Design, Synthesis and Biological Evaluation of New 1,3-Diarylpropenones as Dual Inhibitors of HIV-1 RT.

ESPOSITO, FRANCESCA;Meleddu R;Cannas V;DISTINTO, SIMONA;Del Vecchio C;Biano G;CORONA, ANGELA;COTTIGLIA, FILIPPO;Alcaro S;Parolin C;MACCIONI, ELIAS;TRAMONTANO, ENZO

2013-01-01

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Abstract

A small library of 1,3-diaryl propenones has been designed, and synthesized as dual inhibitors of both HIV-1 reverse transcriptase DNA polymerase and ribonuclease H associated functions. Compounds were assayed on these enzyme activities and exhibited dual inhibition properties in the low micromolar range. Interestingly, amino acids mutations in the Non-Nucleoside inhibitors binding pocket strongly affected the propenone derivatives RNase H inhibition, suggesting long range RT structural effects, without reducing their DNA polymerase inhibition ability. Thus we performed biochemical and computational analyses in order to clarify their mode of action. Notably, these studies indicated that propenone derivatives are characterized by a novel mechanism of action and bind to two different allosteric interdependent pockets. Hence, these results set the basis for the further development of RT inhibitors interacting with a novel RT binding site.