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; Fax: + 1 403 492 1217.--S ummary A series of 5'-O-acyl 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-infeeted T4 lymphocytes. 5'-0-( 12-Azidododecanoyl)thymidine exhibited moderate activity (EC so 4.6 11M) against HIVinfected T4 lymphocytes. 5'-0-(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 (log1 Prange 4.15-6.72) and compared with the theoreticaPvalues 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 10glo 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.

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