One-pot synthesis of quaternary pyridinium salts of lupane triterpenoids and their antimicrobial properties

Abstract

C30-quaternized derivatives of lupane triterpenoids (31 examples) were synthesized with a yield of 85–95% via a one-pot functionalization of a double bond under the action of organic tribromides (TEMPO⁺Br₃⁻, TBABr₃, and Py·HBr·Br₂) and pyridines (pyridine, 4-picoline, 3,5-lutidine, 4-methoxypyridine, and 3-methoxypyridine). As a result of antimicrobial screening in vitro, the examples, were found to show activity against S. aureus, C. neoformans and C. albicans with MICs ≤0.25 µg mL⁻¹ possessing minimal cytotoxic and hemolytic effects. The selectivity of the leading compounds towards the phosphatidylglycerol-containing membranes and a capability to disorder the lipid as a result of a detergent effect was shown. Experimental and theoretical evaluations of the lipophilicity of the quaternized products indicates that their most efficient transport through the cell membranes is most likely realized at log P values of 3.5–5.1. The synthesized quaternary salts could be positioned both as promising antibacterial agents and auxiliary components for known drugs to increase their effectiveness against bacteria and fungi.