title: Design and synthesis of potent C(2)-symmetric diol-based HIV-1 protease inhibitors: effects of fluoro substitution.
abstract: Implementation of derivatized carbohydrates as C(2)-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K(i) values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K(i) value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.
authors.affiliation: Department of Chemistry, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Pyring
authors.forename: J
authors.initials: J
authors.lastname: Lindberg
authors.lastname: Rosenquist A
authors.forename: G
authors.initials: G
authors.lastname: Zuccarello
authors.forename: I
authors.initials: I
authors.lastname: Kvarnström
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Vrang
authors.forename: T
authors.initials: T
authors.lastname: Unge
authors.forename: B
authors.initials: B
authors.lastname: Classon
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
authors.forename: B
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D017320:HIV Protease Inhibitors; D007189:Indans; C435932:N1,N6-bis(2-hydroxy-1--indanyl)-2,5-bis(2,5-difluorobenzyloxy)-3,4-dihydroxyhexanediamide; C435931:N1,N6-bis(2-hydroxy-1-indanyl)-2,5-bis(2,3-difluorobenzyloxy)-3,4-dihydroxyhexanediamide; D016333:HIV Protease