Synthesis, crystal structure, DFT calculation, non-linear optical properties, and molecular docking studies of 7-chloro-3-methyl-2-(4-methylbenzyl)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide: the candidate as AMPA positive allosteric modulator

Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, abbreviated as AMPA, plays a significant role in many neurological diseases as a selective glutamate receptor. These are of particular bearing in the advance of new classes of drugs for the treatment of neurodegenerative and neuropsychiatric diseases. At the forefront of research on AMPA receptor (AMPAR) ligands, new thiazine molecules are being designed, synthesized, and tested as new AMPAR potentiators. In this context, synthesis, X-ray crystal structure, spectroscopic analysis studies, density functional theory (DFT), non-linear optical properties, and molecular docking (MD) studies of 7-chloro-3-methyl-2-(4-methylbenzyl)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (3) (C₁₆H₁₇ClN₂O₂S) in our study belonging to the thiadiazine family were reported. The crystal is in monoclinic space group P21/c with a = 13.9471(19), b = 6.7140(9), c = 17.645(2) Å, β = 107.641(2)°, V = 1574.6(4) ų, Z = 4, D_c = 1.421 g cm⁻³, and µ(MoK_α, λ = 0.71073 Å) = 0.383 mm⁻¹. The optimized structure of 3 was performed and compared with experimental results by using DFT with the 6–311 +  + G(d,p) basis set. The chemical parameters, frontier molecular orbitals, and MEPs of 3 were determined by using DFT calculations. To investigate non-linear optical (NLO) effects of 3, the total molecular dipole moment (μ), linear polarizability (α), and the first-order hyperpolarizability (β) were determined by using quantum mechanical studies. The result yields that β_tot of 3 was compared to urea. In addition to experimental and DFT studies, the MD studies were performed to explain the binding interaction of compound 3 with AMPAR. Based on its physical and chemical properties, compound 3 can be considered a prodrug.