text: Since critical structure information is scarce on HIV integrase catalysis it is difficult to find the exact pharmacophore for its inhibition. Wang et al (2010) hoped that by studying the SAR and pharmacophore of a dual inhibitor scaffold, focusing both on integrase and reverse transcriptase (RT) it would be possible to observe anti-integrase activity. By studying the SAR of HIV integrase inhibitors it was possible to find that for optimal integrase inhibition the pharmacophore requires a regiospecific (N-1) DKA of a specific length. A DKA functionality or its heterocyclic bioisostere that selectively inhibit strand transfer seem to be present in all major chemotypes of integrase inhibitors. As detailed in the SAR discussion above the two necessary structural components of INI are a benzyl hydrophobic moiety and a chelating triad to bind the Mg ions. For the triad to bind the Mg ions has to be ionized (see fig. 5) and thus a pharmacophore bioisostere has to be ionized too and the benzyl pharmacophore bioisostere must to be very hydrophobic.
  However, despite previous success in clinical development (raltegravir), a detailed binding model is lacking so it has proven difficult to structure base the design of integrase inhibitors. When the pharmacophore of salicylic acid and catechol were merged, new chemical scaffolds were created. The adjacent hydroxyl and carboxylic groups on salicylic acid could bind with the metal ions and serve as their pharmacophore. Polyhydroxylated aromatic inhibitors are mostly active against strand transfer reactions and 3‘-processing which suggests a mechanism that targets both steps. This is a very important part of the compound as it can be used to bind to the divalent metal on the active site of IN and as such be effective against viral strains that are resistant to strand transfer specific inhibitors.