Sulfonamide-Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics

Abstract

A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N₂H₄ to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC₅₀0.84 ± 0.12 μM among all other derivatives and is also more active than standard acetazolamide (IC₅₀0.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with K _i value 8.6 μM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.

Scheme 1

Synthesis of azaheterocyclic Schiff base sulfonamide derivatives 3(a-j)

Figure 1

Lineweaver–Burk plots for inhibition of carbonic anhydrase with derivative 3c. (a) Concentrations of 3c were 0.00, 7.1, 14.2, and 28.4 μM, respectively. Substrate p-nitrophenyl acetate concentrations were 0.0625, 0.125, 0.25, 0.5, 1, and 2 mM. (b) The inset shows the plot of the slope versus 3c concentrations to find the inhibition constant. Lines were drawn by linear least squares fit.

Figure 2

Crystal structure of bovine anhydrase II PDBID (1V9E).

Figure 3

Glide docking score of the synthesized compounds 3a-j docking complexes with PDBID (1V9E).

Figure 4

3D docking interactions of 3c with target protein PDBID (1V9E).

Figure 5

2D docking interactions of 3c with target protein PDBID (1V9E).

Figure 6

The effects of azaheterocyclic sulfonamide Schiff bases on cell viability of the MCF-7 cells.

Figure 7

The effects of azaheterocyclic sulfonamide Schiff bases on cell viability of the human keratinocyte (HaCaT) cells.