Easy preparation of novel 3,3-dimethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide: Molecular structure, Hirshfeld surface, NCI analyses and molecular docking on AMPA receptors

We present in this study the synthesis and characterization of a new 3,3-dimethyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide. 3,3-dimethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide 10, was obtained by reacting 2-aminobenzenesulfonamide with acetone. The molecular structures of the starting sulfonamide and the new benzothiadiazine were obtained by X-ray diffraction analysis and the interactions like hydrogen bonds stabilizing the crystal packing were discussed. The contacts are confirmed by non-covalent interaction analysis. Analyses of Hirshfeld surface mapped over d(i), d(e), d(norm) and shapeindex were further used to identify the intermolecular interactions. The fingerprint histogram allow to show that H center dot center dot center dot H (45.7%) and O center dot center dot center dot H (30.1%) contacts are the dominant interactions in the crystal packing of 10. The effects of the molecular environment were accessed by analyzing the electron density isosurface and the 3D-topology of energy frameworks. The prediction of physicochemical properties suggested that 10 could be considered as a lead-like drug. Therefore, molecular docking study was performed on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and suggested that 10 could interact with the allosteric site located on the ligand binding domain of AMPAR and could be a positive allosteric modulator. Docking results show that 10 can bind in a symmetrical way in the GluA2 ligand binding domain with two molecules at the dimer interface. The results also demonstrated that the presence of two methyl groups at the 3-position of the thiadiazine ring induced rotation of 10 in the binding site leading to close contacts with Pro494, Ser497, Ser729 and Ser754. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

This study synthesized and characterized a new 3,3-dimethyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide, and suggested its potential as a lead-like drug through various analyses. Molecular docking results indicated that the compound could interact with the AMPAR and be a positive allosteric modulator, showing potential therapeutic value.