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

Abstract

1<i>H</i>-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-<i>1H</i>-pyrrole-2,5-dione derivatives <b>2a</b>-<b>2f</b> in the reaction of <i>N</i>³-substituted amidrazones with 2,3-dimethylmaleic anhydride and evaluate their structural and biological properties. Compounds <b>2a</b>-<b>2f</b> were studied by the ¹H-¹³C NMR two-dimensional techniques (HMQC, HMBC) and single-crystal X-ray diffraction (derivatives <b>2a</b> and <b>2d</b>). The anti-inflammatory activity of compounds <b>2a</b>-<b>2f</b> 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 <b>2a-2f</b> against <i>Staphylococcus aureus</i>, <i>Enterococcus faecalis</i>, <i>Micrococcus luteus</i>, <i>Esherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Yersinia enterocolitica</i>, <i>Mycobacterium smegmatis</i> and <i>Nocardia corralina</i> strains was determined using the broth microdilution method. Structural studies of <b>2a</b>-<b>2f</b> revealed the presence of distinct <i>Z</i> and <i>E</i> 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 <b>2a</b>-<b>2d</b>. The strongest inhibition of pro-inflammatory cytokine production was observed for the most promising anti-inflammatory compound <b>2a</b>.