Synthesis And Antitumor Evaluation Of Acetamide Derivatives Modified By Nitrogen-containing Six-membered Ring

Nitrogen heterocycles have been widely used in the field of medicine and pesticides because of its unique physiological activity.Nitrogen-containing six-member ring is an important part of drug,such as piperidine,morpholine and piperazine containing secondary amine groups,which have all the typical reaction characteristics of secondary amine groups,and can be constructed amide bond.Using of amide bonding to other active groups can improve the chances of finding excellent activity drugs.Using the principle of molecular splicing,thiazole and nitrogen-containing six-member ring were introduced into one molecular.Two series of 24 compounds were designed and synthesized.Compounds N-(5-(1H-1,2,4-triazole)-4-aryl-thiazole)-2-(piperidin-1-yl)acetamide(A1-A2),N-(5-(1 H-1,2,4-triazole)-4-aryl-thiazole)-2-(morpholin-1-yl)acetamide(B1-B2)and N-(5-(1H-1,2,4-triazole)-4-aryl-thiazole)-2-(piperazin-1-yl)acetamide(C1-C14)were synthesized from 4-aryl-5-(1H-1,2,4-triazole)-2-aminothiazole via chloroacetyl reaction and N-alkylation reaction with piperidine,morpholine and 4-substituted piperazine.N-(4-(t-Butyl)-5-benzylthiazol-2-yl)-2-(4-arylpiperazin-1-yl)acetamide(C15?C20)were synthesized from 2-(t-Butyl)-5-benzyl-2-aminothiazole via chloroacetyl reation and N-alkylation reaction with 4-substituted piperazine.All the new compounds were confirmed by 1H NMR.It was found that the three compounds contained saturated six-membered rings with different conformations.Most of compounds are existed in a stable chair form,and the hydrogen on the six-membered ring is affected by the ortho-coupling and the carbon coupling,which shows broad singlet or broad multiple peaks.And the characteristic compounds were further comfirned by 1H-1H COSY two-dimensional spectrum.N-(5-(1H-1,2,4-Triazole)-4-arylthiazole)-2-(piperidin-1-yl)acetamide(A1?A2),N-(5-(1H-1,2,4-triazoles)4-arylthiazole)-2-(morpholin-1-yl)acetamide(B1-B2)and N-(5-(1H-1,2,4-triazole)-4-arylthiazole)-2-(piperazin-1-yl)acetamide(C1?C14)were tested for their antitumor activity in vitro against Hela,A549 and SW480 cell lines by the MTT colorimetric method.The result showed that compound N-(5-(1H-1,2,4-triazole)-4-(2,4-dichloro-5-fluorophenyl)-thiazol-2-yl)-2-(4-phenylpip-erazin-1-yl)acetamide(C8)has a certain inhibitory activity against Hela and A549 with the inhibitory rates of 46.6%and 46.1%under the concentration of 50 ?M,respectively.As a whole,the antitumor activity of N-(5-(1 H-1,2,4-triazole)-4-aryl-thiazole)-2-(piperazin-1-yl)acetamide(C1-C14)against Hela,A549 and SW480 was better than that of N-(5-(1H-1,2,4-triazole)-4-arylthiazole)-2-(piperidin-1-yl)-acetamide(A1?A2)and N-(5-(1H-1,2,4-triazoles)-4-arylthiazole)-2-(morpholin-1-yl)acetamide(B1-B2).The antitumor activity of N-(5-(1H-1,2,4-triazole)-4-arylthiazole)-2-(4-arylpiperazin-1-yl)acetamide against Hela,A549 and SW480 was better than that of N-(5-(1H-1,2,4-triazole)-4-arylthiazole)-2-(4-alkyl-piperazin-1-yl)-acetamide.The effect of N-(4-(t-butyl)-5-benzylthiazol-2-yl)-2-(4-arylpiperazin-1-yl)acetamide(C16-C18)on the viability of A549 cells was examined by the MTS method.N-(4-(t-Butyl)-5-benzylthiazol-2-yl)-2-(4-aryl-piperazin-1-yl)acetamide(C16-C18)had little effect on the viability of A549 cells under the concentration of 50 ?M.