Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors.

Abstract New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2 { 1 , 2 , 3 , 1 } and 2 { 1 , 2 , 3 , 4 } exhibited the most potent anti-HIV-1 activities (EC 50  = 0.015 μg/mL; 0.046 μM, SI >1667) and (EC 50  = 0.025 μg/mL; 0.086 μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC 50  = 1.01 μg/mL; 3.27 μM, SI >25).