title: Synthesis and structure-activity relationships of a series of penicillin-derived HIV proteinase inhibitors containing a stereochemically unique peptide isostere.
abstract: A series of HIV-1 proteinase inhibitors was synthesized based upon a single penicillin derived thiazolidine moiety. Reaction of the C-4 carboxyl group with (R)-phenylalaninol gave amide 10 which was a moderately potent inhibitor of HIV-1 proteinase (IC50 = 0.15 microM). Further modifications based on molecular modeling studies led to compound 48 which contained a stereochemically unique statine-based isostere. This was a potent competitive inhibitor (Ki = 0.25 nM) with antiviral activity against HIV-1 in vitro (5 microM). Neither modification to the benzyl group in an attempt to improve interaction with the S2' pocket, nor introduction of a hydrogen bond donating group to interact with residue Gly48' resulted in improved inhibitory or antiviral activity.
authors.affiliation: Department of Medicinal Chemistry II, Glaxo Group Research Limited, Greenford, Middlesex, United Kingdom.
authors.forename: D S
authors.initials: DS
authors.lastname: Holmes
authors.forename: R C
authors.initials: RC
authors.lastname: Bethell
authors.forename: N
authors.initials: N
authors.lastname: Cammack
authors.forename: I R
authors.initials: IR
authors.lastname: Clemens
authors.forename: J
authors.initials: J
authors.lastname: Kitchin
authors.forename: P
authors.initials: P
authors.lastname: McMeekin
authors.forename: C L
authors.initials: CL
authors.lastname: Mo
authors.forename: D C
authors.initials: DC
authors.lastname: Orr
authors.forename: B
authors.initials: B
authors.lastname: Patel
authors.forename: I L
authors.initials: IL
authors.lastname: Paternoster
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010406:Penicillins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D010406:Penicillins; D013844:Thiazoles