title: Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance.
abstract: The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.
authors.affiliation: Department of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Sarang
authors.initials: S
authors.lastname: Kulkarni
authors.forename: David D
authors.initials: DD
authors.lastname: Anderson
authors.forename: Lin
authors.initials: L
authors.lastname: Hong
authors.forename: Abigail
authors.initials: A
authors.lastname: Baldridge
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Chumanevich
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Kovalevsky
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tojo
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D008024:Ligands; D047028:Macrocyclic Compounds; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1