title: Design and synthesis of novel dihydroxyindole-2-carboxylic acids as HIV-1 integrase inhibitors.
abstract: In a search for new HIV-1 integrase (IN) inhibitors, we synthesized and evaluated the biological activity of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and a series of its derivatives. These compounds were designed as conformationally constrained analogues of the acrylate moiety of caffeic acid phenethyl ester (CAPE). DHICA, an intermediate in the biosynthesis of melanins, was prepared as a monomeric unit by a novel synthetic route. In order to perform coherent SAR studies, two series of DHICA amides were synthesized. First, to validate the utility of a previously identified three-point pharmacophore based on CAPE in inhibitor design, we prepared a series of benzyl- or phenylethylamine substituted derivatives lacking and containing hydroxyl groups. Second, dimers of DHICA containing various aminoalkylamine linkers were also prepared with a goal to increase potency. All compounds were tested against purified IN and the C65S mutant in enzyme-based assays. They were also tested for cytotoxicity in an ovarian carcinoma cell line and antiviral activity in HIV-1-infected CEM cells. Seven compounds inhibited catalytic activities of purified IN with IC50 values below 10 microM. Further computational docking studies were performed to determine the title compounds' mode of interaction with the IN active site. The residues K156, K159 and D64 were the most important for potency against purified IN.
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: Gianfranco
authors.initials: G
authors.lastname: Angotzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Dallocchio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dessì
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Luciano
authors.initials: L
authors.lastname: Sannia
authors.forename: Alberto
authors.initials: A
authors.lastname: Mariani
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiori
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Leah
authors.initials: L
authors.lastname: Movsessian
authors.forename: Carmen
authors.initials: C
authors.lastname: Plasencia
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D002384:Catalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006678:HIV / Q000187:drug effects; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D007211:Indoles; C030692:5,6-dihydroxy-2-indolylcarboxylic acid; D019427:HIV Integrase