Novel uracil derivatives as anti-cancer agents: Design, synthesis, biological evaluation and computational studies

Abstract

Ten novel uracil-azole hybrides (4a-4j) were designed and synthesized as anti-cancer agents. IR, 1HNMR, 13CNMR, and Mass spectroscopy were applied to confirm the chemical structures of derivatives. Antiproliferative activities of all synthesized compounds were examined towards MCF-7 and SW480 cell lines by the MTT method. Compounds 4e and 4f were found to be the most active compounds with IC50= 14.5 ± 2.4 and 2.85±1.4 μM against the MCF-7 and SW480 cell lines, respectively. In addition, ADME (Absorption, Distribution, Metabolism and Excretion) analysis showed that the synthesized compounds have acceptable predictive physicochemical features. Asp 855, Met 793, Leu 792, Leu 844, Ala 743, Lys 745, Val 726, Thr 854 and Phe 723 are the key resiue in the binding site of EGFR target. To investigate the molecular orbital aspects of the experimental findings, DFT studies were performed on compounds 4b and 4f using the M06–2X/6–31+G (d,p) level of theory. The energy gap, reactivity descriptors, and frequency calculation were studied in detail, and the results are consistent with the experimental data. The results of the docking studies confirmed the biological activity.