Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3H)-ones

Abstract

Conformational restriction applied to dihydrobenzylpyrimidin-4-(3H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N,N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12–14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10–100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as “second generation” NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the (R) absolute configuration at the α-methoxy stereogenic center.

Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles

“…Next, compounds with two substituents on these two phenyl rings were synthesized ( B5–12 ). To be mentioned here, fluorine is of great importance in drug design as the productively influencing conformation, p K a , metabolic pathways, and pharmacokinetic properties. − Moreover, it was well-known that compounds with suitable aqueous solubility are more likely to provide acceptable PK properties upon oral administration . Thus, different acids to generate salts of the target compounds were tested.…”

Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors

“…The early generation NNRTIs (e.g. NVP, DLV and EFV) were reported to be ineffective against the K103N mutant [15][16][17][18]. The second generation NNRTIs, FDA-approved ETR and RPV with the diarylpyrimidine (DAPY) scaffold, showed better antiviral activity, especially against HIV mutants, potentially due to a flexible moiety of the DAPYs.…”

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

“…A series of DAPY analogues, modifying the central pyrimidine such as diarylpyridine (DAPD), 38 diaryltriazines, 39 diarylnicotinamide, 40 diarylaniline, 41 and dihydrobenzylpyrimidin‐4‐( 3H )‐ones 42 have been designed (Figure 8). They were confirmed to possess activity against WT HIV‐1 (EC 50 = 0.2–27 nM).…”