Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A³-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53–96%). The bioactivity of all new compounds was evaluated by Ellman’s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that compounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC₅₀ of 0.25, 0.552, 0.089, 0.746, and 0.121 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.

Introduction. The resistance of microbes to many classes of antimicrobial drugs is a global threat to human health and necessitates the search for new compounds with antimicrobial activity, with low toxicity and a potentially wide range of biological activity. Aim. To study in vitro the ability of new xanthine derivatives (caffeine, 1-butyltheobromine and 7-butyltheophylline) to inhibit growth Staphylococcus (S.) aureus, Bacillus (B.) cereus, Escherichia (E.) coli and Pseudomonas (P.) aeruginosa. Materials and methods. The antibacterial activity of xanthine derivatives synthesized in the Laboratory of Medicinal Chemistry of the N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry was studied in vitro using serial dilutions in a liquid nutrient medium against S. aureus, B. cereus, E. coli and P. aeruginosa cultures. Results. Three substances, including the starting material – caffeine and 7-butyltheophylline, did not show antibacterial properties against test microbes. All xanthine derivatives studied did not inhibit the growth of E. coli and P. aeruginosa; 9 compounds containing fragments of amino acid esters or an acetylene substituent in the position of the C-8 xanthine backbone showed antibacterial activity against S. aureus and (or) B. cereus. Conclusion. When studying the ability of natural xanthine caffeine and 12 of its derivatives to inhibit the growth of cultures of opportunistic bacteria, antibacterial properties against S. aureus and B. cereus were revealed in a number of amino acid derivatives. The best effect was shown by compounds containing fragments of alpha- and beta-amino acid esters (L-valine and beta-phenyl-beta-alanine), which determines the prospects for further research.