Тhio-containing pteridines: Synthesis, modification, and biological activity

The present article is devoted to searching for biologically active agents among novel thio-containing pteridines. Synthetic protocols based on the condensation of 5,6-diamino-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones with dicarbonyl compounds were elaborated and used for the synthesis of target products. The directions for further modification of the obtained thio-containing pteridines were substantiated and realized. The spectral properties of the obtained compounds were studied and described. The results of the in silico study revealed that the predicted affinity of the obtained compounds to the dihydrofolate reductase (DHFR) active site is comparable with the affinity of methotrexate, despite the differences in the nature of the ligand-enzyme interactions. The in vitro study of DHFR-inhibiting activity revealed that the most active compounds 3.9 and 4.2 have lg IC₅₀ values of -5.889 and -5.233, respectively, significantly inferior to methotrexate (lg IC₅₀ = -7.605). Additionally, the synthesized compounds were studied for their antiradical activity as a possible mechanism of pharmacological effects. Among the obtained pteridines, compounds 5.1 (lg EC₅₀ = -4.82) and 5.3 (lg EC₅₀ = -4.92) have antiradical activity higher than the reference compound ascorbic acid (lg EC₅₀ = -4.81). The conducted structure-activity relationship analysis provided valuable data for the further search for biologically active agents among thio-containing pteridines and related compounds.