Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited

Abstract

A series of dihydroxypyrimidine (DHP) derivatives were designed as inhibitors of HIV integrase (IN) based on known homology models. Through chemical synthesis and biochemical assays it was found that the activity profile of these compounds largely deviates from predictions with existing models. With the recently disclosed IN crystal structure of prototype foamy virus (PFV), a new HIV IN homology model was constructed featuring a critical IN/DNA interface previously lacking. With this new model, docking results completely corroborated observed biological activities. This new model should provide a more accurate and improved platform for the design of new inhibitors of HIV IN.

Figure 1.

Representative IN ST inhibitors.

Figure 2.

Scaffold rearrangement of known ST inhibitors. Potent inhibitors 3 and 4 reflect a benzyl group repositioning on a common naphthyridine scaffold. The same operation within DHP inhibitor scaffold 5 could generate two new type of IN inhibitors 6 and 7. Ref: a and b.

Figure 3.

Docking of compounds 5–7 into previously reported homology models of HIV IN. Both models of Chen et al. (a) and Chimirri et al. (PDB: 1WKN) (b) allowed reasonable mode of binding of compounds 5 and 6 in which the parafluorobenzyl substituent binds into each of their proposed hydrophobic binding pocket.

Figure 4.

A new HIV IN model docked based on 3L2T with raltegravir (a) and 3L2U with elvitegravir (b). The observed modes of binding were consistent with that of PFV IN X-ray structures.

Figure 5.

Docking of compounds 1–7 into the new homology model of HIV IN (a–f). Overlay of compounds 1 and 2 showed two distinct modes of binding to the Mg²⁺ ions while retaining reasonable overlap of the halobenzyl group within the hydrophobic binding pocket (a). Major protein and viral DNA residues which formed the interfacial DNA/protein hydrophobic pocket (A17, G4 and C16, P145) (in dotted circle) and the E152-D64-D116 motif which chelates to the two Mg²⁺ ions within the binding pocket are highlighted (d).

Scheme 1.

Synthesis of compounds 7–11. Reagents and conditions: (a) NH₂OH, MeOH, 60 °C, 7 h, 65%; (b) dimethylacetylenedicarboxlate, MeOH, rt, quantitative yield; (c) xylene, MW, 140 °C, 40 min, 23%; (d) RNH2, MW, 150 °C, 4 min, 50–76%; (e) benzoyl chloride, pyridine, 66%; (f) Mel, Cs2CO3, THF, 40 °C, 57%; (g) MeNH₂ (33% solution in EtOH), MW, 150 °C, 4 min, 55%; (h) NaOH, MeOH, rt, overnight, 27%.

Scheme 2.

Synthesis of compound 6. Reagents and conditions: (a) benzoyl chloride, pyridine, 89%; (b) 4–F-benzyl bromide, Cs₂CO₃, THF, 80 °C, 30%; (c) MeNH₂, MW, 150 °C, 4 min, 50%.