In this study, 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides were synthesized, and inhibition effects on AChE, hCA I, and hCA II were evaluated. K values of the compounds toward hCA I were in the range of 24.2 ± 4.6-49.8 ± 12.8 nm, while they were in the range of 37.3 ± 9.0-65.3 ± 16.7 nm toward hCA II. K values of the acetazolamide were 282.1 ± 19.7 nm and 103.60 ± 27.6 nm toward both isoenzymes, respectively. The compounds inhibited AChE with K in the range of 22.7 ± 10.3-109.1 ± 27.0 nm, whereas the tacrine had K value of 66.5 ± 13.8 nm. Electronic structure calculations at M06-L/6-31 + G(d,p)//AM1 level and molecular docking studies were also performed to enlighten inhibition mechanism and to support experimental findings. Results obtained from calculations of molecular properties showed that the compounds obey drug-likeness properties. The experimental and computational findings obtained in this study might be useful in the design of novel inhibitors against hCA I, hCA II, and AChE.

Abstract4-(3-(4-Substituted-phenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamides (9–16) were successfully synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, and HRMS spectra. Carbonic anhydrase I and II inhibitory effects of the compounds were investigated. Ki values of the compounds were in the range of 316.7 ± 9.6–533.1 ± 187.8 nM towards hCA I and 412.5 ± 115.4–624.6 ± 168.2 nM towards hCA II isoenzymes. While Ki values of the reference compound Acetazolamide were 278.8 ± 44.3 nM and 293.4 ± 46.4 nM towards hCA I and hCA II izoenzymes, respectively. Compound 14 with bromine and compound 13 with fluorine substituents can be considered as the leader compounds of the series because of the lowest Ki values in series to make further detailed carbonic anhydrase inhibiton studies.

The effects of isatin Mannich bases incorporating (1-[piperidin-1-yl (P1)/morpholin-4-yl (P2)/Nmethylpiperazin-1-yl (P3)]methyl)-1H-indole-2,3-dione) moieties against human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes hCA I and hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes were evaluated. P1-P3 demonstrated impressive inhibition profiles against AChE and BChE and also inhibited both CAs at nanomolar level. These inhibitory effects were more powerful in all cases than the reference compounds used for all these enzymes. This study suggests that isatin Mannich bases P1-P3 are good candidate compounds especially for the development of new cholinesterase inhibitors since they were 2.2-5.9 times better inhibitors than clinically used drug Tacrine.

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