A new series of betulin derivatives containing one or two pharmacophores bearing an acetylenic and carbonyl function at the C-3 and/or C-28 positions has been synthesized and characterized by ¹H- and ¹³C-NMR, IR, MS and elemental analyses. The crystal structure of 28-O-propynoylbetulin was determined by X-ray structural analysis. All new compounds, as well as betulin, were tested in vitro for their antiproliferative activity against human SW707 colorectal, CCRF/CEM leukemia, T47D breast cancer, and against murine P388 leukemia and Balb3T3 normal fibroblasts cell lines. Most of the compounds showed better cytotoxicity than betulin and cisplatin used as reference agent. 28-O-Propynoylbetulin was the most potent derivative, being over 500 times more potent than betulin and about 100 times more cytotoxic than cisplatin against the human leukemia (CCRF/CEM) cell line, with an ID₅₀ value of 0.02 μg/mL.

Betulin derivatives containing a 1,2,3-triazole ring possess a wide spectrum of biological activities, including antiviral, anticancer, and antibacterial activity. A series of novel triazoles were prepared by the 1,3-dipolar cycloaddition reaction between the alkyne derivatives of betulin and organic azides. The chemical structures of the obtained compounds were defined by ¹H and ¹³C NMR, IR, and high-resolution mass spectrometry (HR-MS) analysis. The target triazoles were screened for their antiviral activity against DNA and RNA viruses. The cytotoxic activity of the obtained compounds 5a–k and 6a–h was determined using five human cancer cell lines (T47D, MCF-7, SNB-19, Colo-829, and C-32) by a WST-1 assay. The bistriazole 6b displayed a promising IC₅₀ value (0.05 μM) against the human ductal carcinoma T47D (500-fold higher potency than cisplatin). The microdilution method was applied for an evaluation of the antimicrobial activity of all of the compounds. The triazole 5e containing a 3′-deoxythymidine-5′-yl moiety exhibited antibacterial activity against two gram-negative bacteria vz. Klebsiella pneumoniae and Escherichia coli (minimal inhibitory concentration (MIC) range of 0.95–1.95 μM).

A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (ΔG) and the physicochemical properties of the tested compounds.

Betulin derivatives are a widely studied group of compounds of natural origin due to their wide spectrum of biological activities. This paper describes new betulin derivatives, containing a phosphonate group. The allyl-vinyl isomerization and synthesis of acetylenic derivatives have been reported. Structural identification of products as E and Z isomers has been carried out using ¹H-, ¹³C-, ³¹P-NMR, and crystallographic analysis. The crystal structure in the orthorhombic space group and analysis of crystal packing contacts for 29-diethoxyphosphoryl-28-cyclopropylpropynoyloxy-lup-20E(29)-en-3β-ol 8a are reported. All new compounds were tested in vitro for their antiproliferative activity against human T47D (breast cancer), SNB-19 (glioblastoma), and C32 (melanoma) cell lines.