Quinazoline derivatives as cathepsins B, H and L inhibitors and cell proliferating agents

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• 作者：Neera Raghav^a ; ^{nraghav.chem@gmail.com} ; Suman Jangra^a ; Ajay Kumar^b ; Shalmoli Bhattacharyya^b
• 关键词：Cathepsin B ; Cathepsin H ; Cathepsin L ; Kinetics studies ; Microwave assisted synthesis
• 刊名：International Journal of Biological Macromolecules
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：94
• 期：part_PA
• 页码：719-727
• 全文大小：1985 K
• 卷排序：94

文摘

Cysteine Cathepsins well known to be involved in cancer, inflammation and regulation of degenerative processes like apoptosis have become specific targets in drug designing. The potential of quinazolines and their derivatives in medicinal chemistry led us to synthesise a novel series of seven compounds of quinazolines to evaluate their effect on cathepsins and cellular aspects of HepG2 cells. In the present work we report the solvent free microwave assisted synthesis of (E)-8-benzylidene-5,6,7,8-tetrahydro-2,4-diarylquinazolines as inhibitors of mammalian hepatic cysteine proteases viz. Cathepsins B, H and L. In vitro inhibition of Cathepsins B, H and L is correlated well with in vitro studies when tested using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay on HepG2 cells, hepatocellular carcinoma cell line. The studies have been extended to evaluate the type of inhibition exhibited by the individual enzyme. Out of the seven compounds 1g i.e. (E)-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-2-phenyl-5, 6, 7, 8-tetrahydroquinazoline has been found to be most inhibitory for Cathepsins B, H and L to a maximum extent with the Ki values of 10−10 M, 10−10 M and 10−9 M order respectively. In silico studies of all compounds have also been done at the active sites of Cathepsin B, H and L.