Identification of a New Pyrazolo[1,5‑<i>a</i>]quinazoline Ligand Highly Affine to γ‑Aminobutyric Type A (GABA_A) Receptor Subtype with Anxiolytic-Like and Antihyperalgesic Activity

Compounds that can act on GABA_A receptor subtype in a selective manner, without the side effects of classical benzodiazepine ligands, represent promising therapeutic tools in neurological disorder as well as for relief of pain or in comorbidity of anxiety states and depression. Continuing our research on GABA_A receptor subtype ligands, here is reported the synthesis of a series of pyrazolo­[1,5-<i>a</i>]­quinazoline 3- and/or 8-substituted as 5-deaza analogues of previous reported pyrazolo­[5,1-<i>c</i>]­[1,2,4]­benzotriazine, already identified as selective GABA_A receptor subtype ligands endowed with anxiolytic-like and antihyperalgesic action or enhancer cognition. Between the new compounds stands out <b>12b</b> for its high affinity value (<i>K</i>_i = 0.27 nM) and for its anxiolytic-like and ability to relieve neuropathic painful conditions evaluated in CCI and STZ murine model

MOESM1 of Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

Additional file 1: Table S1. Elemental analysis

Isoxazol-5(2<i>H</i>)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors

<p>Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2<i>H</i>)-one scaffold. The most potent compound (<b>2o</b>) had a good balance between HNE inhibitory activity (IC₅₀ value =20 nM) and chemical stability in aqueous buffer (<i>t</i>_1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds <b>2o</b> and <b>2s</b> contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups.</p

Synthesis, biological evaluation, and molecular modelling studies of potent human neutrophil elastase (HNE) inhibitors

<p>We report the synthesis and biological evaluation of a new series of 3- or 4-(substituted)phenylisoxazolones as HNE inhibitors. Due to tautomerism of the isoxazolone nucleus, two isomers were obtained as final compounds (2-NCO and 5-OCO) and the 2-NCO derivatives were the most potent with IC₅₀ values in the nanomolar range (20–70 nM). Kinetic experiments indicated that 2-NCO <b>7d</b> and 5-OCO <b>8d</b> are both competitive HNE inhibitors. Molecular modelling on <b>7d</b> and <b>8d</b> suggests for the latter a more crowded region about the site of the nucleophilic attack, which could explain its lowered activity. In addition molecular dynamics (MD) simulations showed that the isomer <b>8d</b> appears more prone to form H-bond interactions which, however, keep the reactive sites quite distant for the attack by Ser195. By contrast the amide <b>7d</b> appears more mobile within the active pocket, since it makes single H-bond interactions affording a favourable orientation for the nucleophilic attack.</p