Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 15; pp. 4018 - 4027
• Main Authors: Adam, Rosa, Bilbao-Ramos, Pablo, López-Molina, Sonia, Abarca, Belén, Ballesteros, Rafael, González-Rosende, M. Eugenia, Dea-Ayuela, M. Auxiliadora, Alzuet-Piña, Gloria
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2014; Elsevier
• Subjects: Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - therapeutic use; Antiprotozoal Agents - toxicity; Binding, Competitive; Biochemistry & Molecular Biology; BSA binding; Cattle; Cell Line; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Disease Models, Animal; DNA - chemistry; DNA - metabolism; DNA interaction; Ketones - chemistry; Ketones - therapeutic use; Ketones - toxicity; Leishmania - drug effects; Leishmaniasis - drug therapy; Leishmaniasis - veterinary; Leishmanicidal activity; Life Sciences & Biomedicine; Liver - parasitology; Mice; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Pyridines - chemistry; Science & Technology; Serum Albumin, Bovine - chemistry; Serum Albumin, Bovine - metabolism; Spectrometry, Fluorescence; Spleen - parasitology; Triazoles - chemistry; Triazolopyridyl ketones; Triazolopyridyl ketones; Leishmanicidal activity; BSA binding; DNA interaction; POTENTIAL HELICATING LIGANDS; COMPLEXES; CYCLOADDITION; HUMAN-SERUM-ALBUMIN; SPECTROSCOPIC APPROACH; ANTIBACTERIAL ACTIVITY; 1,2,3-TRIAZOLES; CHEMISTRY; INHIBITOR; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.05.069

[Display omitted] 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 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=99.8–26.8μM), 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=1.14×105M−1 (6) and 3.26×105M−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=2.5×104M−1 (6) and 1.9×104M−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.