1,2,3,4‐Tetrahydroisoquinolines as inhibitors of HIV‐1 integrase and human LEDGF/p75 interaction

Alkaloids are a class of organic compounds with a wide range of biological properties, including anti‐HIV activity. The 1,2,3,4‐tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4‐tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV‐1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75‐IN interaction in vitro with an IC₅₀ of ~10 μm . Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75‐binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non‐specific DNA. As reported earlier for the inhibitors of LEDGF/p75‐IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV‐1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75‐IN interaction having a higher potency.