Synthesis,in Vitro Anti-Human Immunodeficiency Virus Structure—Activity Relationships and Biological Stability of 5′- O -Myristoyl Analogue Derivatives of 3′-Azido-2′,3′-Dideoxythymidine (AZT) as Potential Prodrugs

Abstract

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 CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure–activity paradigms were developed. 3′-Azido-2′,3′-dideoxy-5′-O-(4-oxate-tradecanoyl)thymidine (EC₅₀=1.4 nM) and 3′-azido-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). These myristoyl analogue derivatives were more lipophilic (calculated log P=4.5–8.1 range) than the parent compound AZT (log P=0.06), and a linear correlation between their log P and HPLC log retention timeswas observed. The ester cleavage half-lives (t_1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the α-substituent (H, Br, F), of the 5′-O-myristoyl analogue moiety. 3′-Azido-2′,3′-dideoxy-5′-O-(11-(4-iodophenoxy) undecanoyl)-thymidine exhibited t_1/2 values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.