New Caffeic Acid Derivatives as Antimicrobial Agents: Design, Synthesis, Evaluation and Docking

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Computational Chemistry

Background:

• Phenolic acids, including caffeic acid, ferulic acid, and p-coumaric acid, are prevalent in plants and possess antimicrobial properties.
• The exploration of novel antimicrobial agents is crucial due to increasing drug resistance.

Purpose of the Study:

• To synthesize novel caffeic acid derivatives predicted by computer-aided methods.
• To evaluate the in vitro antimicrobial efficacy of these derivatives against Gram-positive and Gram-negative bacteria and fungi.

Main Methods:

• In silico prediction of biological activity and mechanisms of action.
• Classical organic synthesis for compound preparation.
• Microdilution method for antimicrobial susceptibility testing.
• Cytotoxicity assessment using PROTOX.

Main Results:

• Twelve synthesized compounds demonstrated significant antibacterial activity, with five exceeding the efficacy of ampicillin and streptomycin.
• All tested compounds exhibited superior antifungal activity compared to ketoconazole, and seven were more potent than bifonazole.
• Computational analysis suggested gyrase inhibition as the antibacterial mechanism and 14α-demethylase inhibition for antifungal action. Predicted non-toxic profiles (LD50 1000-2000 mg/kg).

Conclusions:

• Six new caffeic acid derivatives were synthesized, alongside seven known compounds.
• The twelve tested compounds displayed potent, non-toxic antimicrobial activity against a range of bacteria and fungi.
• These derivatives represent promising candidates for the development of new pharmaceutical antimicrobial agents.