Design,Synthesis And Biological Evaluation Of 1,2,4-Triazolo[3,4-b][1,3,4]-Thiadiazole Derivatives

Src homology 2 domain-containing protein tyrosine phosphatase 2（SHP2）has dephosphorylation function,and SHP2 mutations or overexpression are closely associated with diseases such as diabetes and tumorigenesis.At present,based on the binding sites of small molecules with SHP2,the inhibitors are mainly divided into two types:one is to target the catalytic site,the other one is to target the allosteric site.Among them,orthostatic inhibitors have poor selectivity,low bioavailability,poor membrane permeability that no one to develop to clinical application.Allosteric inhibitors including TNO155,RLY-1971,JAB3068,etc.are in clinical stage.Because of there are no commercial drugs,so it is necessary to develop SHP2inhibitors with good biological activity,high selectivity and novel molecular scaffold.1,2,4-triazolo[3,4-b][1,3,4]-thiadiazole derivatives have a wide range of pharmacological activities such as antibacterial,antiviral,anti-inflammatory,analgesic,and antitumor,and have applications in the field of medicine,food,chemical engineering,agriculture.To explore the structural diversity of SHP2 inhibitors,based on the previous work of our research group,compound libraries 1,2 and benzophenone Schiff base derivatives were designed and synthesized,a total of 61 target molecules.The results showed that the representative compound32(IC₅₀=9.27±1.35μM)had good inhibitory activity and selectivity against SHP2,but not showed significant antiproliferative activity at the concentration of 20μM against Monocytic leukemia cells（MV-4-11）.Molecular docking results showed that the compound formed hydrogen bonds with SHP2 protein residues,Ser502,Gln506,hydrophobic interaction with Leu283.The results showed that all target molecules of compound library 2 had no significant inhibitory activity against SHP2.Benzophenone Schiff base derivatives also had no significant inhibitory activity against SHP2.The project was in the period of the outbreak of the COVID-19,for this reason,we screened the antiviral activity of the target molecules of compound libraries 1 and 2.Some compounds showed good inhibitory activity against the SARS-Co V-2 3-Chymotrypsin like protease(3CL^pro).Among them,compound 52(IC₅₀=1.28±0.17μM)showed potent inhibitory activity,and the pharmacological mechanism is in progress.Compound 52 deeply merged buried deeply into the hydrophobic S2 subsite withπ-electrons with Arg188 and hydrophobic interaction with Met165 and formed strong H-bonds with Asn142,Glu166.Some target molecules with good inhibitory activity against SHP2 in the compound library1 were found,which provided ideas for the development of SHP2 inhibitors;some compounds with good inhibitory activity against SARS-Co V-2 3CL^pro were found in compound library 2,which provided lead compounds for anti-COVID-19 drugs.