Synthesis and in silico studies of triazene-substituted sulfamerazine derivatives as acetylcholinesterase and carbonic anhydrases inhibitors

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Abstract A series of substituted quinolines was screened for their antiproliferative, cytotoxic, antibacterial activities, DNA/protein binding affinity, and anticholinergic properties by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide cell proliferation, lactate dehydrogenase cytotoxicity, and microdilution assays, the Wolfe–Shimmer equality method, the Ellman method, and the esterase assay, respectively. The results of the cytotoxic and anticancer activities of the compounds displayed that 6‐bromotetrahydroquinoline ( 2 ), 6,8‐dibromotetrahydroquinoline ( 3 ), 8‐bromo‐6‐cyanoquinoline ( 10 ), 5‐bromo‐6,8‐dimethoxyquinoline ( 12 ), the novel N ‐nitrated 6,8‐dimethoxyquinoline ( 13 ), and 5,7‐dibromo‐8‐hydroxyquinoline ( 17 ) showed a significant antiproliferative potency against the A549, HeLa, HT29, Hep3B, and MCF7 cancer cell lines (IC 50 = 2–50 μg/ml) and low cytotoxicity (∼7–35%) as the controls, 5‐fluorouracil and cisplatin. The compound–DNA linkages are hyperchromic or hypochromic, causing variations in their spectra. This situation shows that they can be bound to DNA with the groove‐binding mode, with K b value in the range of 2.0 × 10 3 –2.2 × 10 5 M –1 . Studies on human Gram(+) and Gram(−) pathogenic bacteria showed that the substituted quinolines exhibited selective antimicrobial activities with MIC values of 62.50–250 μg/ml. All tested quinoline derivatives were found to be effective inhibitors of acetylcholinesterase (AChE) and the human carbonic anhydrase I and II isoforms (hCA I and II), with K i values of 46.04–956.82 nM for hCA I, 54.95–976.93 nM for hCA II, and 5.51–155.22 nM for AChE. As a result, the preliminary data showed that substituted quinolines displayed effective pharmacological features. Molecular docking studies were performed to investigate the binding modes and interaction energies for compounds 2–17 with AChE (PDB ID: 4EY6), hCA I (PDB ID: 1BMZ), and hCA II (PDB ID: 2ABE).