title: Quinazoline derivatives as cathepsins B, H and L inhibitors and cell proliferating agents.
abstract: 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 Kivalues of 10-10M, 10-10M and 10-9M order respectively. In silico studies of all compounds have also been done at the active sites of Cathepsin B, H and L.
authors: Department of Chemistry, Kurukshetra University, Kurukshetra-136118, Haryana, India. Electronic address: nraghav.chem@gmail.com.
authors: Neera
authors: N
authors: Raghav
authors: Department of Chemistry, Kurukshetra University, Kurukshetra-136118, Haryana, India.
authors: Suman
authors: S
authors: Jangra
authors: PGIMER, Chandigarh, India.
authors: Ajay
authors: A
authors: Kumar
authors: PGIMER, Chandigarh, India.
authors: Shalmoli
authors: S
authors: Bhattacharyya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D056655:Cathepsin H / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006041:Goats; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008872:Microwaves; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D011799:Quinazolines; D002401:Cathepsin B; D056668:Cathepsin L; D056655:Cathepsin H
keywords: Cathepsin B; Cathepsin H; Cathepsin L; Kinetics studies; Microwave assisted synthesis