Inhibitors of HIV integrase are being developed as potential anti-AIDS drugs in collaboration with the Laboratory of Molecular Pharmacology, DBS, NCI. Lead inhibitor structures have initially been derived from several sources, including three-dimensional pharmacophore searching of the more than 250,000 compounds contained within the NCI's chemical repository. Promising compounds have been systematically explored through chemical synthesis of analogues to determine structure-activity relationships (SAR) responsible for integrase inhibition. Information generated in this fashion has been applied to the design and preparation of new analogues having higher potency. It has become evident that potent inhibition frequently requires two isolated aryl systems, although a clear correlation has not developed for these synthetic inhibitors between potent inhibition of HIV integrase in extracellular assays and anti-HIV protection in cellular systems. A primary focus of ongoing work is to further increase inhibitory potency while reducing collateral cellular toxicity. A lead structure in these studies is provided by chicoric acid, which is a natural product previously reported to exhibit potent HIV integrase inhibition as well as protective effects in HIV-infected cells. New synthesis of (+)- and (-)- chicoric acid have been developed and a series of chicoric acid analogues has been prepared. Currently, further SAR studies on this family are being conducted employing medium size libraries of potential inhibitors prepared by solid-phase combinatorial techniques.
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