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Synthesis of novel quinazoline derivatives as a potential multipotent therapeutics against Alzheimer's disease
Tošnerová, Daniela ; Karabanovich, Galina (advisor) ; Matouš, Petr (referee)
1 ABSTRACT Charles University, Faculty of Pharmacy in Hradec Králové Department of: Organic and Bioorganic Chemistry Mentor: Ing. Galina Karabanovich, Ph.D. Consultant: Ing. Barbora Svobodová, Ph.D. Student: Daniela Tošnerová Title of Thesis: Synthesis of novel quinazoline derivatives as a potential multipotent therapeutics against Alzheimer's disease Alzheimer's disease (AD) is a severe neurologic disorder. Current treatments only temporarily delay the progression of disease. The main limiting factor for developing of new therapeutic compounds is the simultaneous presence of multiple pathologies. Thus, a new group of potential drugs called multi-target directed ligands (MTDLs) emerged as an alternative option to combat AD. To this date, dozens of MTDLs have been published. As part of the experimetnal section of this thesis, a series of small molecules based on quinazoline scaffold was rationally designed with the intention to influence the activity of acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A and B (MAO-A/MAO-B), and the GluN1/GluN2B subunit of N-methyl-D-aspartate receptor (NMDAR). Subsequently twenty-four new quinazoline derivatives were synthesized, and biologically evaluated. The overall results highlighted compound II-6h ((5E)-8-chlor-N-cyklohexyl-3-methyl-1-...
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Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro
Janská, Kateřina ; Herink, Josef (advisor) ; Hrdina, Radomír (referee)
Kateřina Janská Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro Diploma thesis Charles University in Prag, Faculty of Pharmacy in Hradec Králové Pharmacy Department of Biological and Medical Sciences Supervisor: Doc. MUDr. Josef Herink, DrSc. Consultant: PharmDr. Vendula Šepsová The aim of the thesis was to determine the type of an inhibition of newly synthesized AChEI and to find out if AChEI structure changes influence the type of an inhibition. Altogether 12 substances (7 tacrine hybrides and 5 7-methoxy- donepezil hybrids) were investigated. The inhibition potential of the tested substances was studied in vitro on the human recombinant AChE. Spectrophotometric Ellman method was utilized as the measurement tool. The noncompetitive type of an inhibition for substances EN 1-5, PC-25 and PC-33, mixed type of an inhibition for substances PC-48 and PC-49, uncompetitive type of an inhibition for substances EN-6, EN-7 and competitive type of an inhibition for the substance PC-37 was determined. The greatest inhibition potential according to Ki values were found for substances EN-7 and PC-37. Substances PC-37 and PC-48 were determined as substances with the biggest affinity to the AChE. The type of an inhibition has been influenced by a substituent position in PC substances and by...
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Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro
Janská, Kateřina ; Herink, Josef (advisor) ; Hrdina, Radomír (referee)
Kateřina Janská Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro Diploma thesis Charles University in Prag, Faculty of Pharmacy in Hradec Králové Pharmacy Department of Biological and Medical Sciences Supervisor: Doc. MUDr. Josef Herink, DrSc. Consultant: PharmDr. Vendula Šepsová The aim of the thesis was to determine the type of an inhibition of newly synthesized AChEI and to find out if AChEI structure changes influence the type of an inhibition. Altogether 12 substances (7 tacrine hybrides and 5 7-methoxy- donepezil hybrids) were investigated. The inhibition potential of the tested substances was studied in vitro on the human recombinant AChE. Spectrophotometric Ellman method was utilized as the measurement tool. The noncompetitive type of an inhibition for substances EN 1-5, PC-25 and PC-33, mixed type of an inhibition for substances PC-48 and PC-49, uncompetitive type of an inhibition for substances EN-6, EN-7 and competitive type of an inhibition for the substance PC-37 was determined. The greatest inhibition potential according to Ki values were found for substances EN-7 and PC-37. Substances PC-37 and PC-48 were determined as substances with the biggest affinity to the AChE. The type of an inhibition has been influenced by a substituent position in PC substances and by...
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