Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding

Abstract

The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pK values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV-vis spectroscopy. The experimental pK of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by H NMR analysis. Five computational methods were applied for estimating the theoretical pK values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pK associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1' binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host-guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2.

Combined NMR Spectroscopy and Quantum-Chemical Calculations in Fluorescent 1,2,3-Triazole-4-carboxylic Acids Fine Structures Analysis

“…This has made them a focus of attention in multiple areas of science: chemistry, biology, medicine, physics, and material chemistry [2,[13][14][15][16][17][18][19]. However, the functional groups and substituents surrounding the heterocyclic core are also very important, since they are effective tools for the design of new fluorophores and biologically active compounds [1,2,[20][21][22][23]. Therefore, the issues in designing new 1,2,3-triazoles in accordance with the requirements of a specific direction of their use are acute and relevant at present.…”

“…Thus, heterocycles and the surrounding substituents are very important from the perspective of the emergence of new prospects for the design of fluorophores as tools for tuning intra-and intermolecular weak interactions. The nature and strength of these prospects determine the properties and stability of the supramolecular structures [22,23]. Thus, the precise knowledge of non-covalent interactions (NCI) is a crucial factor in the understanding of bio-and photoactivity, as well as a powerful tool for tuning these properties in accordance with possible applications [25][26][27][28][29].…”

Prospecting native and analogous peptides with anti-SARS-CoV-2 potential derived from the trypsin inhibitor purified from tamarind seeds

“…The interaction potential energy (IPE) calculation was used ( Freitas et al, 2017 ) to analyze the energy between the peptides and TMPRSS2. IPE is the total interaction between two groups, in this case, between peptides and TMPRSS2.…”

Selective Synthesis of Mono‐ and Disubstituted Quinoxalines via Heteroaromatic Nucleophilic Substitution of 2,3‐Dichloro‐6,7‐dinitroquinoxaline (DCDNQX) with Anilines and Phenols

“…The chemistry of nitrogen‐based heterocyclic compounds is one of the main branches of organic chemistry due to their natural occurrence, physicochemical properties and synthetic protocols, as well as applications in many fields . Among the N ‐heteroaromatic structures, quinoxaline derivatives have attracted considerable attention because of their wide range of applications, including biological activities against many pathologies, or as the antagonist in relevant natural processes ,. On the other hand, these heterocycles are also detachable by their luminescent properties and their unfolding in the chemistry of dyes, chemosensors and probes,, among other applications.…”