Synthesis and Immunotropic Activity of New Heterodimers with a 4-(2-Furyl)pyridine Fragment

Abstract

The aim of this study was to identify new immunotropic compounds among nicotinonitrile and thienoquinoline derivatives conjugated with furan residues. Three new heterodimeric molecules were synthesized: 5-cyano-6-({2-[(4-ethoxyphenyl)amino]-2-oxoethyl}thio)-4-(2-furyl)-2-methyl-N-(2-methylphenyl)-1,4-dihydropyridine-3-carboxamide (XI), ethyl 4-(6-({2-[(3,5-dichlorophenyl)amino]-2-oxoethyl}thio)-5-cyano-4-(2-furyl)-2-methyl-1,4-dihydropyridine-3-carboxamido)benzoate (XII), and (3-amino-4-(5-methyl-2-furyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-2-yl)methanone (XV). Methods: The compounds were synthesized via reactions of cyanothioacetamide with furfural (or 5-methylfurfural), subsequent treatment with N-arylacetoacetamides or 1-(morpholino)cyclohexene and S-alkylation. The structures were confirmed by IR, 1H, and 13C NMR spectroscopy, including 2D NMR experiments. Immunotropic activity was evaluated in vivo in Wistar rats with streptozotocin- and dexamethasone-induced diabetes. The test compounds were administered intragastrically at 1.5 mg/kg for 14 days. Thymus mass (absolute and relative) and histological structure were assessed. Results and Discussion: The synthesized heterodimers significantly increased the absolute and relative thymus mass by 53–87% and 50–90%, respectively, compared to intact animals in both diabetes models. 5-Сyano-6-({2-[(4-ethoxyphenyl)amino]-2-oxoethyl}thio)-4-(2-furyl)-2-methyl-N-(2-methylphenyl)-1,4-dihydropyridine-3-carboxamide showed the most pronounced effect, inducing mitotic activity of thymocytes in the subcapsular cortex and promoting their migration into the bloodstream, indicative of immunostimulatory properties. In silico predictions suggested potential targets for the studied compounds (LFA-1, TBK1, TLR, PPARγ, JAK, RORγ, Ras-specific nucleotide exchange factors), which may underlie the observed immunotropic effects. Conclusions: The novel furan–pyridine heterodimers exhibit significant immunotropic activity, with 5-cyano-6-({2-[(4-ethoxyphenyl)amino]-2-oxoethyl}thio)-4-(2-furyl)-2-methyl-N-(2-methylphenyl)-1,4-dihydropyridine-3-carboxamide being the most promising immunostimulant for potential use in immunosuppressive conditions of various origins. These findings support further research on nicotinonitrile-based hybrid molecules as immunomodulators.