SYNTHESIS, IN-VITRO ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS STRUCTURE-ACTIVITY-RELATIONSHIPS AND BIOLOGICAL STABILITY OF 5'-O-MYRISTOYL ANALOG DERIVATIVES OF 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE (AZT) AS POTENTIAL PRODRUGS

5'-O-Myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect C EM cells against human immunodeficiency virus (HIV)-induced cytopathog enicity was determined and structure-activity paradigms were developed . o-2',3'-dideoxy-5'-O-(4-oxatetradecanoyl)thymidine (EC50=1.4 nM) and ido-2',3'-deoxy-5'-O-(12-bromododecanoyl)thymidine (EC50=3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50=10 nM). T hese myristoyl analogue derivatives were more lipophilic (calculated l og P=4.5-8.1 range) than the parent compound AZT (log P=0.06), and a l inear correlation between their log P and HPLC log retention times was observed. The ester cleavage half-lives (t(1/2)) for esters upon in v itro incubation with porcine liver esterase, rat plasma or rat brain h omogenate was dependent on the steric bulk, and electronegative induct ive effect of the alpha-substituent (H, Br, F), of the 5'-O-myristoyl analogue moiety. 3'-Azido-2',3'-dideoxy-5'-O-(11-(4-iodophenoxy) undec anoyl)thymidine exhibited t(1/2) values of 80.4, 3.7 and 150.0 min upo n incubation with porcine liver esterase, rat plasma and rat brain hom ogenate, respectively.