title: Design and fast synthesis of C-terminal duplicated potent C(2)-symmetric P1/P1'-modified HIV-1 protease inhibitors.
abstract: An analysis of the X-ray structure of a complex of HIV-1 protease with a linear C(2)-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K(i) values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K(i) values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.
authors.affiliation: Department of Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Alterman
authors.forename: H O
authors.initials: HO
authors.lastname: Andersson
authors.forename: N
authors.initials: N
authors.lastname: Garg
authors.forename: G
authors.initials: G
authors.lastname: Ahlsén
authors.forename: S
authors.initials: S
authors.lastname: Lövgren
authors.forename: B
authors.initials: B
authors.lastname: Classon
authors.forename: U H
authors.initials: UH
authors.lastname: Danielson
authors.forename: I
authors.initials: I
authors.lastname: Kvarnström
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: Samuelsson
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors