Background: Phenolic acids (caffeic-, ferulic and p-coumaric acid) are widely distributed in
the plant kingdom and exhibit broad spectrum of biological activities, including antimicrobial activity.
Objective: The goal of this paper is the synthesis of some caffeic acid derivatives selected based on
computer-aided predictions and evaluate their in vitro antimicrobial properties against Gram positive
and Gram negative bacteria and also a series of fungi.
Methods: In silico prediction of biological activity was used to identify the most promising structures
for synthesis and biological testing, and the putative mechanisms of their antimicrobial action. The designed
compounds were synthesized using classical organic synthesis methods. The antimicrobial activity
was studied using microdilution method.
Results: Twelve tested compounds have shown good antibacterial activity. Five out of twelve tested
compounds appeared to be more active than the reference drugs ampicillin and streptomycin. Despite
that all compounds exhibited good activity against all bacteria tested, the sensitivity of bacteria towards
compounds in general was different. The evaluation of antifungal activity revealed that all compounds
were more active than ketoconazole, while seven compounds (2, 3, 4, 5, 7, 8 and 12) appeared to be
more active than bifonazole. Docking results indicate that gyrase inhibition is the putative mechanism of
antibacterial action while the inhibition of 14α-demethylase may be responsible for antifungal action.
Prediction of cytotoxicity by PROTOX showed that compounds are not toxic (LD50 1000-2000 mg/kg).
Conclusion: Thirteen compounds, from which six are new ones, were synthesized, and twelve compounds
were tested for antimicrobial activity. The studied compounds appeared to be promising potent
and non-toxic antimicrobials, which could be considered as leads for new pharmaceutical agents.