Discovery of Biphenyl-Substituted Diarylpyrimidines as New Non-Nucleoside HIV-1 Reverse Transcripttase Inhibitors †
1
Department of Chemistry, Fudan University, Shanghai 200433, China
2
Engineering Center of Catalysis and Synthesis for Chiral Molecules at Fudan University, Engineering Center of Industrial Asymetric Catalysis for Chiral Drugs at Shanghai, Shanghai 200433, China
3
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
*
Authors to whom correspondence should be addressed.
†
Presented at the 1st Molecules Medicinal Chemistry Symposium, Barcelona, Spain, 8 September 2017.
Proceedings 2017, 1(6), 220; https://doi.org/10.3390/proceedings1060220
Published: 19 October 2017
(This article belongs to the Proceedings of Proceedings of the 1st Molecules Medicinal Chemistry Symposium, Barcelona, Spain)
Although Rilpivirine (1, RPV, TMC278) was approved by the FDA in 2011 as a non-nucleoside HIV-1 reverse transcriptase inhibitor to treat Human Immunodeficiency Virus (HIV) [1] for its potent activity against many clinically relevant wild-type (WT) and mutant HIV-1 strains, the corresponding dosing complexity, drug-drug interactions and long-term toxicity of this drug have severely compromised its efficacy [2].
To solve the above problem, herein a novel series of biphenyl-substituted diarylpyrimidine analogues (DAPYs) was designed, synthesized to evaluate the in vitro activity against HIV-1 in MT-4 cells. Some of these compounds exhibited excellent activity with the low nanomolar EC50 to wild-type (WT), single-mutant, and double-mutant HIV-1 strains. The most potent compound 2a displayed an EC50 value of 1 nM against HIV-1 ⅢB, 1.3 nM against L100I, 0.84 nM against K103N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103N + Y181C, nearly 110 nM against F227L + V106 with a selectivity index (SI) value above 2059.
To investigate the possible interaction model between the new chemical entity and the biological target, compound 2a was docked into the allosteric non-nucleoside bind pocket (NNIBP) of HIV-1 RT (PDB code: 2ZD1) [3] by using Sybyl-X 1.2. Compound 2a exhibited a series of well-known kinds of interactions: the biphenyl moiety fitted well into the aromatic-rich sub-pocket consisting of amino acid residues including Tyr181, Tyr188, Phe227 and Trp229, showing the positive face-to-face π–π stacking interactions with the amino acid residues of Tyr181, Tyr188 and Trp229, excluding Phe227. The p-cyano group is protruding toward a tunnel formed by Phe227 and Trp229, indicating a possible polar interaction. The right aromatic ring extended to a solvent exposure region, which was surrounded by amino acid residues His235, Pro236 and Try 318. Additionally, two hydrogen bonds between compound 2a and NNIBP of HIV-1 RT were formed altogether; one is between the NH-linker and the oxygen atom of the carbonyl group on the back-bone of Lys101, another is between the 1-nitrogen atom on pyrimidine between the terminal amino group of Lys101.
Deep SAR analysis of the anti-HIV-1 profile of all the compounds showed that beside keeping the 2,6-dimethyl groups on the left ring of DAPY analogues, introducing a para-substituted cyano group on the second phenyl ring (B) on the biphenyl group might be crucial for enhancing the biological activity against both wild-type and mutant-type HIV-1. This important discovery on the biphenyl-substituted DAPY analogs might guide the further structural modification of our ongoing project of HIV-1 RT inhibitors.
Figure 1.
Design of new DAPY-NNRTIs based on the biphenyl-substituted pyrimidine scaffold.
Acknowledgments
We gratefully acknowledge the financial support from the National Natural Science Foundation of China under Grant No. 21372050.
Author Contributions
K.J., G.M. and F.-E.C. are in charge of the synthetic section. E.D.C.and C.P. are in charge of the biological evaluation work. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
There is no conflicts of interest.
References
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Jin, K.; Meng, G.; Chen, F.-E.; Clercq, E.D.; Pannecouque, C. Discovery of Biphenyl-Substituted Diarylpyrimidines as New Non-Nucleoside HIV-1 Reverse Transcripttase Inhibitors. Proceedings 2017, 1, 220. https://doi.org/10.3390/proceedings1060220
AMA Style
Jin K, Meng G, Chen F-E, Clercq ED, Pannecouque C. Discovery of Biphenyl-Substituted Diarylpyrimidines as New Non-Nucleoside HIV-1 Reverse Transcripttase Inhibitors. Proceedings. 2017; 1(6):220. https://doi.org/10.3390/proceedings1060220
Chicago/Turabian StyleJin, Kaijun, Ge Meng, Fen-Er Chen, Erik De Clercq, and Christophe Pannecouque. 2017. "Discovery of Biphenyl-Substituted Diarylpyrimidines as New Non-Nucleoside HIV-1 Reverse Transcripttase Inhibitors" Proceedings 1, no. 6: 220. https://doi.org/10.3390/proceedings1060220
