Investigating chlorothiophene-based chalcones as anticancer agents: Synthesis, biological evaluation, and computational insight via the p53-targeted pathway

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 chlorothiophene-based chalcone analogs to explore their anticancer activity and selectivity via structural optimization and bio-isosteric 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 (IC 50 = 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.