Synthesis And Bioactivity Of Calix [4] Arene Derivatives Bearing1,3-diketo Moiety At The Lower Rim As HIV-1Integrase Inhibitors

Considering that HIV integrase (IN) plays a key role during the retroviral life cycle and that there is no known human counterpart of HIV IN, it has been fully validated as a new important therapeutic target to design novel antiretroviral agents with high potency and low toxicity.Over the last two decades, numerous small-molecule HIV IN inhibitors have been reported, the most predominant class of inhibitors being the diketo acids (DKAs), and the1,3-diketo moiety was believed to be the most crucial pharmacophore for the inhibition of IN inhibitors. It is believed that their IN-binding mechanism is connected to the presence of DKAs pharmacophoric motif which could be involved in a functional sequestration of one or both divalent metal ions in the enzyme catalytic site to form a ligand-M2+-IN complex. This would subsequently block the transition state of the IN-DNA complex by competing with the target DNA substrate. Recently, calixarenes have been paid special attention as new molecular platforms for the design and development of new drugs. Many pharmacological properties are described for calixarenes (antiviral, antibacterial, antifungal, anticancer and so on). In particular, calixarenes have been increasingly studied for their anti-HIV activity with hign potency and low toxicity. Also, calixarenes are easily amenable to the upper or lower rim functionalization of the macrocyclic skeleton, which stimulate a new hope in designing novel anti-HIV agents.In this study, we used the structure of calixarene as the basic framework to design two kinds of carlix[4]arene derivatives bearing1,3-diketo moiety at the lower rim and synthesized18title compounds as novel HIV-1integrase inhibitors. The chemical structures of these compounds were confirmed by means of1H NMR,13C NMR, ESI-MS and single-crystal X-ray diffraction. The inhibition of the strand transfer process of HIV-1integrase of the title compounds were also evaluated using enzyme linked immunosorbent assay (ELISA). Preliminary bioassays indicated that calix[4]arene-based1,3-diketo derivatives exhibit good inhibition to HIV integrase. Among these compounds, one of them presented the most potent integrase strand transfer inhibitory activity with an IC50value of5.9μmol/L.At last, aided by molecular dynamics simulation, the mode of action between the title compounds and viral protein was built by Autodock4.2and DS3.1software packages. The result of molecular docking study showed that the macrocyclic skeleton of calix[4]arene can occupy the hydrophobic cavity of catalytic core region of IN. One of1,3-diketo pharmacophore moiety could chelate partially with the divalent metal ion, and strong π-π,π-σ interactions and hydrogen bonds exist between the title compounds and viral protein.The outcome of this research lay a good foundation in further structural modification and is beneficial for the screening of new HIV integrase inhibitors with high activities.