Pyae N.Y.L.Maiuthed A.Phongsopitanun W.Ouengwanarat B.Sukma W.Srimongkolpithak N.Pengon J.Rattanajak R.Kamchonwongpaisan S.Ei Z.Z.Chunhacha P.Wilasluck P.Deetanya P.Wangkanont K.Hengphasatporn K.Shigeta Y.Rungrotmongkol T.Chamni S.Mahidol University2023-05-192023-05-192023-02-01Molecules Vol.28 No.3 (2023)https://repository.li.mahidol.ac.th/handle/123456789/81665New N-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 (1) was subsequently transformed in three steps to provide ether 2, amide 3, and amine 4 in good yields at an optimum ratio of 1:3:3, respectively. The evaluation of the biological activities of α-mangostin and analogs 2–4 was described. Amine 4 showed promising cytotoxicity against the non-small-cell lung cancer H460 cell line fourfold more potent than that of cisplatin. Both compounds 3 and 4 possessed antitrypanosomal properties against Trypanosoma brucei rhodesiense at a potency threefold stronger than that of α-mangostin. Furthermore, ether 2 gave potent SARS-CoV-2 main protease inhibition by suppressing 3-chymotrypsinlike protease (3CLpro) activity approximately threefold better than that of 1. Fragment molecular orbital method (FMO–RIMP2/PCM) indicated the improved binding interaction of 2 in the 3CLpro active site regarding an additional ether moiety. Thus, the series of N-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.Biochemistry, Genetics and Molecular BiologyArticleSCOPUS10.3390/molecules280311042-s2.0-851478936871420304936770770