Synthesis And Biological Activity Of N-[4-tert-buty)-5-(1,2,4-triazol-1-yl) Thiazol-2-yl] Amide

Drug design of targeted enzymes and receptors is a hot topic in pharmaceutic development.As enzyme and receptor inhibitors,thiazole compounds have extensive biological activities and have been developing rapidly in the field of medicine.Based on the structure-activity relationship of thiazole compounds as well as the research of anticancer drugs and influenza antiviral drugs,we designed and synthesized a series of novel thiazole derivatives,and evaluated their activities in vitro,expecting to get potent compounds with high activities.A series of N-[4-tert-buty)-5-(1,2,4-triazol-yl)thiazol-2-yl]alkyl amides(4)were designed and synthesized according to the structure features and active-informations of A3 adenosine receptor antagonist.The key intermediate N-(4-tert-buty)-5-(1,2,4-triazol-yl)thiazol-2-amine(3)was obtained from 3,3-dimethyl-l-(1,2,4-triazol-1-yl)butan-2-one(1)via H2O2-NaBr bromation,cyclization with thiourea.And the target compounds were synthesized by the reactions of intermediate 3 with alkyl acids,anhydrides or acyl chloride,respectively.The influences of acylation reagent of the reaction were also investigated.The target compounds were confirmed by 1H NMR,13C NMR,ESI-MS and X-ray single crystal diffraction.The antitumor activities of the target compounds were measured using MTT assay.The preliminary bioassay shows that compounds 4c?4i?4j?4k exhibit potent activity against Hela with IC50 value(MM)of 0.061?0.048?0.030?0.062,respectively;and compounds 4c?4j exhibit good activity against A549 with IC50 value(mM)of 0.052 and 0.017,respectively.A series of neuraminidase(NA)inhibitors against SA and 430-cavity double-binding-site were designed and synthesized,choosing thiazole ring as the core ring.N-[4-tert-buty)-5-(1,2,4-triazol-yl)thiazol-2-yl]benzamides(5)were synthesized by the reactions of intermediate 3 with aryl carboxylic acids and acyl chlorides.Four kinds of N-[4-tert-buty)-5-(1,2,4-triazol-yl)thiazol-2-yl]aminobenzamides(6)were obtained by the reactions of compounds 5 with Raney Ni/N2H4·H2O,and the influences of reductant of the reaction were also investigated.The target compounds were confirmed by 1H NMR,13C NMR and ESI-MS.The NA inhibitory activity of the synthesized compounds were tested in vitro at 40 g/mL.Some compounds show good activity against NA of H1N1.Compounds 5d and 5f exhibit potent activity with inhibition rate of 55.7%and 55.0%,and IC50 values(?g/mL)of 34.9 and 34.2,respectively.Compounds 5d and 5f could be used as lead compounds for further study.