4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

Abstract

Pyrrolidine-2,3-diones are important intermediates in the synthesis of numerous nitrogen-containing heterocycles which possess a broad spectrum of biological and pharmacological activities. In this article, we report the synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones via a reversible transimination reaction between Schiff' base (C=N) linkage-containing pyrrolidine-2,3-dione derivatives and methylamine with yields of 80 to 92%. In addition to nuclear magnetic resonance spectroscopy, the structure of 4-(1-methylamino)ethylidene-1,5-diphenylpyrrolidine-2,3-dione (5a) was also verified through single-crystal X-ray diffraction. Furthermore, the synthesized molecules were evaluated for compliance with established drug-likeness rules (Lipinski, Veber, Ghose, Egan, and Muegge), as well as ADMET properties. All compounds satisfied these criteria, indicating favorable oral bioavailability. Molecular docking analysis showed that compounds 5a-e act as ligands for inducible nitric oxide synthase (iNOS), especially with Cys200 and Ser242 via hydrogen bonds. In addition, van der Waals interactions also contribute to the stabilization of the ligand-iNOS complexes. In particular, 4-(1-methylamino)ethylidene-5-phenyl-1-(3-nitrophenyl)pyrrolidine-2,3-dione (5e) exhibited the strongest binding affinity (-9.51 kcal/mol) and demonstrated significant inhibitory activity against nitric oxide (NO) production, with an IC₅₀ value of 43.69 ± 5.26 µM. The presence of an electron-withdrawing group (-NO₂ group) on the benzene ring at the 1-position of the pyrrolidine-2,3-dione subunit in compound 5e may be responsible for the observed high inhibition activity due to the enhancement and optimization of hydrogen bonding with Cys200. These results underscore the potential of 4-(1-methylamino)ethylidenepyrrolidine-2,3-diones, especially compound 5e, as promising scaffolds for the development of anti-inflammatory agents targeting iNOS-related pathologies.

Keywords: anti-inflammatory pyrrolidine-2,3-dione derivatives; iNOS; pyrrolidine-2,3-dione derivatives; pyrrolidine-2,3-diones; pyrrolidine-2,3-diones targeting reversible transimination reaction.

Figure 1

Natural products and synthetic medicinal compounds containing a 2-pyrrolidinone subunit.

Scheme 1

Synthesis of 4-[1-(4-methoxybenzyl)amino]ethylidene-1,5-disubstituted pyrrolidine-2,3-diones 3a–e.

Scheme 2

Synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones 5a–e.

Scheme 3

Proposed mechanism for the reaction between 4-[1-(4-methoxybenzyl)amino]ethylidene-1,5-disubstituted pyrrolidine-2,3-diones 3a–e and methylamine (4).

Figure 2

The molecular structure of 5a, showing the atom-labelling scheme and displacement ellipsoids at the 30% probability level. The intramolecular hydrogen bond is shown as red dashed line.

Figure 3

The bioavailability radar of studied compounds 5a–e.

Figure 4

The interactions of potential drugs 5a–c in the active site of enzyme iNOS.

Figure 5

The interactions of potential drugs 5d and 5e and control drug (DEX) in the active site of enzyme iNOS.