Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors

Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 07/2011; 19(18):5553-8. DOI: 10.1016/j.bmc.2011.07.037
Source: PubMed


A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5 g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC(50) value of 3.17 and 17.88 μM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.

Download full-text


Available from: Xuan Zhang, Mar 25, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A series of new quinolone-3-carboxylic acids as HIV-1 integrase inhibitors featuring a fluorine atom at C-5 position were synthesized and evaluated for their antiviral activity in C8166 cell culture. These newly synthesized compounds showed anti-HIV activity against wild-type virus with an EC(50) value ranging from 29.85 to 0.032 μΜ. The most active compound 4e exhibited activity against wild-type virus and the mutant virus A17 with an EC(50) value of 0.032 and 0.082 μΜ, respectively. Preliminary structure-activity relationship of these 5-fluoroquinolone-3-carboxylic acids was also investigated.
    Full-text · Article · Apr 2012 · Journal of Enzyme Inhibition and Medicinal Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: Validated comparative 2D- and 3D-QSAR modeling and docking studies were performed for forty-five quinolone carboxylic acids having cytotoxic, antiviral, and anti-HIV-1 IN activity. Statistically significant 2D-QSAR model was developed through MLR and PLS analyses on unsplitted as well as splitted dataset and validated. The models were validated on external set compounds. Chemical potential, Mulliken charge at C8, and ETSA index at C3 are important for cytotoxicity. Global hardness, electrophilic frontier electron density at C10, ETSA index at O21, and C13 play pivotal role for antiviral activity. Mulliken charge at C5, ETSA index at C14, RTSA index at C8, and C13 and LUMO density on C7 are important for anti-HIV-1 IN activity. HQSAR study suggested that maximum contributing fragments include C2 and C14 and substitutions at C13 and C14 for anti-HIV-1 IN activity and antiviral activity, respectively. The positively contributing fragments include C8, C9, C10, C11, and C16 are beneficial for cytotoxicity. CoMFA study suggested that favorable steric region located near C14 is important for anti-HIV-1 IN activity, steric factor at C8 substitution is important for antiviral and cytotoxicity activities. CoMSIA study correlates the steric region found in CoMFA study; hydrophobic favorable regions are located around C8 and near C13. For antiviral activity, unfavorable hydrogen bond acceptor region is observed near C8 substitution, favorable hydrogen bond acceptor region is observed at N1 substitution. For cytotoxic activity, favorable electrostatic region is located around quinolone and benzene ring. Docking study suggested that Glu152, Gln148, and Asn155 residues of the HIV-1 integrase enzyme bind with the molecule.
    No preview · Article · Jun 2014 · Medicinal Chemistry Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The review summarizes published data on the methods of the synthesis of fused nitrogen-containing heterocycles via pushpull enamines (mainly enaminones). Both intermolecular (cyclocondensations) and intramolecular (cyclizations) transformations of enamines, in which both nucleophilic centres of enamine (carbon and nitrogen) are incorporated into the resulting heterocycle, are considered. The data on the reactivity of enamines cover a broad range of facile methods for the preparation of diverse fused pyridines (quinolines, isoquinolines, pyridopyridines, etc.) and pyrroles (indoles, tetrahydrocarbazoles, pyrrolopyridines, etc.). The bibliography includes 191 references.
    Full-text · Article · Jan 2015 · Russian Chemical Reviews