N-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents
2023
Nan Yadanar Lin Pyae | Arnatchai Maiuthed | Wongsakorn Phongsopitanun | Bongkot Ouengwanarat | Warongrit Sukma | Nitipol Srimongkolpithak | Jutharat Pengon | Roonglawan Rattanajak | Sumalee Kamchonwongpaisan | Zin Zin Ei | Preedakorn Chunhacha | Patcharin Wilasluck | Peerapon Deetanya | Kittikhun Wangkanont | Kowit Hengphasatporn | Yasuteru Shigeta | Thanyada Rungrotmongkol | Supakarn Chamni
New N-containing xanthone analogs of &alpha:-mangostin were synthesized via one-pot Smiles rearrangement. Using cesium carbonate in the presence of 2-chloroacetamide and catalytic potassium iodide, &alpha:-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 &alpha:-mangostin and analogs 2&ndash: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 &alpha:-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&ndash: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 &alpha:-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.
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