title: Synthesis, structure-activity relationships studies of benzoxazinone derivatives as α-chymotrypsin inhibitors.
abstract: A series of benzoxazinones 1-28 were synthesized via reaction of anthranilic acid with various substituted benzoyl chlorides in the presence of triethylamine in chloroform. Compounds 1-18 showed a good inhibition of α-chymotrypsin with IC50±SEM values between 6.5 and 341.1μM. Preliminary structure-activity relationships studies indicated that the presence of substituents on benzene ring reduces the inhibitory potential of benzoxazinone. Also the increased inhibitory potential due to fluoro group at phenyl substituent was observed followed by chloro and bromo substituents. Compounds with strong electron donating or withdrawing groups on phenyl substituent, showed a good inhibitory potential at ortho>meta>para position. Kinetics studies showed diverse types of inhibition, except uncompetitive-type inhibition. The Ki values ranged between 4.7 and 341.2μM. Interestingly, most of these compounds were non-cytotoxic to 3T3 cell line at 30μM, except compounds 6, 14 and 15. Competitive inhibitors of chymotrypsin are like to inhibit other α-chymotrypsin-like serine proteases due to structural and functional similarities between them. The inhibitors identified during the current study deserve to be further studied for their therapeutic potential against abnormalities mediated by chymotrypsin or other serine protease.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Marasini
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Fazal
authors.initials: F
authors.lastname: Rahim
authors.affiliation: PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Perveen
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Aneela
authors.initials: A
authors.lastname: Karim
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: hassaan2@super.net.pk.
authors.forename: Khalid
authors.initials: K
authors.lastname: Mohammed Khan
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.lastname: Atta-Ur-Rahman
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 214421, Saudi Arabia. Electronic address: hej@cyber.net.pk.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D016475:3T3 Cells; D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; D011480:Protease Inhibitors; D002918:Chymotrypsin; C117608:alpha-chymotrypsin
keywords: 3T3 cell line; Benzoxazinone; Cytotoxicity; Serine protease; α-Chymotrypsin inhibition