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.

A Review of the Biological Activity of Amidrazone Derivatives

“…Compound 58 , possessing two phenyl substituents, significantly reduced the production of IL-6 (by 64%) in LPS-stimulated PBMC cultures. Both compounds 58 and 59 inhibited the proliferation of PBMC even at a low dose of 10 µg/mL, and the strongest effect was observed for the latter, possessing two 2-pyridine rings [ 54 ].…”

Evaluation of Anthelmintic and Anti-Inflammatory Activity of 1,2,4-Triazole Derivatives

“…The percentage of viable cells for new compounds 12 , 19 – 22 was in the range of 90.56–93.40%, which is higher than the control culture containing the same concentration of DMSO (87.27%). For comparison, five by six 1 H -pyrrole-2,5-dione derivatives (obtained from the same amidrazones 1 – 8 as compounds 11 – 22 ) showed about 79–92% of viable cells [ 46 ]. In general, derivatives 17 – 22 were less toxic than 9 – 16 while compounds 10 and 18 possessing phenyl and 2-pyridine rings were the most toxic within those two groups.…”

A facile and efficient synthesis of highly functionalized pyrroles via a four-component one-pot reaction in the presence of Ni(II) Schiff base/SBA-15 heterogeneous catalyst

“…Its derivatives are, moreover, present in the majority of synthetic and natural drug chemical structures. As well as playing a key role in organic synthesis, pyrrole derivatives have biological signi cance activities including antimalarial 11 , antitumor 12 , antiallergic 13 , fungicidal 14 , antiviral 15 , antidiabetic 16 , antibacterial 17 , antioxidant 18 , antitubercular 19 , anti-in ammatory agents 20 , and tyrosine kinase inhibiting agents 21 . Various strategies are employed to prepare these precious compounds, namely Hantzsch 22 , Paal-Knorr 23 , transition metal-catalyzed 24 , and multicomponent couplings.…”