Synthesis, Characterization and In Vitro Acetylcholinesterase Inhibitory Evaluation of 3-Substituted 3,4-Dihydro-2H-1,2,4 benzothiadiazine 1,1-Dioxide Derivatives as Potential Anti-Alzheimer Agents

Author

Priya M, Archana A, Hameedhash R, Ajin TS, Sergin P, Praveen Kumar D


Abstract

 Introduction: Alzheimer’s disease (AD) is characterised by a cholinergic deficit, and inhibition of acetylcholinesterase (AChE) remains a mainstay of symptomatic therapy. The 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold has been explored mainly for AMPA-receptor modulation, and its activity against AChE has not been examined experimentally. The present study describes the synthesis, characterisation and in vitro AChE inhibitory evaluation of five 3-substituted derivatives (CPD 1–5; phenyl, 4-chlorophenyl, 2-phenylethenyl, 4-hydroxy-3-methoxyphenyl and furan-2-yl).

Materials and Methods: The derivatives were prepared by acid-catalysed condensation of 2-aminobenzenesulfonamide with the corresponding aldehydes in refluxing ethanol (78–80 °C, 2–3 h) and recrystallised from hot ethanol. They were characterised by melting point, thin-layer chromatography (TLC), FT-IR (KBr), ¹H NMR (500 MHz, CDCl₃) and mass spectrometry. AChE inhibition by CPD 3 was determined by Ellman’s colorimetric method, with physostigmine as the standard.

Results and Discussion: The compounds were obtained in 75–84 % yield with melting points of 185–200 °C and a single TLC spot (Rf 0.45–0.60). IR spectra showed N–H stretching at 3368–3393 cm⁻¹ and SO₂ stretching at 1272–1329 cm⁻¹ (asymmetric) and 1154–1157 cm⁻¹ (symmetric); ¹H NMR spectra showed aromatic protons at δ 7.0–8.8 and ring methine protons at δ 4.2–5.7; molecular-ion peaks were observed at m/z 242–303. CPD 3 inhibited AChE in a concentration-dependent manner, from 10.33 % at 0.2 µg/mL to 55.37 % at 1.0 µg/mL, with an IC50 of 0.93 µg/mL.

Conclusion: A one-step, acid-catalysed route gave five 3-substituted benzothiadiazine 1,1-dioxides in good yield, and the 3-(2-phenylethenyl) derivative (CPD 3) showed concentration-dependent AChE inhibition in vitro. The scaffold merits further evaluation, including the remaining derivatives, enzyme kinetics and selectivity studies.



Keywords

acetylcholinesterase, Alzheimer’s disease, benzothiadiazine 1,1-dioxide, synthesis, characterisation, Ellman’s method.



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References


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