Enzyme-Targeted Antiproliferative Effects of Novel Indole–Acrylamide Xenobiotics Acting on Cyclooxygenase Pathways

The indole scaffold is common in natural products and bioactive compounds, including anti-cancer and anti-inflammatory medicines. In this work, a series of indole-acrylamide derivatives was synthesized, and their antiproliferative and anti-inflammatory effects were evaluated on COX enzymes and against a panel of cancer cell lines. All the final compounds were characterized via HRMS and (¹H & ¹³C)-NMR. Anticancer and anti-inflammatory activities were evaluated using standard biomedical techniques by SRB, MTS, and COX kit assays. Additionally, the molecular docking analysis was conducted using the AutoDock Vina tool. The results demonstrated that the produced compounds displayed significant inhibitory effects on the COX-2 enzyme, with IC₅₀ values of 128 nM to 1.04 µM. <b>6a</b> demonstrated significant COX-2 selectivity with an IC₅₀ of 128 nM and an SI of 352, highlighting its preference for COX-2 over COX-1. <b>6c</b> exhibited potent COX-2 inhibition with an IC₅₀ of 0.215 µM and an SI of 10.6. The assessed compounds exhibited substantial cytotoxic effects on cancer cells, especially against liver cancer cell lines (Huh7, HepG2, Mahlavu, and SNU475), and breast cancer (MCF-7). <b>6d</b> compound was the most COX-1 selective inhibitor, which observed potent activity against hepatocellular carcinoma, with IC₅₀ values as low as 3.5 µM, and was highly effective against MCF-7. Additionally, COX-2 selective inhibitors, <b>6a</b> and <b>6b</b>, exhibited strong antiproliferative effects against both breast cancer (MCF-7) and melanoma (B16F1), with IC₅₀ values ranging from 4.75 to 15.4 µM. Furthermore, the molecular docking of <b>6a</b> demonstrated a strong affinity for the COX-2 enzyme, with energy scores (S) of -8.392 kcal/mol, comparable to celecoxib's score of -10.96 kcal/mol. The findings suggest a possible correlation between COX-2 inhibition and anticancer efficacy, especially for compounds <b>6a</b> and <b>6c</b>, which demonstrate excellent COX-2 selectivity and notable antiproliferative effects, positioning them as prospective candidates for further advancement in cancer treatment.