Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands

Ghosh, Arun K.; Shaktah, Ryan; Ghosh, Ajay K.; Johnson, Megan E.; Bhandari, Dipendra; Amano, Masayuki; Aoki, Manabu; Kovalevsky, Andrey Y.; Mitsuya, Hiroaki

doi:10.1016/j.ejmech.2025.117880

Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands

Journal Article · Fri Jun 20 00:00:00 EDT 2025 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2025.117880· OSTI ID:3002309

^[1]; Shaktah, Ryan ^[1]; Ghosh, Ajay K. ^[1]; Johnson, Megan E. ^[1]; ^[2]; Amano, Masayuki ^[3]; Aoki, Manabu ^[3]; ^[2]; Mitsuya, Hiroaki ^[4]

Purdue University, West Lafayette, IN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Kumamoto University (Japan)
Kumamoto University (Japan); National Center for Global Health and Medicine (NCGM), Tokyo (Japan); National Cancer Institute, Bethesda, MD (United States)

Here, we report here the design, synthesis and evaluation of a series of HIV-1 protease inhibitors that incorporate substituted oxaspirocyclic carbamate derivatives to serve as the P2 ligands. Various substituted ligand derivatives were synthesized in a racemic manner, using a tandem Prins/pinacol reaction as the key reaction. This reaction sets the relative stereochemistry of the oxaspirocyclic template in a highly diastereoselective manner. Reaction of the resulting ketone with enantiopure (S)-tert-butyl sulfinamide provided a convenient pathway to resolve the oxaspirocyclic ketone derivatives. The absolute stereochemical identity was determined by X-ray crystallography. The structure-activity studies demonstrate the effect of the stereochemistry of the oxaspirocyclic ring systems as well as the substitution effect on the aromatic ring. Several inhibitors exhibited potent HIV-1 protease inhibitory activity. One of these inhibitors displayed subnanomolar HIV-1 protease affinity and also exhibited potent antiviral activity. A high-resolution X-ray crystal structure of this inhibitor-bound HIV-1 protease show that the oxaspirocyclic P2 ligand forms an unconventional C–H⋯O bond with the backbone carboxyl group of Gly48’ and an interesting N–H … π interaction with the aromatic ring in the S2 subsite of HIV-1 protease active site.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: Japan Agency for Medical Research and Development (AMED); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 3002309

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Vol. 297; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (48)

Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV Ghosh, Arun K.; Anderson, David D.; Weber, Irene T. Angewandte Chemie International Edition, Vol. 51, Issue 8 https://doi.org/10.1002/anie.201102762	journal	January 2012
Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance Ghosh, Arun K.; Ramu Sridhar, Perali; Kumaragurubaran, Nagaswamy ChemMedChem, Vol. 1, Issue 9 https://doi.org/10.1002/cmdc.200600103	journal	September 2006
Current developments in Coot for macromolecular model building of Electron Cryo‐microscopy and Crystallographic Data Casañal, Ana; Lohkamp, Bernhard; Emsley, Paul Protein Science, Vol. 29, Issue 4 https://doi.org/10.1002/pro.3791	journal	March 2020
Structural implications of drug-resistant mutants of HIV-1 protease: High-resolution crystal structures of the mutant protease/substrate analogue complexes Mahalingam, Bhuvaneshwari; Louis, John M.; Hung, Jason Proteins: Structure, Function, and Genetics, Vol. 43, Issue 4 https://doi.org/10.1002/prot.1057	journal	January 2001
A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population Chawla, Anita; Wang, Christina; Patton, Cody Infectious Diseases and Therapy, Vol. 7, Issue 2 https://doi.org/10.1007/s40121-018-0201-6	journal	May 2018
Long-term effects of protease-inhibitor-based combination therapy Barbaro, Giuseppe The Lancet, Vol. 363, Issue 9412 https://doi.org/10.1016/S0140-6736(04)15753-X	journal	March 2004
Darunavir en primeras líneas. Estudio TITAN Curran, Adrian; Ribera Pascuet, Esteve Enfermedades Infecciosas y Microbiología Clínica, Vol. 26 https://doi.org/10.1016/S0213-005X(08)76549-2	journal	October 2008
The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic Broder, Samuel Antiviral Research, Vol. 85, Issue 1 https://doi.org/10.1016/j.antiviral.2009.10.002	journal	January 2010
Current status and challenges of antiretroviral research and therapy Esté, José A.; Cihlar, Tomas Antiviral Research, Vol. 85, Issue 1 https://doi.org/10.1016/j.antiviral.2009.10.007	journal	January 2010
Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV Ghosh, Arun K.; Dawson, Zachary L.; Mitsuya, Hiroaki Bioorganic & Medicinal Chemistry, Vol. 15, Issue 24 https://doi.org/10.1016/j.bmc.2007.09.010	journal	December 2007
High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains Tie, Yunfeng; Boross, Peter I.; Wang, Yuan-Fang Journal of Molecular Biology, Vol. 338, Issue 2 https://doi.org/10.1016/j.jmb.2004.02.052	journal	April 2004
Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114 Kovalevsky, Andrey Y.; Liu, Fengling; Leshchenko, Sofiya Journal of Molecular Biology, Vol. 363, Issue 1 https://doi.org/10.1016/j.jmb.2006.08.007	journal	October 2006
Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X-ray Structural Studies Ghosh, Arun K.; Yu, Xufen; Osswald, Heather L. Journal of Medicinal Chemistry, Vol. 58, Issue 13 https://doi.org/10.1021/acs.jmedchem.5b00676	journal	June 2015
Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS Ghosh, Arun K.; Osswald, Heather L.; Prato, Gary Journal of Medicinal Chemistry, Vol. 59, Issue 11 https://doi.org/10.1021/acs.jmedchem.5b01697	journal	January 2016
Mechanism and Origins of Stereoselectivity of the Aldol-Tishchenko Reaction of Sulfinimines Turlik, Aneta; Ando, Kaori; Mackey, Pamela The Journal of Organic Chemistry, Vol. 86, Issue 5 https://doi.org/10.1021/acs.joc.0c02862	journal	February 2021
Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance Ghosh, Arun K.; Chapsal, Bruno D.; Weber, Irene T. Accounts of Chemical Research, Vol. 41, Issue 1 https://doi.org/10.1021/ar7001232	journal	January 2008
Influence of Flanking Sequences on the Dimer Stability of Human Immunodeficiency Virus Type 1 Protease ^† Wondrak, Ewald M.; Louis, John M. Biochemistry, Vol. 35, Issue 39 https://doi.org/10.1021/bi960984y	journal	January 1996
Nuclear magnetic resonance enantiomer regents. Configurational correlations via nuclear magnetic resonance chemical shifts of diastereomeric mandelate, O-methylmandelate, and .alpha.-methoxy-.alpha.-trifluoromethylphenylacetate (MTPA) esters Dale, James A.; Mosher, Harry S. Journal of the American Chemical Society, Vol. 95, Issue 2 https://doi.org/10.1021/ja00783a034	journal	January 1973
Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance Ghosh, Arun K.; Sridhar, Perali Ramu; Leshchenko, Sofiya Journal of Medicinal Chemistry, Vol. 49, Issue 17 https://doi.org/10.1021/jm060561m	journal	August 2006
Joint X-ray/Neutron Crystallographic Study of HIV-1 Protease with Clinical Inhibitor Amprenavir: Insights for Drug Design Weber, Irene T.; Waltman, Mary Jo; Mustyakimov, Marat Journal of Medicinal Chemistry, Vol. 56, Issue 13 https://doi.org/10.1021/jm400684f	journal	June 2013
Stereoselective Synthesis of Hexahydro-1H-pyrano- and thiopyrano[3,4-c]quinoline Derivatives through a Prins Cascade Cyclization Subba Reddy, B. V.; Medaboina, Durgaprasad; Sridhar, B. The Journal of Organic Chemistry, Vol. 78, Issue 16 https://doi.org/10.1021/jo4009657	journal	July 2013
Synthesis of Enantiomerically Pure N - tert -Butanesulfinyl Imines ( tert -Butanesulfinimines) by the Direct Condensation of tert -Butanesulfinamide with Aldehydes and Ketones Liu, Guangcheng; Cogan, Derek A.; Owens, Timothy D. The Journal of Organic Chemistry, Vol. 64, Issue 4 https://doi.org/10.1021/jo982059i	journal	February 1999
Design and Synthesis of Stereochemically Defined Novel Spirocyclic P2-Ligands for HIV-1 Protease Inhibitors Ghosh, Arun K.; Chapsal, Bruno D.; Baldridge, Abigail Organic Letters, Vol. 10, Issue 22 https://doi.org/10.1021/ol8020308	journal	October 2008
Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons Hoye, Thomas R.; Jeffrey, Christopher S.; Shao, Feng Nature Protocols, Vol. 2, Issue 10 https://doi.org/10.1038/nprot.2007.354	journal	October 2007
Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021 Deeks, Steven G.; Archin, Nancie; Cannon, Paula Nature Medicine, Vol. 27, Issue 12 https://doi.org/10.1038/s41591-021-01590-5	journal	December 2021
Tandem Prins/pinacol reaction for the synthesis of oxaspiro[4.5]decan-1-one scaffolds Subba Reddy, B. V.; Gopal Reddy, S.; Ramana Reddy, M. Organic & Biomolecular Chemistry, Vol. 12, Issue 37 https://doi.org/10.1039/C4OB01188K	journal	July 2014
Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance Ghosh, Arun K.; Weber, Irene T.; Mitsuya, Hiroaki Chemical Communications, Vol. 58, Issue 84 https://doi.org/10.1039/D2CC04541A	journal	January 2022
Applying Public Health Principles to the HIV Epidemic — How Are We Doing? Frieden, Thomas R.; Foti, Kathryn E.; Mermin, Jonathan New England Journal of Medicine, Vol. 373, Issue 23 https://doi.org/10.1056/NEJMms1513641	journal	December 2015
Prevention of HIV-1 Infection with Early Antiretroviral Therapy Cohen, Myron S.; Chen, Ying Q.; McCauley, Marybeth New England Journal of Medicine, Vol. 365, Issue 6 https://doi.org/10.1056/NEJMoa1105243	journal	August 2011
Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir Hayashi, H.; Takamune, N.; Nirasawa, T. Proceedings of the National Academy of Sciences, Vol. 111, Issue 33 https://doi.org/10.1073/pnas.1400027111	journal	August 2014
The Protein Data Bank Berman, H. M. Nucleic Acids Research, Vol. 28, Issue 1 https://doi.org/10.1093/nar/28.1.235	journal	January 2000
Current and future priorities for the development of optimal HIV drugs Vitoria, Marco; Rangaraj, Ajay; Ford, Nathan Current Opinion in HIV and AIDS, Vol. 14, Issue 2 https://doi.org/10.1097/COH.0000000000000527	journal	March 2019
Origins of HIV and the AIDS Pandemic Sharp, P. M.; Hahn, B. H. Cold Spring Harbor Perspectives in Medicine, Vol. 1, Issue 1 https://doi.org/10.1101/cshperspect.a006841	journal	September 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10 https://doi.org/10.1107/S0907444909029436	journal	September 2009
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
A simple, continuous fluorometric assay for HIV protease Toth, Mihaly V.; Marshall, Garland R. International Journal of Peptide and Protein Research, Vol. 36, Issue 6 https://doi.org/10.1111/j.1399-3011.1990.tb00994.x	journal	December 1990
TMC114, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor Active against Protease Inhibitor-Resistant Viruses, Including a Broad Range of Clinical Isolates De Meyer, S.; Azijn, H.; Surleraux, D. Antimicrobial Agents and Chemotherapy, Vol. 49, Issue 6 https://doi.org/10.1128/AAC.49.6.2314-2321.2005	journal	May 2005
In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors Koh, Y.; Amano, M.; Towata, T. Journal of Virology, Vol. 84, Issue 22 https://doi.org/10.1128/JVI.00967-10	journal	September 2010
A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site Yoshimura, K.; Kato, R.; Kavlick, M. F. Journal of Virology, Vol. 76, Issue 3 https://doi.org/10.1128/JVI.76.3.1349-1358.2002	journal	February 2002
Rational Approach to AIDS Drug Design Through Structural Biology Wlodawer, Alexander Annual Review of Medicine, Vol. 53, Issue 1 https://doi.org/10.1146/annurev.med.53.052901.131947	journal	February 2002
Vital Signs: Deaths Among Persons with Diagnosed HIV Infection, United States, 2010–2018 Bosh, Karin A.; Johnson, Anna Satcher; Hernandez, Angela L. MMWR. Morbidity and Mortality Weekly Report, Vol. 69, Issue 46 https://doi.org/10.15585/mmwr.mm6946a1	journal	November 2020
Thirty Years of HIV and AIDS: Future Challenges and Opportunities Dieffenbach, Carl W.; Fauci, Anthony S. Annals of Internal Medicine, Vol. 154, Issue 11 https://doi.org/10.7326/0003-4819-154-11-201106070-00345	journal	June 2011

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Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands

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