Design, Synthesis, In Silico Studies, and HIV-1 RT Inhibitory Activity of 1,3-Oxazolidine Pyrimidine Nucleoside Analogues.

A series of 1,3-oxazolidine nucleoside analogues (1-6) was designed and synthesized for their anti-HIV activity. The purpose of this study was to determine whether the antiviral activity of the pyrimidine ring is affected by oxazolidine ring substitution. The synthesized compounds were tested for their HIV-1 RT inhibitory activity by a colorimetric HIV reverse transcriptase (HIVRT) test. The fluoro (S4) and bromo (S5) derivatives of these compounds showed the highest HIV-1 reverse transcriptase IC50 values, 19.27 and 22.80 µM, respectively. Modest activity was observed for the remaining compounds. The molecular docking experiments with the crystal structure of HIV-1 reverse transcriptase (PDB ID: 1RT1) revealed that S4 and S5 have good binding affinities of -7.6 and -7.3 kcal/mol, respectively, with multiple hydrogen bonds and π-interactions with key residues in the active site. The properties of all the synthesized compounds were found to be in accordance with Lipinski Rule of Five and showed a favorable ADME profile, indicating good drug-likeness, acceptable solubility, and potential oral bioavailability. Halogen substitution enhances electronic dispersion and hydrophobic interactions, but the oxazolidine scaffold is superior to thiazolidine scaffolds. Halogenated oxazolidine compounds are generally promising HIV-1 reverse transcriptase inhibitors.