Evaluation of an octahydroisochromene scaffold used as a novel SARS 3CL protease inhibitor |
| |
| Affiliation: | 1. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan;2. Center for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan;1. College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian 116044, PR China;2. Department of Hematology, Institute of Respiratory Diseases, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;3. Dalian Buyun Biological Technology Co., Ltd., 116085, PR China;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India;2. Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, T. S., India;3. Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto, Fiorentino, Florence, Italy;1. Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People′s Republic of China;2. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China;3. Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping 136001, People’s Republic of China;1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States;2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States;3. Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States;4. Department of Biological Sciences, Ohio University, Athens, OH 45701, United States;5. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, United States;6. Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, United States;7. Campus Chemical Instrument Center, The Ohio State University, Columbus, OH 43210, United States;8. Institute of Ecology and Biological Resources, Vietnam Academy of Science and Technology, Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam;9. Department of Biomedical Sciences, Ohio University, Athens, OH 45701, United States;10. Science and Education, Field Museum of Natural History, Chicago, IL 60605, United States |
| |
| Abstract: | An octahydroisochromene scaffold has been introduced into a known SARS 3CL protease inhibitor as a novel hydrophobic core to interact with the S2 pocket of the protease. An alkyl or aryl substituent was also introduced at the 1-position of the octahydroisochromene scaffold and expected to introduce additional interactions with the protease. Sharpless–Katsuki asymmetric epoxidation and Sharpless asymmetric dihydroxylation were employed to construct the octahydroisochromene scaffold. The introductions of the P1 site His-al and the substituent at 1-position was achieved using successive reductive amination reactions. Our initial evaluations of the diastereo-isomeric mixtures (16a–d) revealed that the octahydroisochromene moiety functions as a core hydrophobic scaffold for the S2 pocket of the protease and the substituent at the 1-position may form additional interactions with the protease. The inhibitory activities of the diastereoisomerically-pure inhibitors (3a–d) strongly suggest that a specific stereo-isomer of the octahydroisochromene scaffold, (1S, 3S) 3b, directs the P1 site imidazole, the warhead aldehyde, and substituent at the 1-position of the fused ring to their appropriate pockets in the protease. |
| |
| Keywords: | SARS 3CL protease Inhibitor Fused ring scaffold Octahydroisochromene |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
