title: Synthesis, biological activity, and ADME properties of novel S-DABOs/N-DABOs as HIV reverse transcriptase inhibitors.
abstract: 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. In vitro 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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, University of Siena, Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Mafalda
authors.initials: M
authors.lastname: Pagano
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.forename: Daniele
authors.initials: D
authors.lastname: Castagnolo
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Gianni
authors.initials: G
authors.lastname: Casaluce
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.forename: Elena
authors.initials: E
authors.lastname: Dreassi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Encarna
authors.initials: E
authors.lastname: Gonzalo
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000327:Adsorption; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D004364:Pharmaceutical Preparations; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D014867:Water