The topoisomerase II β -kinase associated with HIV-1 is a potential target for pyridine-bischalcones' anti-HIV-1 activity.

Topoisomerase II (TopoII) is a critical component of HIV-1 integration, proviral DNA synthesis, and reverse transcription. During HIV-1 infection, the TopoIIβkinase (TopoIIβK) phosphorylates TopoIIβ. Our earlier research demonstrated that the pyridine scaffold has potent anti-HIV-1 activity by specifically inhibiting TopoIIβK activity. 3D QSAR results showed the presence of molecular features for interaction with TopoIIβK requiring chemically induced proximity for potential interaction. In this study, the chalcone and methyl groups were added to the pyridine scaffold's core to achieve the desired proximity length between the pyridine scaffold and charged centers, which resulted in an inhibitory activity against TopoIIβK and viral replication. According to the findings, the TopoIIβKactivity was inhibited by the inclusion of the pyridine scaffold with the chalcone group, leading to better anti-HIV-1 activity. The water-soluble methylated pyridinium chalcones' showed significant TopoIIβK antagonism, anti-HIV-1 activity (from IC > 500 nM to ID 25 nM), and reduced cytotoxicity (CC = 2 mM). These activities could be associated with the charge on the pyridine and extended proximity. Therefore, it is clear that within the scope of this work, altering the proximity length and charge centers of pyridine molecules are critical for the design and development of effective anti-HIV-1 leads, specifically targeting TopoIIβK.