STRUCTURE-BASED DESIGN OF PIPERIDINYLETHYL)]-N'-[2-(5-BROMOPYRIDYL]-THIOUREA AND IPERAZINYLETHYL)]-N'-[2-(5-BROMOPYRIDYL)]-THIOUREA AS POTENT NONNUCLEOSIDE INHIBITORS OF HIV-1 REVERSE-TRANSCRIPTASE

A novel computer model of the HIV reverse transcriptase (RT) non-nucle oside inhibitor (NNI) binding pocket, which was generated using high r esolution crystal structure information from 9 individual RT/NNI compl exes, revealed previously unrecognized ligand derivatization sites for phenethylthiazolylthiourea (PETT) derivatives. Spatial gaps surroundi ng the pyridyl ring of the active PETT derivative trovirdine were disc overed during modeling procedures. Docking studies using the computer- generated model of the binding pocket (composite binding pocket) sugge sted that the replacement of the planar pyridyl ring of trovirdine wit h a nonplanar piperidinyl or piperazinyl ring, which occupy larger vol umes, would better fill the spacious Wing 2 region of the butterfly-sh aped NNI binding pocket. The anti-HIV activity of the synthesized hete rocyclic compounds iperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and piperazinylethyl)]-N'-[2(5-bromopyridyl)]-thiourea was examined in HTLVIIIB-infected peripheral blood mononuclear cells. Both compounds were more potent than trovirdine and abrogated HIV replication at nano molar concentrations without any evidence of cytotoxicity. (C) 1998 El sevier Science Ltd. All rights reserved.