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

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-, TBABr(3), and Py center dot HBr center dot Br-2) 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 mu g 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.

Automated summary

31 examples of C30-quaternized derivatives of lupane triterpenoids were synthesized with high yield using organic tribromides and pyridines. These derivatives showed activity against S. aureus, C. neoformans and C. albicans with low MICs and minimal cytotoxic and hemolytic effects. The quaternized products had a selective effect on phosphatidylglycerol-containing membranes and showed potential as antibacterial agents and auxiliary components for enhancing the effectiveness of known drugs against bacteria and fungi.