Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl3-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl3 was disclosed. Meantime, to establish a comprehensive structure-activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI center dot HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-t hiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC50 values of 3.5 mu M and 7.5 mu M, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.

Automated summary

This study presents a regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles from readily available thiosemicarbazides using POCl3. Additionally, 2-amino-1,3,4-oxadiazole derivatives were prepared via cyclization of thiosemicarbazide intermediates. In vitro assays demonstrated the inhibitory activities of selected compounds against influenza A virus strains.