Document Report Card
Basic Information
ID: ALA2385011
Journal: Bioorg Med Chem Lett
Title: Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 1: addressing configurational instability through scaffold modification.
Authors: Fader LD, Landry S, Morin S, Kawai SH, Bousquet Y, Hucke O, Goudreau N, Lemke CT, Bonneau P, Titolo S, Mason S, Simoneau B.
Abstract: The optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly that possess a labile stereocenter at C3 is described. Quaternization of the C3 position of compound 1 in order to prevent racemization gave compound 2, which was inactive in our capsid disassembly assay. A likely explanation for this finding was revealed by in silico analysis predicting a dramatic increase in energy of the bioactive conformation upon quaternization of the C3 position. Replacement of the C3 of the diazepine ring with a nitrogen atom to give the 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-dione analog 4 was well tolerated. Introduction of a rigid spirocyclic system at the C3 position gave configurationally stable 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione analog 5, which was able to access the bioactive conformation without a severe energetic penalty and inhibit capsid assembly. Preliminary structure-activity relationships (SAR) and X-ray crystallographic data show that knowledge from the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly can be transferred to these new scaffolds.
CiteXplore: 23583513