title: Use of a hexasubstituted benzene scaffold in the development of multivalent HIV-1 integrase inhibitors.
abstract: The highly directional hexasubstituted benzene moiety was used as the central scaffold to create new human immunodeficiency virus (HIV)-1 integrase inhibitors through the attachment of multiple active groups. A series of potential inhibitors having substituted polyhydroxylated mono, bis and tris-cinnamoyl derivatives connected on the scaffold were prepared through Claisen-Schmidt condensations with substituted benzaldehydes, followed by partial demethylation to uncover the active phenolic groups required for the interactions with the integrase enzyme active sites. Using a multiplate integration assay method, four compounds carrying at least two sets of interacting moieties were found to be relatively potent integrase inhibitors with IC50 values in the low micromolar range. The results confirmed that multiple polyhydroxylated groups were required on the platform in order to effectively interact with the enzyme. The results from molecular docking studies consistently complemented the experimental results and revealed the nature of the potential key binding interactions responsible for the apparent activity of the active compounds.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University.
authors.forename: Wipa
authors.initials: W
authors.lastname: Tupchiangmai
authors.forename: Saowanaporn
authors.initials: S
authors.lastname: Choksakulporn
authors.forename: Supinya
authors.initials: S
authors.lastname: Tewtrakul
authors.forename: Somsak
authors.initials: S
authors.lastname: Pianwanit
authors.forename: Yongsak
authors.initials: Y
authors.lastname: Sritana-anant
mesh_terms: D001554:Benzene / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; D001554:Benzene; C514801:p31 integrase protein, Human immunodeficiency virus 1