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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2016 Apr 13

PMID 27070547

Citations 12

Authors

Na Liu

Lei Wei

Li Huang

Fei Yu

Weifan Zheng

Bingjie Qin

Dong-Qin Zhu

Susan L Morris-Natschke

Shibo Jiang

Chin-Ho Chen

Kuo-Hsiung Lee

Lan Xie

Affiliations

Soon will be listed here.

Abstract

Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.

Citing Articles

Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability.

Sang Y, Pannecouque C, De Clercq E, Wang S, Chen F Acta Pharm Sin B. 2023; 13(7):3054-3066.

PMID: 37521857 PMC: 10372819. DOI: 10.1016/j.apsb.2023.03.022.

Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.

Prener L, Baszczynski O, Kaiser M, Dracinsky M, Stepan G, Lee Y J Med Chem. 2023; 66(3):1761-1777.

PMID: 36652602 PMC: 10017027. DOI: 10.1021/acs.jmedchem.2c01574.

Lead Optimization: Synthesis and Biological Evaluation of PBT-1 Derivatives as Novel Antitumor Agents.

Xie L, Goto M, Chen X, Morris-Natschke S, Lee K ACS Med Chem Lett. 2021; 12(12):1948-1954.

PMID: 34917259 PMC: 8667301. DOI: 10.1021/acsmedchemlett.1c00505.

The Fellowship of Privileged Scaffolds-One Structure to Inhibit Them All.

Skorenski M, Sienczyk M Pharmaceuticals (Basel). 2021; 14(11).

PMID: 34832946 PMC: 8622370. DOI: 10.3390/ph14111164.

Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors.

Li J, Jiang X, Dick A, Sharma P, Chen C, Rathi B Bioorg Med Chem. 2021; 48:116414.

PMID: 34562701 PMC: 9127657. DOI: 10.1016/j.bmc.2021.116414.

References

Di L, Kerns E, Li S, Petusky S . High throughput microsomal stability assay for insoluble compounds. Int J Pharm. 2006; 317(1):54-60. DOI: 10.1016/j.ijpharm.2006.03.007. View

De Luca L, Giacomelli G, Porcheddu A . An efficient route to alkyl chlorides from alcohols using the complex TCT/DMF. Org Lett. 2002; 4(4):553-5. DOI: 10.1021/ol017168p. View

Janssen P, Lewi P, Arnold E, Daeyaert F, De Jonge M, Heeres J . In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem. 2005; 48(6):1901-9. DOI: 10.1021/jm040840e. View

Tian X, Qin B, Lu H, Lai W, Jiang S, Lee K . Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg Med Chem Lett. 2009; 19(18):5482-5. PMC: 2770631. DOI: 10.1016/j.bmcl.2009.07.080. View

Lansdon E, Brendza K, Hung M, Wang R, Mukund S, Jin D . Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design. J Med Chem. 2010; 53(10):4295-9. DOI: 10.1021/jm1002233. View

Ripamonti D, Bombana E, Rizzi M . Rilpivirine: drug profile of a second-generation non-nucleoside reverse transcriptase HIV-inhibitor. Expert Rev Anti Infect Ther. 2013; 12(1):13-29. DOI: 10.1586/14787210.2014.863708. View

Kaufmann G, Cooper D . Antiretroviral therapy of HIV-1 infection: established treatment strategies and new therapeutic options. Curr Opin Microbiol. 2000; 3(5):508-14. DOI: 10.1016/s1369-5274(00)00131-4. View

Hopkins A, Groom C, Alex A . Ligand efficiency: a useful metric for lead selection. Drug Discov Today. 2004; 9(10):430-1. DOI: 10.1016/S1359-6446(04)03069-7. View

Das K, Clark Jr A, Lewi P, Heeres J, de Jonge M, Koymans L . Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1.... J Med Chem. 2004; 47(10):2550-60. DOI: 10.1021/jm030558s. View

10.

Ren J, Nichols C, Stamp A, Chamberlain P, Ferris R, Weaver K . Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138. FEBS J. 2006; 273(16):3850-60. DOI: 10.1111/j.1742-4658.2006.05392.x. View

11.

Tarcsay A, Nyiri K, Keseru G . Impact of lipophilic efficiency on compound quality. J Med Chem. 2012; 55(3):1252-60. DOI: 10.1021/jm201388p. View

12.

Wu Z, Liu N, Qin B, Huang L, Yu F, Qian K . Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS. ChemMedChem. 2014; 9(7):1546-55. PMC: 4085996. DOI: 10.1002/cmdc.201400075. View

13.

Keseru G, Makara G . The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov. 2009; 8(3):203-12. DOI: 10.1038/nrd2796. View

14.

Wang R, Chen J, Qin B, Xie J, Li H, Xie L . [Metabolite profiling of two anti-HIV lead compounds in rat liver microsomes]. Yao Xue Xue Bao. 2013; 47(12):1671-7. View

15.

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

16.

Dang Z, Lai W, Qian K, Ho P, Lee K, Chen C . Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors. J Med Chem. 2009; 52(23):7887-91. PMC: 2788670. DOI: 10.1021/jm9004253. View

17.

Wainberg M . Combination therapies, effectiveness, and adherence in patients with HIV infection: clinical utility of a single tablet of emtricitabine, rilpivirine, and tenofovir. HIV AIDS (Auckl). 2013; 5:41-9. PMC: 3570078. DOI: 10.2147/HIV.S32377. View

18.

Leeson P, Springthorpe B . The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov. 2007; 6(11):881-90. DOI: 10.1038/nrd2445. View

19.

Tian X, Qin B, Wu Z, Wang X, Lu H, Morris-Natschke S . Design, synthesis, and evaluation of diarylpyridines and diarylanilines as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. J Med Chem. 2010; 53(23):8287-97. PMC: 3050082. DOI: 10.1021/jm100738d. View

20.

Anta L, Llibre J, Poveda E, Blanco J, Alvarez M, Perez-Elias M . Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies. AIDS. 2012; 27(1):81-5. DOI: 10.1097/QAD.0b013e3283584500. View