title: Design of novel bioisosteres of beta-diketo acid inhibitors of HIV-1 integrase.
abstract: HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. Significant efforts have been devoted to the identification of IN inhibitors using various methods. In this context, through virtual screening of the NCI database and structure-based drug design strategies, we identified several pharmacophoric fragments and incorporated them on various aromatic or heteroaromatic rings. In addition, we designed and synthesized a series of 5-aryl(heteroaryl)-isoxazole-3-carboxylic acids as biological isosteric analogues of beta-diketo acid containing inhibitors of HIV-1 IN and their derivatives. Further computational docking studies were performed to investigate the mode of interactions of the most active ligands with the IN active site. Results suggested that some of the tested compounds could be considered as lead compounds and suitable for further optimization.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Sassari, Italy. mario.sechi@uniss.it
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Luciano
authors.initials: L
authors.lastname: Sannia
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Michele
authors.initials: M
authors.lastname: Palomba
authors.forename: Roberto
authors.initials: R
authors.lastname: Dallocchio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dessì
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Derudas
authors.forename: Zahrah
authors.initials: Z
authors.lastname: Zawahir
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019427:HIV Integrase / Q000737:chemistry / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D007651:Keto Acids / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D019427:HIV Integrase