Identification of Boronate-Containing Diarylpyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

In this study, privileged boronic acid ester was introduced into the right wing of etravirine (ETR) to obtain a series of novel boronate-containing derivatives. These newly synthesized derivatives were evaluated for their anti-HIV potency in MT-4 cells using the MTT method, and their inhibitory activity to HIV-1 reverse transcriptase (RT) was assayed by the ELISA method. Most of the synthesized compounds displayed promising antiviral activity against the wild-type and a wide range of HIV-1 mutant strains. In particular, 4a exhibited the most potent activity against the wild-type and a panel of single mutations (L100I, K103N, Y181C, and E138K) with EC₅₀ values ranging from 0.005 to 0.648 μM, which were much superior to those of nevirapine (EC₅₀ = 0.151 μM). Moreover, 4b turned out to be an effective inhibitor against the double-mutant strains F227L + V106A and RES056 with EC₅₀ values of 3.21 and 2.30 μM, respectively. RT inhibition activity and molecular docking were also investigated.

Keywords: DAPY; HIV-1; NNIBP; NNRTIs; boronate; drug design.

Figure 1

Chemical structures of approved NNRTIs drugs.

Figure 2

The design strategy of the newly designed phenylboronic acid pinacol ester-containing compounds.

Scheme 1

Synthesis of 3a–j and 4a–c. (Reagents and conditions: (i) 4-aminophenylboronic acid pinacol ester, Pd₂(dba)₃, BINAP, Cs₂CO₃, 1,4-dioxane, N₂, 90 °C).

Figure 3

(A) The overlapping conformations of 4a with the lead compound ETR (green, 4a; yellow, ETR). (B) Predicted binding modes of 4a with HIV-1 WT RT (PDB code: 6C0J; green, 4a); (C) Predicted binding modes of 4a with HIV-1 K103N/Y181C mutant RT (PDB code: 6C0R). (D) Overlapping patterns of 3a with 4a (green, 4a; slate, 3a). The hydrogen bonds between the inhibitors and amino acid residues are indicated with dashed lines (red). Nonpolar-hydrogen atoms are omitted for clarity.