Synthesis, antimicrobial, and in silico studies of c5'- O -substituted cytidine derivatives: cinnamoylation leads to improvement of antimicrobial activity.

Nucleoside derivatives are important therapeutic drugs that have drawn significant attention recently. In this study, cytidine ( 1 ) was first exposed to react with cinnamoyl chloride in N , N -dimethylformamide, and trimethylamine to obtain 5'- O -(cinnamoyl)cytidine, which was further treated with several acylating agents to obtain a series of 2',3'-di- O -acyl derivatives. The chemical structures of the synthesized compounds were established through spectral, analytical, and physicochemical techniques. In vitro antimicrobial efficacy was evaluated, and the antimicrobial effect was greater than that of the precursor compound; in particular, compound 3 exhibited the most promising activity. Cytotoxicity measurements revealed that the compounds demonstrated a decreased degree of toxicity. A structure-activity relationship (SAR) study showed that the ribose moiety combined with the acyl chains (C-12/C13) and (C6 H5 CH = CHCO) had enhanced effects on bacteria and fungi. Molecular docking was applied for the potential inhibitors ( 3 , 4 , and 6 ) to predict their mode of action and confirm their efficacy against isozymes, tubulin-like protein TubZ, Bacillus cereus [PDB: 4ei9], and dihydrofolate reductase of Aspergillus flavus [PDB: 6dtc]. A molecular dynamics simulation study was performed to evaluate the deformability, flexibility, and stiffness of the target enzyme residues. Density functional theory (DFT) indicates the high polarizability and chemical reactivity of the synthesized compounds. The ADMET (absorption, distribution, mechanism, excretion, and toxicity) study suggested that all the designed molecules have moderate human intestinal absorption and good distribution values in addition to the absence of CNS side effects and structural toxicity. Above all else, these cytidine derivatives possess potential antimicrobial behavior, thereby rendering them suitable drug candidate(s) for additional exploration.