4-Hydroxy-1,2,3-triazole moiety as bioisostere of the carboxylic acid function: a novel scaffold to probe the orthosteric γ-aminobutyric acid receptor binding site

• Published in: European journal of medicinal chemistry 2018-10, Vol.158, p.311-321
• Main Authors: Giraudo, Alessandro, Krall, Jacob, Nielsen, Birgitte, Sørensen, Troels E., Kongstad, Kenneth T., Rolando, Barbara, Boschi, Donatella, Frølund, Bente, Lolli, Marco L.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Bioisosterism; GABAA receptor; gamma-Aminobutyric Acid - analogs & derivatives; gamma-Aminobutyric Acid - metabolism; Humans; Hydroxy-1,2,3-triazole; Hydroxylation; Male; Models, Molecular; Protein Binding; Rats; Receptors, GABA-A - chemistry; Receptors, GABA-A - metabolism; Scaffold hopping; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.094

The correct application of bio(iso)steric replacement, a potent tool for the design of optimized compounds, requires the continuous development of new isosters able to respond to specific target requirements. Among carboxylic acid isosters, as the hydroxylated pentatomic heterocyclic systems, the hydroxy-1,2,3-triazole represents one of the most versatile but less investigated. With the purpose to enlarge its bioisosteric application, we report the results of a study devoted to obtain potential biomimetics of the γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS). A series of N1- and N2- functionalized 4-hydroxy-1,2,3-triazole analogues of the previous reported GABAAR ligands, including muscimol, 4-PIOL, and 4-PHP has been synthesized and characterized pharmacologically. Furthermore, this study led to development of straightforward chemical strategies directed to decorate the hydroxytriazole core scaffold, opening for further elaborative studies based on this system. The unsubstituted N1- and N2-piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues (3a, 4a) of 4-PIOL and 4-PHP showed weak affinity (high to medium micromolar range), whereas substituting the 5-position of the triazole core with a 2-naphthylmethyl or 3,3-diphenylpropyl led to binding affinities in the low micromolar range. Based on electrostatic analysis and docking studies using a α1β2γ2 GABAAR homology model we were able to rationalize the observed divergence in SAR for the series of N1- and N2- piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues, offering more detailed insight into the orthosteric GABAAR binding site. [Display omitted] •Hydroxy-1,2,3-triazole is a poorly investigated bioisostere of the carboxylic acid.•New GABAAR ligands were designed and synthetized using hydroxytriazole scaffolds.•Eight compounds were assayed for GABAAR binding affinity.•Modelling was used to speculate the interaction with the GABAAR binding site.