1. Academic Validation
  2. Discovery of honokiol thioethers containing 1,3,4-oxadiazole moieties as potential α-glucosidase and SARS-CoV-2 entry inhibitors

Discovery of honokiol thioethers containing 1,3,4-oxadiazole moieties as potential α-glucosidase and SARS-CoV-2 entry inhibitors

  • Bioorg Med Chem. 2022 Aug 1;67:116838. doi: 10.1016/j.bmc.2022.116838.
Ting Xu 1 Jie-Ru Meng 2 Wanqing Cheng 3 Jia-Zheng Liu 2 Junyan Chu 3 Qian Zhang 3 Nannan Ma 3 Li-Ping Bai 4 Yong Guo 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau.
  • 2 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau.
  • 3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China.
  • 4 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau. Electronic address: [email protected].
  • 5 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China. Electronic address: [email protected].
Abstract

Honokiol, isolated from a traditional Chinese medicine (TCM) Magnolia officinalis, is a biphenolic compound with several biological activities. To improve and broaden its biological activity, herein, two series of honokiol thioethers bearing 1,3,4-oxadiazole moieties were prepared and assessed for their α-glucosidase and SARS-CoV-2 entry inhibitory activities. Among all the honokiol thioethers, compound 7l exhibited the strongest α-glucosidase inhibitory effect with an IC50 value of 18.9 ± 2.3 µM, which was superior to the reference drug acarbose (IC50 = 24.4 ± 0.3 µM). Some interesting results of structure-activity relationships (SARs) have also been discussed. Enzyme kinetic study demonstrated that 7l was a noncompetitive α-glucosidase inhibitor, which was further supported by the results of molecular docking. Moreover, honokiol thioethers 7e, 9a, 9e, and 9r exhibited potent Antiviral activity against SARS-CoV-2 pseudovirus entering into HEK-293 T-ACE2h. Especially 9a displayed the strongest inhibitory activity against SARS-CoV-2 pseudovirus entry with an IC50 value of 16.96 ± 2.45 μM, which was lower than the positive control Evans blue (21.98 ± 1.98 μM). Biolayer interferometry (BLI) binding and docking studies suggested that 9a and 9r may effectively block the binding of SARS-CoV-2 to the host ACE2 receptor through dual recognition of SARS-CoV-2 spike RBD and human ACE2. Additionally, the potent honokiol thioethers 7l, 9a, and 9r displayed relatively no cytotoxicity to normal cells (LO2). These findings will provide a theoretical basis for the discovery of honokiol derivatives as potential both α-glucosidase and SARS-CoV-2 entry inhibitors.

Keywords

1,3,4-Oxadiazole; Honokiol; SARS-CoV-2 entry inhibitor; Thioethers; α-Glucosidase inhibitor.

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