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 Chemjournal_title
Bioorganic & medicinal chemistryauthors
Hunter R,Younis Y,Muhanji CI,Curtin TL,Naidoo KJ,Petersen M,Bailey CM,Basavapathruni A,Anderson KSdoi
10.1016/j.bmc.2008.10.048subject
Has Abstractpub_date
2008-12-15 00:00:00pages
10270-80issue
24eissn
0968-0896issn
1464-3391pii
S0968-0896(08)00997-8journal_volume
16pub_type
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