Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates

Abstract

Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.

Figure 1

Next-generation NNRTI drugs and DAAN lead 3.

Figure 2

Leads DAANs, known SAR, and further optimization strategy

Scheme 1

a) ClSO₃H, 0–140 °C; b) NH₄OH/THF, 0 °C, 0.5 h; c) HNO₃/H₂SO₄, 2h; d) H₂SO₄/MeOH, reflux, 2 h; e) t-BuOK/DMF, r.t. 1 h.

Scheme 2

a) K₂CO₃/DMF, 190 °C, MW, 15 min or traditional heating at 130 °C, 5 h; b) (EtO)₂P(O)CH₂CN, t-BuOK/THF, 0 °C – r.t., 3 h; c) aq NaOH/THF/MeOH, r.t., 4 h; d) (i) SOCl₂/CH₂Cl₂, reflux, 3 h; (ii) NH₄OH/THF, 0 °C, 0.5 h; e) (i) SOCl₂/CH₂Cl₂, reflux, 3 h; (ii) NH₂CH₃ in THF, 0 °C, 0.5 h; f) (i) SOCl₂/CH₂Cl₂, reflux, 3 h; (ii) N₂H₄·H₂O, r.t, 1 h; g) CH₃COCH₃, MeOH/aq NaOH (10%), 0 °C – rt, 1 h; h) LiBH₄, THF/MeOH, 1 h; i) Na₂S₂O₄/NH₄OH, THF/H₂O (v/v 1:1), r.t.; j) H₂/Pd-C, EtOH, 2–4 h; k) CH(OEt)₃, HCl (1N), C₂H₅OC₂H₅/DMF, r.t. 3 h.