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. © 2018 John Wiley & Sons A/S