| Abstrak/Abstract |
Chalcone, a prominent flavonoid known for its diverse biological effects, has been widely used in anticancer drug development to create compounds with improved selectivity. This study synthesized nine chlorothiophenebased chalcone analogs to explore their anticancer activity and selectivity via structural optimization and bioisosteric replacement. Our compounds were synthesized using the Claisen–Schmidt condensation reaction and this method was proven to be highly effective, yielding our desired compounds at levels ranging from 68% to 96%. These compounds exhibited toxicity against various cancer cell lines, with compounds C4 and C6 exerting the strongest toxicity on WiDr colorectal cancer cells (IC50 = 0.77 and 0.45 µg/mL) and promising selectivity toward normal cells. Compounds C4 and C6 were selected for computational analysis to understand their inhibitory mechanisms. The analysis revealed binding energy values ranging from −6.2 to −6.6 kcal/mol, indicating moderate interactions with the anti-apoptotic proteins MDM2 and Bcl-2. Molecular dynamics simulation trajectories of C4 revealed stability profiles for Bcl-2 of up to 500 ns. Meanwhile, Density functional theory (DFT) studies provided insights into the designed compounds’ Highest occupied molecular orbital, lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and Molecular electrostatic potential (MEP) plot. In addition, ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) analyses indicated the potential for oral drug development across all compounds. |
