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

Marco Radi, Mafalda Pagano, Luigi Franchi, Daniele Castagnolo, Silvia Schenone, Gianni Casaluce, Claudio Zamperini, Elena Dreassi, Giovanni Maga, Alberta Samuele, Encarna Gonzalo, Bonaventura Clotet, José A. Esté, Maurizio Botta

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)


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 compound suffers from a suboptimal ADME profile typical of many S-DABO analogues, 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 derivatives were synthesized to obtain additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. Invitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Original languageEnglish
Pages (from-to)883-896
Issue number5
Publication statusPublished - 1 May 2012


  • ADME
  • Antiviral agents
  • Lead optimization
  • NNRTIs
  • Reverse transcriptase


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