Synthesis, Evaluation of Biological Activity, and Structure–Activity Relationships of New Amidrazone Derivatives Containing Cyclohex-1-ene-1-Carboxylic Acid

In recent years, the incidence of acute and chronic inflammatory diseases has increased significantly worldwide, intensifying the search for new therapeutic agents, especially anti-inflammatory drugs. Therefore, the aim of this work was to synthesize, biologically assess, and explore the structure-activity relationships of new compounds containing the cyclohex-1-ene-1-carboxylic acid moiety. Six new derivatives, <b>2a</b>-<b>2f</b>, were synthesized through the reaction of amidrazones <b>1a</b>-<b>1f</b> with 3,4,5,6-tetrahydrophthalic anhydride. Their toxicity was evaluated in cultures of human peripheral blood mononuclear cells (PBMCs). Additionally, their antiproliferative properties and effects on the synthesis of TNF-α, IL-6, IL-10, and IL-1β were assessed in mitogen-stimulated PBMCs. The antimicrobial activity of derivatives <b>2a</b>-<b>2f</b> was determined by measuring the minimal inhibitory concentration (MIC) values against five bacterial strains-<i>Staphylococcus aureus</i>, <i>Mycobacterium smegmatis</i>, <i>Escherichia coli</i>, <i>Yersinia enterocolitica</i>, and <i>Klebsiella pneumoniae</i>-and the fungal strain <i>Candida albicans.</i> All compounds demonstrated antiproliferative activity, with derivatives <b>2a</b>, <b>2d</b>, and <b>2f</b> at a concentration of 100 µg/mL being more effective than ibuprofen. Compound <b>2f</b> strongly inhibited the secretion of TNF-α by approximately 66-81% at all studied doses (10, 50, and 100 µg/mL). Derivative <b>2b</b> significantly reduced the release of cytokines, including TNF-α, IL-6, and IL-10, at a high dose (by approximately 92-99%). Compound <b>2c</b> exhibited bacteriostatic activity against <i>S. aureus</i> and <i>M. smegmatis</i>, while derivative <b>2b</b> selectively inhibited the growth of <i>Y. enterocolitica</i> (MIC = 64 µg/mL). Some structure-activity relationships were established for the studied compounds.