Design, synthesis of novel thiazole‐thiomorpholine derivatives and evaluation of their anticancer activity via in vitro and in silico studies

Continuous efforts are carried out to find new cancer treatments. Compounds including thiazole or thiomorpholine rings showed favorable biological activities for various diseases including cancer. In this study, a new series of 4-(4-{[2-(4-phenylthiazol-2-yl)hydrazono]methyl}phenyl)thiomorpholine derivatives were synthesized and tested in vitro for their anticancer activity. Twelve compounds including various 4-phenylthiazol and a single 4-(2-naphthyl)thiazole derivatives were synthesized and analyzed by ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, and high-resolution mass spectrometry (HRMS). The cytotoxic effects of the compounds were tested on the A549 lung cancer cell line and the L929 healthy cell line. Six compounds (3a, 3b, 3c, 3d, 3e, and 3f) showed better inhibitory activity against A549 cells than the reference drug cisplatin. Compound 3f (4-CH₃ phenyl derivative) was the most potent with an IC₅₀ of 3.72 µM. The cytotoxic activity against the healthy cell line L929 was evaluated and all of the tested compounds displayed IC₅₀ values of more than 500 µM, indicating a selectivity toward the cancer cell line A549. Activity against matrix metalloproteinase-9 was also tested and the result indicated a %inhibition of 68.02 and 52.77 for compounds 3g and 3j, respectively. In silico evaluation was achieved via Density Functional Theory calculations and molecular dynamic simulations and the results were in line with those of the in vitro tests.