Heme oxygenase (HO) is a cytoprotective enzyme that gets overexpressed under some pathological conditions, like cancer where it provides growth advantage and protection against radiotherapy, chemotheraphy and photodynamic therapy. Earlier studies on HO inhibition were carried out with metalloporphyrins, which not only inhibit HO‐1 but also other constitutively expressed HOs and other heme‐dependent enzymes. Hence, the present study was aimed at synthesizing highly‐substituted imidazole heterocycles as inhibitors of heme oxygenase‐1 (HO‐1). The synthesized compounds were structurally characterized by IR, 1H, 13C NMR, CHN and single crystal XRD analysis. Among the synthesized compounds, compound 6(3‐(4,5‐diphenyl‐1H‐imidazol‐2‐yl)‐6‐methoxy‐1H‐quinoline‐2‐one) showed > 50% HO‐1 inhibitory activity at a least concentration of 9.2 μM and like many pharmaceutically important drugs, it showed competitive inhibition which was confirmed by Lineweaver‐Burk plot. Compound 6 was also tested for cytotoxicity against cancer (A549, MG63, MCF7) and normal cell (HEK293). The compound showed maximum efficacy against A549 cell line and moderate activity against other cell lines. In order to determine the molecular interactions of compound 6 with HO, the molecular docking study was carried out using Schrodinger software, which was in good agreement with experimental observations.
A series of 4-quinolone-3-carboxylic acid-containing spirooxindole-pyrrolidine derivatives was synthesized via multicomponent 1,3-dipolar cycloaddition reactions of azomethine ylides with new (E)-4-oxo-6-(3-phenyl-acryloyl)-1,4-dihydroquinoline-3-carboxylic acids in good yields with high regioselectivity. The cycloadducts were characterized by analytical and spectral data including [Formula: see text], [Formula: see text], 2D NMR and mass spectroscopy. The structure of one of the compounds (8a) was investigated theoretically by computational techniques. DFT studies support the proposed mechanism for this cycloaddition reaction. Furthermore, antibacterial activities of the new compounds were evaluated against Gram-positive and Gram-negative bacterial strains. Compounds 8f, 8m and 8p showed potent inhibition activities against selected bacteria. The in vitro cytotoxicity of spirooxindole derivatives (8a-r) was evaluated against MCF-7 breast cancer cell line. Among the various compounds tested, compound 8f [Formula: see text] showed significant cytotoxic activity compared to the standard drug doxorubicin [Formula: see text].
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