Synthesis And Activity Of Benzothiazole Derivatives Bearing Fused Heterocyclic

Cancer is still a major disease that endangers human health worldwidely.An important problem for human beings is to find effective ways to treat cancer.At present,molecular targeted therapy is a common method to treat cancer.In this paper,we introduced the classification of molecular targeted therapy and their respective mechanisms of action,then reviewed the importance of benzothiazole and indole skeleton in drug discovery and the research progress of their derivatives as anticancer small molecule inhibitors.Based on this,four series of target compounds were designed based on the structure-based molecular hybridization strategy,and expect them to be small molecule targeted inhibitors.In this work,we mainly explored the synthesis of four series of target compounds,measured the proliferation activity of the target compounds in vitro,predicted the potential target of the target compounds by molecular docking method,and explored the way of their interaction with the target in detail.The details are as follows:1.Synthesis of benzothiazole derivatives: 2-amino-6-substituted benzothiazole derivatives were synthesized through a series of reactions using 4-nitrobenzyl bromide as a raw material;2-amino-6-Substituted benzothiazole was used as a raw material to synthesize 2-aminothiophenol derivatives;2-aminothiophenol was used as a raw material to synthesize ethyl benzothiazole-2-carboxylic acid derivatives;Using benzothiazole-2-carboxylic acid ethyl ester derivatives as raw materials,benzothiazole-2-carbohydrazide and 6-methylbenzothiazole-2-carbohydrazide were synthesized.2.Synthesis of indole derivatives: 1-substituted indole-3-carbaldehyde derivatives were synthesized using indole as raw materials;1-substituted Indole-3-carboxylic acid derivatives were synthesized using indole-3-carboxylic acid as raw material;indole-2-carboxylic acid was synthesized using substituted phenylhydrazine hydrochloride as raw material.3.Synthesis of the target compounds: The benzothiazole and indole derivatives were condensed by N-acylhydrazone or 1,3,4-oxadiazole through condensation or cyclization reaction,four series of target compounds {(E)-N'-[(1H-indol-3-yl)methylene]benzothiazole-2-carbohydrazide and its derivatives,(E)-N'-(2-oxoindolin-3-ylidene)benzothiazole-2-carbohydrazide,2-(benzothiazol-2-yl)-5-(1H-indol-3-yl)-1,3,4-oxadiazole and its derivatives,2-(benzothiazol-2-yl)-5-(1H-indol-2-yl)-1,3,4-oxadiazole} were synthesized.4.In vitro antiproliferative activity evaluation:(E)-N'-[(1H-indol-3-yl)methylene] benzothiazole-2-carbohydrazide and its derivatives were screened for in vitro antiproliferative activity against cancer cell lines.There are two target compounds exhibited excellent antiproliferative activity against both of HepG2 and MCF7.5.Molecular docking: Taking(E)-N'-[(1H-indol-3-yl)methylene]benzothiazole-2-carbohydrazide as the research object,four potential cancer-related drug targets were predicted by reverse molecular docking,which were MAPKs,CDK-2,Lck and Tie-2.Then,it was used as a ligand to dock with the predicted four target molecules respectively,and the specific way of its interaction with the target protein was explored.According to the results of molecular docking,CDK-2 is a potential target of(E)-N'-[(1H-indol-3-yl)methylene]benzothiazole-2-carbohydrazide.