Synthesis, antimicrobial, SAR, PASS, molecular docking, molecular dynamics and pharmacokinetics studies of 5′-O-uridine derivatives bearing acyl moieties: POM study and identification of the pharmacophore sites

Abstract Because of their superior antibacterial and pharmacokinetic capabilities, many nucleoside-based esters show potential against microorganisms, and may be used as pharmacological agents to address multidrug-resistant pathogenic problems. In this study, several aliphatic and aromatic groups were inserted to synthesize various 5′-O-decanoyluridine (2–5) and 5′-O-lauroyluridine derivatives (6–7) for antimicrobial, in silico computational, pharmacokinetic and POM (Petra/Osiris/Molinspiration). The chemical structures of the synthesized uridine derivatives were confirmed by physicochemical, elemental, and spectroscopic analyses. In vitro antimicrobial screening against five bacteria and two fungi, as well as the prediction of substance activity spectra (PASS), revealed that these uridine derivatives have promising antifungal properties when compared to the antibacterial activities. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties. Molecular docking was conducted against lanosterol 14a-demethylase CYP51A1 (3JUV) and Aspergillus flavus (1R4U) and revealed binding affinities and non-covalent interactions with the target. Then, a 150 ns molecular dynamic simulation was performed to confirm the behavior of the complex structure formed by microbial protein under in silico physiological conditions to examine its stability over time, which revealed a stable conformation and binding pattern in a stimulating environment of uridine derivatives. The acyl chain {CH3(CH2)9CO-} and {CH3(CH2)10CO-} in conjunction with sugar, was determined to have the most potent activity against bacterial and fungal pathogens in a structure-activity relationships (SAR) investigation. POM analyses were conducted with the presence of an antifungal (O δ− –- O’ δ−) pharmacophore site. Overall, the present study might be useful for the development of uridine-based novel multidrug-resistant antimicrobial. Graphical Abstract HIGHLIGHTS Novel uridine derivatives were designed and synthesized. The chemical structures and purity of these new uridine derivatives were confirmed by usual spectroscopic techniques. In vitro antimicrobial activity and SAR study was investigated. The incorporation of various aliphatic and aromatic groups in uridine structure significantly increased their biological activity. PASS prediction analysis indicated that the compounds were less potent as anti-carcinogenic agents (0.31 < Pa < 0.52) than as antimicrobial agents. Molecular docking analysis showed that the novel uridine derivatives 2, 5 and 6 may possess excellent effectiveness for lanosterol 14a-demethylase CYP51A1 (3JUV) and Aspergillus flavus (1R4U). The stability of the docked complex was confirmed by performing molecular dynamics along with an estimation of MMPB/GBSA binding free energy which ensured that complex of derivatives 2, 5 and 6 were reported in improved dynamics stability as revealed by their uniform RMSD and RMSF profiles. In silico ADMET calculations predicted improved pharmacokinetic properties of all uridine derivatives. The POM analysis showed the presence of an antifungal (O δ− --- O’ δ−) pharmacophore site.