title: Thiazolothiazepine inhibitors of HIV-1 integrase.
abstract: A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN. By contrast, compounds with a naphthalene ring system showed enhanced potency, suggesting that a hydrophobic pocket in the IN active site might accommodate an aromatic system rather than a halogen. The position of sulfur in the thiazole ring appears important for potency against IN, as its replacement with an oxygen or carbon abolished activity. Further extension of the thiazole ring diminished potency. Compounds 1, 19, and 20 showed antiviral activity and inhibited IN within similar concentrations. These compounds inhibited IN when Mn(2+) or Mg(2+) was used as cofactor. None of these compounds showed detectable activities against HIV-1 reverse transcriptase, protease, virus attachment, or nucleocapsid protein zinc fingers. Therefore, thiazolothiazepines are potentially important lead compounds for development as inhibitors of IN and HIV replication.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892-4255, USA. neamatin@pop.nci.nih.gov
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: J A
authors.initials: JA
authors.lastname: Turpin
authors.forename: H E
authors.initials: HE
authors.lastname: Winslow
authors.forename: J L
authors.initials: JL
authors.lastname: Christensen
authors.forename: K
authors.initials: K
authors.lastname: Williamson
authors.forename: A
authors.initials: A
authors.lastname: Orr
authors.forename: W G
authors.initials: WG
authors.lastname: Rice
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: A
authors.initials: A
authors.lastname: Garofalo
authors.forename: A
authors.initials: A
authors.lastname: Brizzi
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: I
authors.initials: I
authors.lastname: Fiorini
authors.forename: V
authors.initials: V
authors.lastname: Nacci
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1; D008274:Magnesium / Q000737:chemistry; D008345:Manganese / Q000737:chemistry; D019590:Nucleocapsid Proteins / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045162:Thiazolidinediones; D014779:Virus Replication / Q000187:drug effects; D016335:Zinc Fingers / Q000187:drug effects
chemical_list: C121214:1,13a-dihydro-3H,5H,13H-naphtho(2,3-f)thiazolo(4,3-c)(1,4)thiazepine-5,13-dione; C121213:2,3-dihydro-5H-naphtho(2,3-f)thiazolo(2,3-c)(1,4)thiazepine-5,13(1aH)-dione; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D019590:Nucleocapsid Proteins; D018894:Reverse Transcriptase Inhibitors; D013841:Thiazepines; D013844:Thiazoles; D045162:Thiazolidinediones; D008345:Manganese; D008274:Magnesium