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One-pot Synthesis of Betulin Triterpenoid Quaternized Pyridine Derivatives and their Antimicrobial Activity



A wide range of biological activity, relatively low toxicity and multiple
pharmacological effects of triterpenoids are major advantages of these compounds in the prevention
and treatment of various diseases. They include the lupane- type triterpenoids that proved to be a
promising platform for the synthesis of analogs with a wide range of biological activities, including
anti-inflammatory, antitumor, antiparasitic and antiviral properties. The main disadvantage complicating
the use of all known derivatives of lupane acids in medical practice is low bioavailability associated
with poor solubility in biologic fluids, limiting their effective interaction with the biological
targets.



The objective of this study is the synthesis of new amphiphilic betulin derivatives on the
base of pyridinium salts with antifungal and antibacterial activity.



 In this study we have developed an effective one-pot method for the preparation of new
quaternized pyridine derivatives 4-6 of the betulinic series based on the reaction of the initial triterpenes
1-3 with the Tempo+Br3
- reagent in the pyridine. The synthesized and initial compounds were
tested for their antimicrobial and antifungal activity.



The data presented in this document indicate that all synthesized compounds 4-6 exhibited
high activity against both gram-positive Staphylococcus aureus bacteria and gram-negative Pseudomonas
aeruginosa strains, as well as Candida albicans and Cryptococcus neoformans fungi with
the >90% coverage of the inhibition zone. The best result in a series of compounds 4-6 was found
for the derivative 6 at the minimum inhibitory concentration of 1 µg/ml against S. aureus bacteria,
C. albicans and C. neoformans fungi at the concentration of 8 µg/ml.



Thus, we have demonstrated the first example of the pyridine quaternization using the
betulin triterpenoids as the lipophilic substrates and Tempo+Br3
- cation. The obtained quaternized
pyridine analogs of betulin triterpenes showed high antibacterial and antifungal activity in comparison
with the initial compounds.
