text: Changes in the imidoylthiourea complexes led to the synthesis of a new class of compounds, diaryltriazine (DATA). In these compounds, the thiourea part of the ITU compounds was replaced by a triazine ring. The DATA compounds were more potent than the ITU compounds against common NNRTI resistant mutant strains. R106168, a prototype DATA compound, was rather easy to synthesize. Multiple substitutions were made at different positions on all of the three rings and on the linkers connecting the rings. In the pocket, most of the DATA derivatives conformed a horseshoe conformation. The two wings in R106168 (2,6-dichlorobenzyl and 4-cyanoanilino) occupied positions in the pocket similar to that of the two wings of the derivatives of ITU. The central part of the DATA compounds, in which the triazine ring replaced the thiourea group of ITU derivatives, is positioned between the side chains of L100 and V179. This removed a number of torsional degrees of freedom in the central part while keeping the flexibility between the triazine ring and the wings.
  Chemical substitution or modification in the three-aromatic-ring backbone of the DATA compounds had substantial effect on the activity. R120393, a DATA analog, was designed with a chloroindole part in wing I to expand interactions with the side chain of conserved W229 of the polymerase primer grip loop. R120393 had similar effect as R106168 against most of the NNRTI-resistant mutants.  The cloroindole part interacted with the hydrophobic core of the pocket and influenced the binding mode of the R120393 so it went deeper into the pocket compared to the wing I position of other DATA analogs. Crystal structures showed that the DATA compounds could bind the NNIBP in different conformations. The capability to bind in multiple modes made the NNRTIs stronger against drug-resistance mutations. Variability between the inhibitors could be seen when the chemical composition, size of wing I and the two linker groups connecting the rings were altered. The potency of the NNRTIs changed when the triazine nitrogen atoms were substituted with carbons.