Novel Sulfonylhydrazones With Sulfonate Ester Framework: Promising Dual Inhibitors of AChE and hCAs

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of individuals worldwide. Treatment strategies for AD vary depending on cognitive and behavioral symptoms, with cholinergic replacement therapy using acetylcholinesterase (AChE) inhibitors being one of the primary approaches. Recent studies have also identified human carbonic anhydrases (hCAs) as significant therapeutic targets for AD, offering new opportunities for the development of innovative treatments. Carbonic anhydrase inhibitors have been shown to prevent early mitochondrial damage and inhibit H₂O₂ production, thereby reducing amyloid plaque formation. Building on the promising potential of hydrazones particularly sulfonyl hydrazones as anticholinesterase agents, we synthesized 12 novel chlorine-substituted sulfonyl hydrazone compounds containing aryl sulfonate ester groups. These compounds were evaluated for their inhibitory effects on AChE, hCA I, and hCA II enzymes. The synthesized compounds exhibited low nanomolar inhibitory activity, with K_i values ranging from 9.58 ± 2.22 to 104.04 ± 23.82 nM for AChE, 9.12 ± 2.21 to 477.63 ± 218.52 nM for hCA I, and 17.54 ± 7.74 to 564.62 ± 213.98 nM for hCA II. Notably, compound 6 showed strong inhibitory activity against hCA I (K_i = 9.12 ± 2.21 nM; acetazolamide (AZA) = 26.54 ± 3.11 nM) and hCA II (K_i = 17.54 ± 7.74 nM; AZA = 21.73 ± 2.42 nM), whereas compound 4 exhibited superior AChE inhibition (K_i = 9.58 ± 2.22 nM; TAC = 23.12 ± 2.05 nM). The chemical structures of the synthesized compounds were characterized using advanced spectroscopic techniques, including FT-IR, ¹H-NMR, and ¹³C-NMR spectroscopy.