P
authors: Bilbao-Ramos
authors: Departament de Química Orgànica, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot (Valencia), Spain.
authors: Sonia
authors: S
authors: López-Molina
authors: 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.
authors: Belén
authors: B
authors: Abarca
authors: 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.
authors: Rafael
authors: R
authors: Ballesteros
authors: Departamento de Farmacia, Universidad CEU Cardenal Herrera, Avda. Seminario s/n, 46113 Moncada (Valencia), Spain.
authors: M Eugenia
authors: ME
authors: González-Rosende
authors: 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.
authors: M Auxiliadora
authors: MA
authors: Dea-Ayuela
authors: 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.
authors: Gloria
authors: G
authors: Alzuet-Piña
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001667:Binding, Competitive; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D007659:Ketones / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D007891:Leishmania / Q000187:drug effects; D007896:Leishmaniasis / Q000188:drug therapy / Q000662:veterinary; D008099:Liver / Q000469:parasitology; D051379:Mice; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013154:Spleen / Q000469:parasitology; D014230:Triazoles / Q000737:chemistry
chemical_list: D000981:Antiprotozoal Agents; D007659:Ketones; D011725:Pyridines; D014230:Triazoles; D012710:Serum Albumin, Bovine; D004247:DNA; C023666:pyridine
keywords: BSA binding; DNA interaction; Leishmanicidal activity; Triazolopyridyl ketones