Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TIBO) derivatives

  • J Med Chem. 1991 Feb;34(2):746-51. doi: 10.1021/jm00106a040.
M J Kukla  1 ,  H J Breslin ,  R Pauwels ,  C L Fedde ,  M Miranda ,  M K Scott ,  R G Sherrill ,  A Raeymaekers ,  J Van Gelder ,  K Andries
Affiliations
  • 1. Janssen Research Foundation, Spring House, Pennsylvania 19477.
PMID: 1995896 DOI: 10.1021/jm00106a040
Abstract

A series of 6-substituted 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-ones (9) have been synthesized and tested for their ability to inhibit the replication of the HIV-1 virus in MT-4 cells. Two synthetic methods are described, one of which allows the synthesis of single enantiomers of the final products. A structure-activity study was done within the series of compounds to determine the optimum group for the 6-position substitution and to determine whether the activity was enantiospecific at the 5-position, which was substituted with a methyl group. The best analogue, 9jj, inhibited HIV-1 with an IC50 of 4 microM, which is comparable to the activity level of DDI, a 2',3'-dideoxynucleoside-type structure undergoing clinical trials as an anti-AIDS therapy.