A Practical Method of N-Methylpyrrole Disulfonamides Synthesis: Computational Studies, Carbonic Anhydrase Inhibition and Electrochemical DNA Binding Investigations

摘要

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 substitu- tion 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 3e (1-Methyl-N3,N4-bis(2-(pyridin-2-yl)ethyl)-1H-pyrrole-3,4-di- sulfonamide) and 3j (N3,N4,1-trimethyl-1H-pyrrole-3,4-disulfo- namide) 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 3e a noncompetitive inhibitor with Km and Ki values as 0.34 mM and 18.2 μM respectively. The compounds 3e and 3j 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 3e and 3j 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 spec- troscopy (hypochromism in intercalator’s peak); mixed binding mode (intercalation + groove binding) was suggested for 3e and intercalation for 3j with stronger DNA binding of 3e than 3j. Based on our results 3e and 3j may be proposed to serve as a lead structure for designing potentially more active CAIs.