Design, synthesis, and biological evaluation of 1,3-diarylpropenones as dual inhibitors of HIV-1 reverse transcriptase

MELEDDU, RITA;CANNAS, VALERIA;DISTINTO, SIMONA

;SARAIS, GIORGIA;Del Vecchio C;ESPOSITO, FRANCESCA;Bianco G;CORONA, ANGELA;COTTIGLIA, FILIPPO;Alcaro S;Parolin C;Artese A;Scalise D;Fresta M;Arridu A;Ortuso F;MACCIONI, ELIAS

;TRAMONTANO, ENZO

2014-01-01

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Abstract

A small library of 1,3-diarylpropenones was designed and synthesized as dual inhibitors of both HIV-1 reverse transcriptase (RT) DNA polymerase (DP) and ribonuclease H (RNase H) associated functions. Compounds were assayed on these enzyme activities, which highlighted dual inhibition properties in the low-micromolar range. Interestingly, mutations in the non-nucleoside RT inhibitor binding pocket strongly affected RNase H inhibition by the propenone derivatives without decreasing their capacity to inhibit DP activity, which suggests long-range RT structural effects. Biochemical and computational studies indicated that the propenone derivatives bind two different interdependent allosteric pockets.