-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents.

New -containing xanthone analogs of α-mangostin were synthesized via one-pot Smiles rearrangement. Using cesium carbonate in the presence of 2-chloroacetamide and catalytic potassium iodide, α-mangostin () was subsequently transformed in three steps to provide ether , amide , and amine in good yields at an optimum ratio of 1:3:3, respectively. The evaluation of the biological activities of α-mangostin and analogs - was described. Amine showed promising cytotoxicity against the non-small-cell lung cancer H460 cell line fourfold more potent than that of cisplatin. Both compounds and possessed antitrypanosomal properties against at a potency threefold stronger than that of α-mangostin. Furthermore, ether gave potent SARS-CoV-2 main protease inhibition by suppressing 3-chymotrypsinlike protease (3CL) activity approximately threefold better than that of . Fragment molecular orbital method (FMO-RIMP2/PCM) indicated the improved binding interaction of in the 3CL active site regarding an additional ether moiety. Thus, the series of -containing α-mangostin analogs prospectively enhance druglike properties based on isosteric replacement and would be further studied as potential biotically active chemical entries, particularly for anti-lung-cancer, antitrypanosomal, and anti-SARS-CoV-2 main protease applications.