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proposed mechanisms. For example, as will be seen, many topoisomerase II inhibitors also inhibit HIV
integrase. While screening of chemical databases is likely underway at several pharmaceutical
companies, results have either not been made available or are discouraging (see below). One foray into
integrase inhibitor design—rather than discovery—has recently been described using a peptide
combinatorial library approach [43]. We summarize below published reports to date (March 1996) in
which compounds have been identified that inhibit integrase in in vitro assays with IC 50 values of 100
μM or less (IC 50 is the concentration at which the measured activity is inhibited by 50%). In vitro
inhibition data is compiled in Table 1; structures of selected compounds are shown in Figure 9.
An Effective Pharmacophore: Multiple Hydroxyl Groups on Aromatic Rings
The first report of a class of compounds that inhibits HIV integrase appeared in 1992 [44].
Aurintricarboxylic acid (I) and its derivatives, known to inhibit other enzymes that process nucleic acids,
were determined to inhibit 3' processing with moderate IC 50 values of 10–50 μM. As shown in Figure 9,
a recurring structural theme was established early on in which integrase inhibitors often possess
aromatic rings with multiple hydroxy substituents that are either located
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