SYNTHESES AND BIOLOGICAL EVALUATION OF 5'-O-MYRISTOYL DERIVATIVES OF THYMIDINE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS

A series of 5'-O-acyl derivatives of thymidine (dThd) were prepared by direct acylation of thymidine using the Mitsunobu reaction. Further r eaction of the bromo analogues with sodium azide gave azido ester anal ogues. Anti-human immunodeficiency virus type 1 (HIV-1) activities wer e determined against HIV-infected T4 lymphocytes. 5'-O-(12-Azidododeca noyl)thymidine exhibited moderate activity (EC50 4.6 mu M) against HIV -infected T4 lymphocytes. 5'-O-(2-Bromotetrodecanoyl)-thymidine was fo und to be the most stable ester (t(1/2) 15.3 min) to hydrolysis by por cine liver esterase in vitro. Partition coefficients (P) in n-octanol- phosphate buffer were determined (log(10) P range 4.15-6.72) and compa red with the theoretical values calculated (log(10) P 3.96-6.53) using the PALLAS program. Anti-HIV structure-activity data suggest that the experimental partition coefficient should be in the log(10) P 4.6-4.8 range for optimum anti-HIV activity. The structures of these thymidin e 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 e xhibited similar energies for the lowest energy conformer. A quantitat ive structure-activity relationship (QSAR) regression equation was dev eloped, 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.