Synthesis, Biological Activity, and ADME Properties of Novel S-DABOs/N-DABOs as HIV Reverse Transcriptase Inhibitors

Previous studies aimed at exploring the SAR of C2-functionalized S-DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild-type RT and drug-resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild-type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compd. suffers from a suboptimal ADME profile typical of many S-DABO analogs, but it could, however, represent a promising candidate as an anti-HIV microbicide. In the present work, a new series of S-DABO/N-DABO derivs. were synthesized to obtain addnl. SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. In vitro ADME properties (PAMPA permeation, water soly., and metabolic stability) were also exptl. evaluated for the most interesting compds. to obtain a reliable indication of their plasma levels after oral administration.