Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2022)

Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents

  • Juliusz Maksymilian Walczak,
  • Dorota Iwaszkiewicz-Grześ,
  • Michalina Ziomkowska,
  • Magdalena Śliwka-Kaszyńska,
  • Mateusz Daśko,
  • Piotr Trzonkowski,
  • Grzegorz Cholewiński

DOI
https://doi.org/10.1080/14756366.2022.2127701
Journal volume & issue
Vol. 37, no. 1
pp. 2725 – 2741

Abstract

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The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

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