Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Abstract

Based on the structures and activities of our previously identified non-nucleoside reverse transcriptase inhibitors (NNRTIs), we designed and synthesized two sets of derivatives, diarylpyridines (A) and diarylanilines (B), and tested their anti-HIV-1 activity against infection by HIV-1 NL4-3 and IIIB in TZM-bl and MT-2 cells, respectively. The results showed that most compounds exhibited potent anti-HIV-1 activity with low nanomolar EC50 values, and some of them, such as 13m, 14c, and 14e, displayed high potency with subnanomolar EC50 values, which were more potent than etravirine (TMC125, 1) in the same assays. Notably, these compounds were also highly effective against infection by multi-RTI-resistant strains, suggesting a high potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile.

Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

“…Modifications on the phenol ring (C-ring) were performed as shown in Schemes 1 and 3 to produce new DAPA series 6a-n and 8a-e . 6-Chloro-2-(4-cyanophenyl)amino-3-nitropyridine ( 3 ), prepared from commercially available 2,6-dichloro-3-nitropyridine and 4-cyano phenol as described in our previous publication, [8] was coupled with various halogenated phenols in DMF in the presence of cesium carbonate or potassium carbonate under microwave irradiation at 90-100 °C for 10-15 min to afford corresponding halogenated 2,6-diaryl-3-nitropyridines 4a-e , 5a-b , and 7a , respectively. The aldehyde group on the C-ring in 4a was reduced with NaBH 4 to produce hydroxymethyl compound 5c , followed by esterification with acetyl chloride to afford 5d .…”

“…In our prior studies on novel NNRTI agents, we discovered diarylpyridinamines (DAPAs) [7,8] with extremely high potency against HIV-1 wild-type and drug-resistant viral strains. As an example, DAPA lead compounds 2a and 2b (Figure 2) exhibited subnanomolar potencies against HIV-1 wild-type (EC 50 0.63 and 0.71 nM) and RT multidrug-resistant (RTMDR) viral strains (EC 50 0.96 and 0.59 nM), which were better or comparable to those of new-generation NNRTI drugs 1a (EC 50 1.4 and 1.0 nM) and 1b (EC 50 0.51 and 0.49 nM), respectively, in the same assays.…”

Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus

“…The initial leads 2a and 3a exhibited high anti-HIV potency against wild-type HIV-1 replication with low to subnanomolar EC 50 values of 3.0 and 0.71 nM, respectively, comparable to those of 1a (EC 50 = 1.5 nM) and 1b (EC 50 = 0.51 nM) in the same assays. 10, 12 However, very low bioavailability ( F % < 3) in rats impeded their further development. Subsequently, multiple structural modifications were introduced to identify structure-activity relationship (SAR) and structure-property relationship (SPR) correlations for DAANs and DAPAs as new HIV-1 NNRTI agents.…”

Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

“…In our prior studies, several diarylanilines (DAANs) were identified as novel class of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) agents with low nanomolar anti-HIV potency against wild-type and mutated viral strains 6,7 , both comparable to and better than new-generation NNRTI drugs 1a and 1b . These DAANs are shown in Figure 1 as leads 2a and 2b .…”