2-Aminonicotinic Acid 1-Oxides Are Chemically Stable Inhibitors of Quinolinic Acid Synthesis in the Mammalian Brain: A Step toward New Antiexcitotoxic Agents

Abstract

3-Hydroxyanthranilic acid 3,4-dioxygenase (3-HAO) is the enzyme responsible for the production of the neurotoxic tryptophan metabolite quinolinic acid (QUIN). Elevated brain levels of QUIN are observed in several neurodegenerative diseases, but pharmacological investigation on its role in the pathogenesis of these conditions is difficult because only one class of substrate-analogue 3-HAO inhibitors, with poor chemical stability, has been reported so far. Here we describe the design, synthesis, and biological evaluation of a novel class of chemically stable inhibitors based on the 2-aminonicotinic acid 1-oxide nucleus. After the preliminary in vitro evaluation of newly synthesized compounds using brain tissue homogenate, we selected the most active inhibitor and showed its ability to acutely reduce the production of QUIN in the rat brain in vivo. These findings provide a novel pharmacological tool for the study of the mechanisms underlying the onset and propagation of neurodegenerative diseases.

Kynurenines and Glutamate

“…However, efficacy has been demonstrated in established in vivo seizure models in rats and mice (Luthman, 2000), and protective effects have been shown against both anoxia- and inflammation-induced neuronal damage in organotypic tissue cultures (Luthman, Radesäter, & Oberg, 1998). These results bode well for further hypothesis testing with newly developed inhibitors of this enzyme (Vallerini et al, 2013). …”

Discovery of New Potential Anti‐Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target‐Focused Repurposing Approaches

“…The analysis revealed that, among others, the most abundant fragments are 2‐aminothiazole ( 1 ), 2‐phenylcyclopropane‐1‐amino ( 2 ), 2‐hydroxypyridinium ( 3 ), pyridine‐ N ‐oxide ( 4 ), cyclopropanecarboxylic acid( 5 ), and benzoic acid ( 6 ; Figure ). Taking into account that most of the compounds available in our lab were designed as antimicrobial agents or inhibitors of metalloenzymes, we decided to focus our attention on all of those targets that satisfied the following criteria: 1) they are metalloenzymes ubiquitously expressed in most living organisms, and 2) there are reported inhibitors that are characterized by fragments similar to those present in our library. An extensive knowledge‐based literature search allowed us to identify the carbonic anhydrase superfamily as an eligible protein class .…”

“…The affinity of our compounds, either pyridine‐ N ‐oxides or phenylcyclopropane carboxylates, is much lower than that of reference compounds such as AAZ. Nevertheless, it must be stressed that our compounds come from a recycling approach and that they were optimized against very different targets . We are confident that some of them can still be highly optimized against microbial CAs.…”

“…Among the tested compounds, 18 is quite a promising one, because it shows the best combination of selectivity over h CAs, LE and BEI parameters, and, interestingly, was devoid of any activity toward the target for which was originally designed, which thus highly decreases the risk of cross‐interaction with other receptors/enzymes.…”

“…Compounds 17 , 18 , and 19 were obtained by starting from the commercially available 2‐chloro‐6‐methylnicotinonitrile, which reacted with methyl iodide in the presence of NaH as a base to yield compound 29 . The chlorine atom in position 2 was substituted by an amino group through the reaction of compound 29 with benzylamine, conducted in a microwave oven, which led to compound 30 .…”