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 N 2 H 4 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 IC 50 0:84 ± 0:12 μM among all other derivatives and is also more active than standard acetazolamide (IC 50 0:91 ± 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.
Heterocyclic compounds bearing sulfonamide moiety have been reported to possess carbonic anhydrase inhibitory activity. In the present study, a series of novel N‐methylpyrrole 3(a–j) derivatives bearing disulfonamide functional group have been synthesized by following a simple nucleophilic substitution reaction route to explore their carbonic anhydrase inhibitory activity. N‐methylpyrrole (1) was converted into N‐methylpyrrole disulfonyl chloride (2), which upon condensation with various aliphatic and aromatic amines, yielded the final products 3(a–j). In silico docking results predicted strong binding of synthesized compounds in an enzymatic pocket of human carbonic anhydrase isozyme II (PDB ID 4Q6D). In vitro carbonic anhydrase inhibitory assays revealed that analogues 3 e (1‐Methyl‐N3,N4‐bis(2‐(pyridin‐2‐yl)ethyl)‐1H‐pyrrole‐3,4‐disulfonamide) and 3j (N3,N4,1‐trimethyl‐1H‐pyrrole‐3,4‐disulfonamide) were most potent with IC50 0.38±0.01 μM and 0.75±0.88 μM respectively in comparison to standard acetazolamide (IC50 0.99±0.04 μM). The enzyme inhibitory kinetics exhibited 3 e a noncompetitive inhibitor with Km and Ki values as 0.34 mM and 18.2 μM respectively. The compounds 3 e and 3 j showed very little cytotoxicity against human keratinocyte (HaCaT) with 80 % cell viability and the anticancer activity performed against MCF‐7 cell line showed that the compounds 3 e and 3 j caused 80 % and 45 % cell death respectively at 125 μM concentrations. Combining the results of DNA binding analysis through the UV‐Vis spectroscopy (hypochromism), cyclic voltammetry (current decrease), and fluorescence spectroscopy (hypochromism in intercalator's peak); mixed binding mode (intercalation + groove binding) was suggested for 3 e and intercalation for 3 j with stronger DNA binding of 3 e than 3 j. Based on our results 3 e and 3 j may be proposed to serve as a lead structure for designing potentially more active CAIs.
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