Syntheses and Biological Evaluation of 5′- O -Myristoyl Derivatives of Thymidine against Human Immunodeficiency Virus

A series of 5′-Oacyl derivatives of thymidine (dThd) were prepared by direct acylation of thymidine using the Mitsunobu reaction. Further reaction of the bromo analogues with sodium azide gave azido ester analogues. Anti-human immunodeficiency virus type 1 (HIV-1) activities were determined against HIV-infected T4 lymphocytes. 5′-O-(12-Azidododecanoyl)thymidine exhibited moderate activity (EC₅₀ 4.6 μM) against HIV-infected T4 lymphocytes. 5-O-(2-Bromotetradecanoyl)-thymidine was found to be the most stable ester (t_1/2 15.3 min) to hydrolysis by porcine liver esterase in vitro. Partition coefficients (P) in n-octanol-phosphate buffer were determined (log₁₀ P range 4.15–6.72) and compared with the theoretical values calculated (log₁₀ P 3.96–6.53) using the PALLAS program. Anti-HIV structure-activity data suggest that the experimental partition coefficient should be in the log₁₀ P 4.6–4.8 range for optimum anti-HIV activity. The structures of these thymidine analogues were optimized using molecular mechanics (MM⁺ force field) and semi-empirical quantum mechanics PM3 calculations. The moderately active compounds adopted a similar C-2′ endo sugar conformation and exhibited similar energies for the lowest energy conformer. A quantitative structure-activity relationship (QSAR) regression equation was developed, based on the optimized structures and anti-HIV data using the SciQSAR program, which showed that log P was a determinant of anti-HIV activity.