title: 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.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa. Roger.Hunter@uct.ac.za
authors.forename: Roger
authors.initials: R
authors.lastname: Hunter
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.forename: Clare I
authors.initials: CI
authors.lastname: Muhanji
authors.forename: Tanith-Lea
authors.initials: TL
authors.lastname: Curtin
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Naidoo
authors.forename: Melissa
authors.initials: M
authors.lastname: Petersen
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.forename: Aravind
authors.initials: A
authors.lastname: Basavapathruni
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003198:Computer Simulation; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; C121245:HI 236; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D013890:Thiourea