title: Efficient synthesis and utilization of phenyl-substituted heteroaromatic carboxylic acids as aryl diketo acid isosteres in the design of novel HIV-1 integrase inhibitors.
abstract: Three new types of aryl diketo acid (ADK) isosteres were designed by conversion of the biologically labile 1,3-diketo unit into heteroaromatic motif such as isoxazole, isothiazole, or 1H-pyrazole to improve the physicochemical property of ADK-based HIV-1 integrase (IN) inhibitors. The synthesis of the heteroaromatic carboxylic acids was established by employing phenyl beta-diketoester or benzaldehyde as the starting material and 1,3-dipolar cycloaddition as the key reaction. Of the compounds tested, the 3-benzyloxyphenyl-substituted isoxazole carboxylic acid displayed the best IN inhibitory and antiviral activities, with N-hydroxylamidation enhancing the in vitro and in vivo potency. These findings are important for further optimization of ADK-based IN inhibitors.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Zeng
authors.forename: Hu-Shan
authors.initials: HS
authors.lastname: Zhang
authors.forename: Yun-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D020816:Amino Acid Motifs; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007651:Keto Acids / Q000737:chemistry; D008956:Models, Chemical; D013844:Thiazoles / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D013844:Thiazoles