title: Hydrazide-containing inhibitors of HIV-1 integrase.
abstract: Inhibitors of HIV integrase are currently being sought as potential new therapeutics for the treatment of AIDS. A large number of inhibitors discovered to date contain the o-bis-hydroxy catechol structure. In an effort to discover structural leads for the development of new HIV integrase inhibitors which do not rely on this potentially cytotoxic catechol substructure, NSC 310217 was identified using a three-point pharmacophore search based on its assigned structure N-(2-hydroxybenzoyl)-N-(2-hydroxy-3-phenoxypropyl)hydrazine (1). When a sample of NSC 310217 was obtained from the NCI repository, it was shown to exhibit potent inhibition of HIV-1 integrase (3'-processing IC50 = 0.6 microgram/mL). In work reported herein, we demonstrate that NSC 310217, rather than containing 1, which has no inhibitory potency against HIV-1 integrase, is comprised of roughly a 1:1 mixture of N-(2-hydroxybenzoyl)-N'-(2-hydroxy-3-phenoxypropyl)hydrazine (6) and N,N'-bis-salicylhydrazine 7, with all inhibitory potency residing with compound 7(IC50 = 0.7 microM for strand transfer). In subsequent structure-activity studies on 7, it is shown that removing a single amide carbonyl (compound 14, IC50 = 5.2 microM) or replacing one aromatic ring system with a naphthyl ring (compound 19, IC50 = 1.1 microM) can be accomplished with little loss of inhibitory potency. Additionally, replacing a single hydroxyl with a sulfhydryl (compound 23, IC50 = 5.8 microM) results in only moderate loss of potency. All other modifications examined, including the replacement of a single hydroxyl with an amino group (compound 22), resulted in complete loss of potency. Being potent, structurally simple, and non-catechol-containing, compounds such as 7 and 14 may provide useful leads for the development of a new class of HIV integrase inhibitor.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: S
authors.initials: S
authors.lastname: Sunder
authors.forename: H
authors.initials: H
authors.lastname: Hong
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: G W
authors.initials: GW
authors.lastname: Milne
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: T R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D016208:Databases, Factual; D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012457:Salicylamides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D006834:Hydrazines; D012457:Salicylamides; C105325:N,N'-bis(salicyl)hydrazine; D019427:HIV Integrase