Novel chitosan hybrid fluorinated thiourea derivatives as dual anti-microbial and anti-biofilm agents: tailoring molecular interactions, in silico toxicity, and docking simulation

Abstract

This article presents the synthesis of chitosan isothiocyanate, followed by hybridization with promising fluorinated aromatic amines, producing three chitosan fluorinated-thiourea samples (CHTUD1–3). Covalent modification of the chitosan and chitosan isothiocyanate backbones was confirmed by a notable reduction in ion exchange capacity (IEC). IEC decreased from 10.88 ± 0.23 for native chitosan and 3.21 ± 0.65 meq g⁻¹ for CHNCS to 4.25 ± 0.35 meq g⁻¹ for the final chitosan fluorinated-thiourea samples. This reduction strongly supports successful covalent grafting, meaning that the desired chemical modification was achieved. The modified chitosan (CHTUD1–3) was evaluated for antimicrobial activity. It showed significant effectiveness against the tested strains. These derivatives demonstrated significant antimicrobial activity, with MIC values ranging from 7.8 to 31.25 µg mL⁻¹ against Gram-positive strains, whereas native chitosan exhibited an MIC of 62.5 µg mL⁻¹. In contrast, the MIC values for Gram-negative strains ranged from 15.62 to 62.5 µg mL⁻¹, compared with native chitosan, which showed an MIC of 125 µg mL⁻¹ against the tested strains. The designed CHTUD1–3 derivatives demonstrated significant antimicrobial activity against S. aureus, with an MIC of 7.8 µg mL⁻¹, which is significantly more promising than that of chitosan (62.5 µg mL⁻¹), indicating that chemical modification with fluorinated derivatives enhances antibacterial potency. Furthermore, these derivatives also showed potential against C. albicans with an MIC of 15.62 µg mL⁻¹, while native chitosan had an MIC of 62.5 µg mL⁻¹. Regarding biofilm inhibition, the percentages against S. aureus and S. typhi showed significant dose-dependent responses. Specifically, the new derivatives achieved ≥90% inhibition at 75% MBC and 70% inhibition at 25% MBC. However, CHTUD2 exhibited 61.27% inhibition. In silico toxicity prediction revealed a favorable toxicity profile. Finally, molecular docking simulations revealed promising binding affinities. This suggests that these derivatives could inhibit biofilm formation by disrupting adhesion through sortase A and preventing biofilm formation via LpxC enzymes.