Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.
Bibliographical noteFunding Information:
This research was supported by the Center for Drug Design at the University of Minnesota . We thank Dr. Yuk Sham for helpful discussion, Daniel Wilson for assistance in IN assay, Roger Ptak at Southern Research Institute for cell-based HIV assay, Dr. Robert Craigie of NIH for the integrase plasmid and Dr. William Shannon for consultation.