Sintese e estudo antimicrobiano in silico/vitro de amido (ceto) ésteres cinâmicos e avaliação da toxicidade sobre Artemia salina

Abstract

The increasing resistance of microorganisms to commonly used drugs has hindered the treatment of diseases in humans and animals, making it essential to conduct new studies on the synthesis of novel bioactive drugs targeting multidrug-resistant microorganisms. In this context, cinnamic derivatives have emerged as promising antimicrobial agents due to their broad potential and the possibility of structural modifications with pharmacophoric groups to enhance pharmacological effects with reduced toxicity in humans. This study reports the synthesis of two series of cinnamic derivatives: cinnamic ketoesters 9–11(a–g) and cinnamic amidoesters 14a–l. The cinnamic ketoesters were synthesized via nucleophilic substitution (SN) reactions between potassium cinnamate salts and substituted α-bromoacetophenones, with yields ranging from 51% to 88%. The cinnamic amidoesters were also obtained via SN reactions between potassium cinnamate salts and N-aryl-2-chloroacetamides, with yields ranging from 60% to 81%. The compounds were characterized using spectroscopic techniques, including infrared (IR), nuclear magnetic resonance (NMR) of Hydrogen (¹H) and Carbon (¹³C), and highresolution mass spectrometry, confirming the structure of the final products. In silico studies indicate that cinnamic amidoesters and ketoesters possess physicochemical and structural characteristics suggesting favorable oral bioavailability; however, further experimental studies are required to validate their potential as drug candidates. In vitro studies showed significant activity for cinnamic ketoesters, with compounds 9f (R = H; R’ = 4-NO₂) and 10d (R = 3,4,5- OMe; R’ = 4-Cl) exhibiting minimum inhibitory concentrations (MIC) of 625 µg.mL⁻¹ against Escherichia coli and Staphylococcus aureus, respectively. Cinnamic ketoesters and amidoesters displayed activity against Candida albicans and Pseudomonas aeruginosa only at the maximum tested concentration (5000 µg.mL⁻¹). Compound 11g demonstrated the highest efficacy against Mycobacterium tuberculosis, with an MIC of 100 μM. Conversely, cinnamic amidoesters exhibited more significant antimicrobial activity, notably compound 14h (R’’ = Cl), which showed an MIC of 156.25 µg.mL⁻¹ against S. aureus. Regarding antituberculosis activity, compound 14f (R’’ = Bu) stood out with an MIC of 200 μM, also being the most lipophilic in the series, as suggested by ADMET in silico tests, indicating that higher lipophilicity might enhance antituberculosis activity. Molecular docking and toxicity studies were conducted for the most promising cinnamic amidoesters, suggesting that TtRNA synthetase is the main target for compounds 14a, 14c, 14h, and 14i, with compound 14i (R’’ = Br) displaying the strongest interaction (-140.52 kcal.mol⁻¹). Enhancements in hydrogen bond formation capacity could further improve the efficacy of these compounds. In toxicity assays, only compound 14a (R’’ = H) was classified as moderately toxic to Artemia salina larvae (LC₅₀ = 316.22 µg.mL⁻¹), while compounds 14c, 14f, and 14h–i exhibited no toxicity to Artemia salina larvae (LC₅₀ > 1000 µg.mL⁻¹).