C-2-aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors.

Abstract:

:Several novel thiourea derivatives of the NNRTI HI-236 substituted at the C-2 oxygen of the phenyl ring have been synthesized and evaluated for their inhibitory activity against HIV-1 (IIIB) replication in MT-2 cell cultures. The compounds were synthesized in order to fine-tune the activity of HI-236 as well as to gain insight into spatial characteristics in the pocket pertaining to the positional choice of tether in the design of [NRTI]-tether-[HI-236] bifunctional inhibitors. Two of the thiourea derivatives bearing a butynyl (6c) or hydroxyethyl tether (6n) were endowed with improved anti-HIV activity compared to HI-236. NNRTI activity was confirmed by a cell-free RT assay on six of the derivatives in which 6c returned an IC(50) of 3.8 nM compared to 28 nM for HI-236, establishing it as an improved lead for HI-236. The structure-activity profile is discussed in terms of potential interactions in the NNRTI pocket as suggested by a docking model using AutoDock, which have a bearing on the bifunctional drug design.

journal_name

Bioorg Med Chem

authors

Hunter R,Younis Y,Muhanji CI,Curtin TL,Naidoo KJ,Petersen M,Bailey CM,Basavapathruni A,Anderson KS

doi

10.1016/j.bmc.2008.10.048

subject

Has Abstract

pub_date

2008-12-15 00:00:00

pages

10270-80

issue

24

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)00997-8

journal_volume

16

pub_type

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