| Summary: | Pyridine, 1,3,4-thiadiazole, and 1,3-thiazole derivatives have various biological activities, such as antimicrobial, analgesic, anticonvulsant, and antitubercular, as well as other anticipated biological properties, including anticancer activity. The starting 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2<i>H</i>)-yl)-3-phenylthiourea (<b>2</b>) was prepared and reacted with various hydrazonoyl halides <b>3a</b>–<b>h,</b> α-haloketones <b>5a</b>–<b>d</b>, 3-chloropentane-2,4-dione <b>7a</b> and ethyl 2-chloro-3-oxobutanoate <b>7b</b>, which afforded the 3-aryl-5-substituted 1,3,4-thiadiazoles <b>4a</b>–<b>h,</b> 3-phenyl-4-arylthiazoles <b>6a</b>–<b>d</b> and the 4-methyl-3- phenyl-5-substituted thiazoles <b>8a,b</b>, respectively. The structures of the synthesized products were confirmed by spectral data. All of the compounds also showed remarkable anticancer activity against the cell line of human colon carcinoma (HTC-116) as well as hepatocellular carcinoma (HepG-2) compared with the Harmine as a reference under in vitro condition. 1,3,4-Thiadiazole <b>4h</b> was found to be most promising and an excellent performer against both cancer cell lines (IC<sub>50</sub> = 2.03 ± 0.72 and 2.17 ± 0.83 µM, respectively), better than the reference drug (IC<sub>50</sub> = 2.40 ± 0.12 and 2.54 ± 0.82 µM, respectively). In order to check the binding modes of the above thiadiazole derivatives, molecular docking studies were performed that established a binding site with EGFR TK.
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