Synthesis and Structural Study of Amidrazone Derived Pyrrole-2,5-Dione Derivatives: Potential Anti-Inflammatory Agents.

Abstract

1H-pyrrole-2,5-dione derivatives are known for their wide range of pharmacological properties, including anti-inflammatory and antimicrobial activities. This study aimed to synthesize new 3,4-dimethyl-1H-pyrrole-2,5-dione derivatives 2a–2f in the reaction of N3-substituted amidrazones with 2,3-dimethylmaleic anhydride and evaluate their structural and biological properties. Compounds 2a–2f were studied by the 1H-13C NMR two-dimensional techniques (HMQC, HMBC) and single-crystal X-ray diffraction (derivatives 2a and 2d). The anti-inflammatory activity of compounds 2a–2f was examined by both an anti-proliferative study and a production study on the inhibition of pro-inflammatory cytokines (IL-6 and TNF-α) in anti-CD3 antibody- or lipopolysaccharide-stimulated human peripheral blood mononuclear cell (PBMC) cultures. The antibacterial activity of compounds 2a–2f against Staphylococcus aureus, Enterococcus faecalis, Micrococcus luteus, Esherichia coli, Pseudomonas aeruginosa, Yersinia enterocolitica, Mycobacterium smegmatis and Nocardia corralina strains was determined using the broth microdilution method. Structural studies of 2a–2f revealed the presence of distinct Z and E stereoisomers in the solid state and the solution. All compounds significantly inhibited the proliferation of PBMCs in anti-CD3-stimulated cultures. The strongest effect was observed for derivatives 2a–2d. The strongest inhibition of pro-inflammatory cytokine production was observed for the most promising anti-inflammatory compound 2a.