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

Abstract

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.

Graphical Abstract

Keywords:

• Mycophenolic acid
• amide derivatives
• heterocycles
• benzoxazole
• IMPDH inhibition

Acknowledgements

NMR studies were performed in the Nuclear Magnetic Resonance Laboratory of Gdańsk University of Technology.

Disclosure statement

The authors do not report any competing financial interests or personal interrelations which could have governed publication’s outcomes.

Additional information

Funding

Financial support for this work was supported by the internal grant DS035136 of Gdańsk University of Technology and statutory grant no. 02–10022/272 of Medical University of Gdańsk.