title: Synthesis of P1'-functionalized macrocyclic transition-state mimicking HIV-1 protease inhibitors encompassing a tertiary alcohol.
abstract: Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macrocyclization, 14- and 15-membered macrocyclic PIs were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 10f, with a 2-thiazolyl group in the P1' position, was the most potent PI of this new series (Ki 2.2 nM, EC50 0.2 μM). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.
authors: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors: Maria
authors: M
authors: De Rosa
authors: Johan
authors: J
authors: Unge
authors: Hitesh V
authors: HV
authors: Motwani
authors: Åsa
authors: Å
authors: Rosenquist
authors: Lotta
authors: L
authors: Vrang
authors: Hans
authors: H
authors: Wallberg
authors: Mats
authors: M
authors: Larhed
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000438:Alcohols; D017320:HIV Protease Inhibitors; D006834:Hydrazines; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; C000594990:methyl (1-(2-(3-(3-hydroxy-6-isopropyl-4,7-dioxo-5,8-diaza-1(1,4)-benzenacyclododecaphan-10-en-3-yl)propyl)-2-(4-(thiazol-2-yl)benzyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1