title: 2,3-Dihydroquinazolin-4(1H)-one derivatives as potential non-peptidyl inhibitors of cathepsins B and H.
abstract: A direct correlation between cathepsin expression-cancer progression and elevated levels of cathepsins due to an imbalance in cellular inhibitors-cathepsins ratio in inflammatory diseases necessitates the work on the identification of potential inhibitors to cathepsins. In the present work we report the synthesis of some 2,3-dihydroquinazolin-4(1H)-ones followed by their evaluation as cysteine protease inhibitors in general and cathepsin B and cathepsin H inhibitors in particular. 2,3-Dihydroquinazolin-4(1H)-ones, synthesized by the condensation of anthranilamide and carbonyl compound in presence of PPA-SiO2 catalyst, were characterized by spectral analysis. The designed compounds were screened as inhibitors to proteolysis on endogenous protein substrates. Further, a distinct differential pattern of inhibition was obtained for cathepsins B and H. The inhibition was more to cathepsin B with Ki values in nanomolar range. However, cathepsin H was inhibited at micromolar concentration. Maximum inhibition was shown by compounds, 1e and 1f for cathepsin B and compounds 1c and 1f for cathepsin H. The synthesized compounds were established as reversible inhibitors of cathepsins B and H. The results were also compared with the energy of interaction between enzyme active site and compounds using iGemdock software.
authors: Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
authors: Mamta
authors: M
authors: Singh
authors: Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India. Electronic address: nraghav.chem@gmail.com.
authors: Neera
authors: N
authors: Raghav
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D056655:Cathepsin H / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D006041:Goats; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D052999:Quinazolinones; D002401:Cathepsin B; D056655:Cathepsin H
keywords: 2,3-Dihydroquinazolin-4(1H)-one derivatives; Cathepsin B; Cathepsin H; Endogenous proteolysis; Non peptidyl inhibitors