Synthesis, structure elucidation, and in vitro pharmacological evaluation of novel polyfluoro substituted pyrazoline type sulfonamides as multi-target agents for inhibition of acetylcholinesterase and carbonic anhydrase I and II enzymes

Abstract

A novel series of 4-(3-(difluorophenyl)-5-(dimethoxyphenyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides 1-8 were designed since sulfonamide and pyrazoline pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Comprehensive structure elucidation of the compounds synthesized was carried out by ¹H NMR, ¹³C NMR, ¹⁹F NMR, DEPT 90-135, ¹H-¹H COSY, ¹H-¹³C HMQC, HMBC, and HRMS spectra. The chemical shifts and splitting patterns of the protons and carbons were affected by the fluorine atoms and exciting splitting patterns were also recorded for the fluorinated compounds. In vitro enzyme assays obviously showed that the novel compounds had a significant inhibitory profile against hCA I, hCA II and AChE enzymes at the nanomolar levels. Ki values were in the range of 3.30 ± 1.09-5.95 ± 2.26 nM for hCA I and 4.29 ± 0.91-7.14 ± 3.15 nM for hCA II, while Ki values for AChE were in the range of 3.28 ± 1.47-9.77 ± 1.86 nM. Many of thecompounds in this study can be considered as promising AChE and CA inhibitors.

Keywords: Acetylcholinesterase; Carbonic anhydrase; Fluorine; Pyrazoline; Sulfonamide.