Synthesis and molecular modeling of new multi-cinnamy as hiv-1 integrase inhibitors

Abstract

Twenty one multi-cinnamoyl-based analogs on the hexasubstituted benzene platform were synthesized and tested as a new group of synthetic inhibitors of HIV-1 integrase (IN). They were prepared from the Claisen-Schmidt condensations of 335 and the corresponding substituted benzaldehydes in various ranges of yields (3-49%). Partial demethylations of the methoxy groups on the flanking phenyl rings gave the free phenolic or catecholic moieties. The most potent compound 353 showed the inhibition activity against HIV-1 integrase in multiplate integration assay (MIA) with IC₅₀ value of 3.5 µM. To understand the binding of these inhibitors to HIV-1 IN, the flexible models of selected 21 multi-cinnamoyl compounds were computationally docked into the catalytic core domain of HIV-1 IN using Autodock 4.0 program. The obtained docking parameters, mainly hydrogen bonding and binding energy, can be used to explain biological activity of most compounds. In general, it is found that active inhibitors forms more hydrogen bonds with IN than inactive analogs.