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 (C6H5CH = 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.
Keywords: ADMET; Cytidine; antimicrobial; cinnamoylation; molecular docking; molecular dynamics.
A series of cinnamoyl cytidine derivatives were designed and synthesized. The chemical structures of these newly acylated derivatives were confirmed by state-of-the-art spectroscopic techniques.The antimicrobial activity of the synthesized cytidine derivatives was greatly enhanced by the addition of several aliphatic and aromatic acyl groups to the cytidine structure.The cytotoxicity assessment indicated that the compounds exhibited less toxicity.In a molecular docking investigation of the Bacillus cereus tubulin-like protein TubZ and Aspergillus flavus dihydrofolate reductase inhibitors, the catalytic active site revealed promising binding and interaction scores.A molecular dynamics simulation study was performed to evaluate the deformability, flexibility, and stiffness of the target enzyme residues toward the bacterio-fungal dual active inhibitor 4.In silico ADMET studies showed that all the provided compounds had moderate human intestine absorption, good distribution, no CNS side effects, and structural toxicity toward PAINS.