The Synthesis and Biological Activity of Amidrazone Derivatives Obtained in Reaction with cis-1,2,3,6-Tetrahydrophthalic Anhydride ^†

Abstract

Amidrazones are known for the broad biological activity of their derivatives (antimicrobial, anti-inflammatory, antiparasitic, antitumor and others). While searching for new drugs, twelve new derivatives of N³-substituted amidrazones were obtained in the reaction with cis-1,2,3,6-tetrahydrophthalic anhydride. The structures of obtained linear compounds and 1,2,4-triazole derivatives were confirmed by ¹H NMR, ¹³C NMR and MS. Toxicity and inflammatory activity of obtained compounds (at concentrations of 10, 50 and 100 µg/mL) were studied in human peripheral blood mononuclear cells (PBMC). The influence of new derivatives on cytokine production (TNF-α, IL-6 and IL-10) was examined in PBMC cultures stimulated by LPS. Antiproliferative activity of compounds was studied in PBMC cultures stimulated by phytohaemagglutinin. Minimal inhibitory activity of compounds was studied by broth microdilution method on Gram-positive (S. aureus, M. smegmatis) and Gram-negative (E. coli, Y. enterocolitica, K. pneumonia) bacterial and fungal C. albicans strain. Obtained 1,2,4-triazole derivatives were not toxic to PBMC at a concentration range of 10–100 µg/mL. Only one 1,2,4-triazole derivative showed significant antiproliferative activity at the highest dose. Five 1,2,4-triazole derivatives showed significant, stronger than ibuprofen, inhibition of pro-inflammatory TNF-α production at concentrations 10 and 50 µg/mL, as well as significant elevation of levels of anti-inflammatory cytokine IL-10 at each used dose. Two linear compounds showed antibacterial activity against Gram-positive bacteria. In conclusion, five obtained compounds showed a strong anti-inflammatory effect and deserve further research.