Design of Novel Bioisosteres of β-Diketo Acid Inhibitors of HIV-1 Integrase

• Published in: Antiviral chemistry & chemotherapy Vol. 16; no. 1; pp. 41 - 61
• Main Authors: Sechi, Mario, Sannia, Luciano, Carta, Fabrizio, Palomba, Michele, Dallocchio, Roberto, Dessì, Alessandro, Derudas, Massimiliano, Zawahir, Zahrah, Neamati, Nouri
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 2005; International Medical Press; Sage Publications Ltd
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Carboxylic acids; Computer applications; Drug development; HIV; HIV Integrase - chemistry; HIV Integrase - drug effects; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; Human immunodeficiency virus; Human immunodeficiency virus 1; Integrase; Keto Acids - analysis; Keto Acids - chemical synthesis; Keto Acids - chemistry; Keto Acids - pharmacology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; drug discovery; 3D-database; high throughput docking; isoxazole carboxylic acids; bioisosterism; lead compounds; HIV-1 integrase inhibitors; High throughput screening; Antiretroviral agent; Isoxazole derivatives; HIV-1 virus; Research and development; Carboxylic acid; Database; Antiviral; Drug; Immunopathology; Retroviridae; Enzyme inhibitor; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Viral disease; Human immunodeficiency virus
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020501600105

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 β-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.