Design of novel bioisosteres of beta-diketoacid inhibitors of HIV-1 integrase

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.
Keywords: HIV-1 integrase inhibitors, lead
compounds, drug discovery, high throughput
docking, 3D-database, isoxazole carboxylic acids,
bioisosterism