Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

Abstract

The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

“…Docking analysis was applied to further explain the experimental results on the most promising compound 16y and the precursor 12a. Similar to other biphenyl-DAPYs, 6,7,11,22 these two compounds were predicted to well fit into the hydrophobic pocket formed by the key amino acid residues Y181, Y188, F227 and W229 (Fig. 4).…”

“…The mutant 3D structures were generated from this PDB by site-specific mutation and minimized by Schrodinger Bio-Luminate. 8,22 Similar to other biphenyl-DAPYs, 6,7,11,23 these two compounds were predicted to fit well into the hydrophobic pocket formed by the key amino acid residues Y181, Y188, F227, and W229 (Figure 4). For the binding modes with the WT HIV RT enzyme (Figure 4A,B), as shown in Figure 2, a water-mediated hydrogen-bonding network (NH…”

“…The synthetic route of compounds 16y and 19z was illustrated in Scheme 2. The intermediate 17 was synthesized from 14a 7,11,16 and methyl iodide, the Cs the desired target molecules 16 via the Suzuki-Miyaura cross coupling. 17 All of the final structures were characterized by 1 H NMR and 13 C NMR spectroscopy and HRMS.…”

“…6 Compound 4 with replacement of the dimethyl groups by a difluoro moiety maintained the antiviral activity, especially exhibiting much lower cytotoxicity (SI > 238,095). Furthermore, a series of biphenyl-DAPY compounds (5−7) with different CH-R linkers (R = OH, 10 CN, 7 and NOH 11 ) were also developed by adjusting the flexibility of the molecules to adopt the RT enzyme. 13 Most of them were demonstrated to show excellent antiviral activities toward WT HIV-1 and the moderate cytotoxicity.…”

“…Diarylpyrimidine (DAPY) derivatives are the most highly potent class of NNRTIs with two FDA-approved drugs (etravirine, ETR, 1 and rilpivirine, RPV, 2 ). , With these compounds as the leads, our group first designed the biphenyl-DAPYs with prominent activity against HIV WT and related mutants (Figure ). − …”