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, H-1-NMR, and C-13-NMR spectroscopy.

Journal

BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY

Year

2025

Volume

72

Issue

6

Pages

1752-1762

ISSN

0885-4513

eISSN

1470-8744

DOI

10.1002/bab.2780

WoS UID

WOS:001480814500001