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 gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS). A series of N-1- and N-2-functionalized 4-hydroxy-1,2,3-triazole analogues of the previous reported GABA(A)R 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 N-1- and N-2-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 alpha(1)beta(2)gamma(2) GABA(A)R homology model we were able to rationalize the observed divergence in SAR for the series of N-1- and N-2- piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues, offering more detailed insight into the orthosteric GABA(A)R binding site. (C) 2018 Elsevier Masson SAS. All rights reserved.

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

Giraudo, Alessandro;Rolando, Barbara;Boschi, Donatella;Lolli, Marco L.
Last
2018

Abstract

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 gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS). A series of N-1- and N-2-functionalized 4-hydroxy-1,2,3-triazole analogues of the previous reported GABA(A)R 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 N-1- and N-2-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 alpha(1)beta(2)gamma(2) GABA(A)R homology model we were able to rationalize the observed divergence in SAR for the series of N-1- and N-2- piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues, offering more detailed insight into the orthosteric GABA(A)R binding site. (C) 2018 Elsevier Masson SAS. All rights reserved.
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https://pubs.acs.org/doi/abs/10.1021/jm051288b
Hydroxy-1,2,3-triazole; Bioisosterism; Scaffold hopping; GABA(A) receptor
Giraudo, Alessandro; Krall, Jacob; Nielsen, Birgitte; Sørensen, Troels E.; Kongstad, Kenneth T.; Rolando, Barbara; Boschi, Donatella; Frølund, Bente; Lolli, Marco L.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1686358
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