Design and Synthesis of Novel Dihydroxyindole-2-Carboxylic Acids as HIV-1 Integrase Inhibitors

• Published in: Antiviral chemistry & chemotherapy Vol. 15; no. 2; pp. 67 - 81
• Main Authors: Sechi, Mario, Angotzi, Gianfranco, Dallocchio, Roberto, Dessì, Alessandro, Carta, Fabrizio, Sannia, Luciano, Mariani, Alberto, Fiori, Stefano, Sanchez, Tino, Movsessian, Leah, Plasencia, Carmen, Neamati, Nouri
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.04.2004; International Medical Press; Sage Publications Ltd
• Subjects: Amides; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral activity; Antiviral agents; Biological activity; Biological and medical sciences; Caffeic acid; Carboxylic acids; Catalysis - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Computer applications; Computer Simulation; Cytotoxicity; Drug Design; Drug Evaluation, Preclinical; Female; HIV; HIV - drug effects; HIV Integrase - drug effects; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Indoles - chemical synthesis; Indoles - chemistry; Integrase; Medical sciences; Models, Molecular; Molecular Structure; Mutants; Ovarian carcinoma; Pharmacology. Drug treatments; Phenethylamine; Structure-Activity Relationship; docking studies; 5,6-dihydroxyindole-2-carboxylic acid; catechol derivatives; HIV-1 integrase inhibitors; Antiretroviral agent; HIV-1 virus; Retroviridae; Enzyme inhibitor; Pyrocatechol; Lentivirus; Virus; Design; Phenols; Antiviral; Human immunodeficiency virus; Chemical synthesis
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020401500203

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 μM. 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.