Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility

Abstract

In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC₅₀ at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4⁺ cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity.

Keywords: HIV; NNRTI; drug solubility; reverse transcriptase.

Graphical abstract

Figure 1.

Structures of a catechol diether with the lowest EC₅₀ reported to date (1) and doravirine (2).

Figure 2.

Structures of several diaryl ether NNRTIs (3–5), RDEA806 (6), and our newly designed compounds (7a, 8a).

Figure 3.

Synthesis scheme (a) K₂CO₃, N-methylpyrrolidone, 120 °C, 4 h (b) BBr₃, CH₂Cl₂, 0–25 °C, 5 days (c) ethyl chloroacetate, K₂CO₃, KI, acetone, reflux, 4 h (d) NaOH, CH₂Cl₂ – CH₃OH (9:1), 25 °C 1 h, then diluted HCl (e) CH₃OH, p-toluenesulfonic acid, reflux, 4 h (f) N-bromosuccinimide, p-toluenesulfonic acid, CHCl₃, 25 °C, 12 h (g) K₂CO₃, acetone, 25 °C, 4 h (h) K₂CO₃, CH₂Cl₂ – CH₃OH – H₂O, 25 °C, 1–2 days (i) Cu(CH₃COO)₂, pyridine, CH₂Cl₂, 25 °C, 2–3 days. R1-R4 groups are as in Table 1.

Figure 4.

(a) Predicted binding mode of 7a (PDB: 3C6T). Turquoise dashed lines – π–π stacking, red dashed lines – hydrogen bonds, purple dashed line – halogen bond. (b) Predicted binding mode of 7e (PDB: 3C6T) viewed from the entrance to the NNRTIs binding site. Some residues removed for clarity.

Figure 5.

Comparison of docking scores of 7e and RPV to selected RT mutants.

Figure 6.

Cells were incubated with dilutions of 7e and infected with HIV-1. Plots indicate concentration (in µM) vs. infection rate (normalised to level without inhibitor) for (a) SupT1 and (b) CD4⁺ T cells.