Green Synthesis of Tetrahydropyrazino[2,1-a:5,4-a']diisoquinolines as SARS-CoV-2 Entry Inhibitors

Sowndarya Palla; Srinivasa Rao Palla; Jia-Jin Liu; Tai-Ling Chao; Ting-Hui Lee; Veerababurao Kavala; I-Chen Liu; Lily Hui-Ching Wang; Sui-Yuan Chang; Ching-Fa Yao; Po-Huang Liang

doi:10.1021/acsomega.4c08640

Green Synthesis of Tetrahydropyrazino[2,1-a:5,4-a']diisoquinolines as SARS-CoV-2 Entry Inhibitors

ACS Omega. 2024 Dec 20;10(1):1164-1176. doi: 10.1021/acsomega.4c08640. eCollection 2025 Jan 14.

Authors

Sowndarya Palla¹, Srinivasa Rao Palla^{2

3}, Jia-Jin Liu², Tai-Ling Chao⁴, Ting-Hui Lee⁵, Veerababurao Kavala¹, I-Chen Liu², Lily Hui-Ching Wang⁶, Sui-Yuan Chang^{4

7}, Ching-Fa Yao¹, Po-Huang Liang^{8

2

3}

Affiliations

¹ Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
² Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan.
³ Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan.
⁴ Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan.
⁵ Department of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan.
⁶ Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
⁷ Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.
⁸ Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.

Abstract

A class of tetrahydropyrazino[2,1-a:5,4-a']diisoquinoline derivatives were synthesized under environmentally friendly conditions using water as the solvent. The 3-D structures of some synthesized compounds were determined by X-ray diffraction. Since naturally occurring isoquinoline alkaloids have significant antiviral activities against a wide range of viruses, including coronaviruses, the synthesized compounds were assayed for their inhibitory activities against SARS-CoV-2. Our results showed that the active compounds 50 and 96 blocked the delta SARS-CoV-2 entry into VeroE6 cells to display EC₅₀ of 26.5 ± 6.9 and 17.0 ± 3.7 μM, respectively, by inhibiting the interaction between SARS-CoV-2 Spike's receptor binding domain (RBD) and human receptor angiotensin-converting enzyme 2 (ACE2), and CC₅₀ greater than 100 μM. This study provides a green synthesis method of tetrahydropyrazinodiisoquinoline for antiviral or other applications.