Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy

In this communication, wereport the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer¿s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 M), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.R.A., M.S., P.B., and K.M. were supported by European Regional Development Fund/European Social Fund (ERDF/ESF, project PharmaBrain, no. CZ.02.1.01/0.0/0.0/16_025/0007444), University of Hradec Kralove (no. SV2113-2019, VT2019-2021), and EU COST action CA15135 MuTaLig. J.M.C. thanks Ministerio de Economía (MINECO, SAF2015-65586-R) and Universidad Camilo José Cela (UCJC, grants UCJC 2020-03, and UCJC 2020-33) for support

Nefrotoxic effects of drugs

Bakalářská práce se zabývá nefrotoxickým působením léčiv. V úvodní části je stručně popsána anatomie a histologie ledvin, zajišťující jejich správnou funkci. Zde je pojednáváno zejména o jednotlivých strukturách základní stavební jednotky ledvin, nefronu. Dále jsou popsány obecné mechanismy nefrotoxicity a účast důležitých enzymů při metabolismu léčiv, které hrají významnou roli v toxickém poškození ledvin. Jednotlivé kapitoly této práce jsou zaměřeny na vybraná nefrotoxicky působící léčiva a to především analgetika, antibiotika a protinádorová léčiva. Kapitola týkající se analgetik je věnována zejména paracetamolu. Jedná se o jedno z nejběžněji užívaných léčiv, které se metabolizuje především v játrech cestou glukuronační a sulfatační, za vzniku nefrotoxického metabolitu N-acetyl-p-benzochinonu. Dále jsou detailně popsána především aminoglykosidová antibiotika, mezi která patří gentamicin, jež se váže k lipidickým složkám membrány kartáčového lemu proximálního tubulu a následně proniká až do lysozomu buněk. V lysozomech se gentamicin hromadí a způsobuje jejich prasknutí. Dalšími antibiotiky jsou beta-laktamová antibiotika, která jsou přenášena peptidovými transportéry na bazolaterální stěně proximálního tubulu a způsobují tak akutní nekrózu proximálního tubulu. Závěrečná kapitola je věnována cisplatině, patřící mezi protinádorová léčiva. Cisplatina poskytuje volné thioly, které reaguji s glutathion-S-transferázou a dávají vznik metabolitům, které mohou způsobovat ischemické poruchy ledvin.This bachelor thesis deals with nephrotoxic effects of drugs. In the first part, the anatomy, histology and function of kidney has been described briefly. It focuses mainly on individual parts of nephron, which is the basic structural and functional unit of the kidney. In the next chapter, general principles of nephrotoxicity and enzymes involved in drug metabolism are described. These enzymes can cause harmful toxicity in kidney. The third chapter is devoted to the nephrotoxic groups of drugs, especially to analgesics, antibiotics and antitumor drugs. The most important analgesic, acetaminophen, is metabolized in liver to glucuronate and sulfate, and also to a toxic metabolite, N-acetyl-p-benzoquinone imine. Gentamicin is one of typical nephrotoxic antibiotics, aminoglycosides. It is a nephrotoxic drug which binds to membrane lipids of brush border of proximal tubule. Consequently, gentamicin is transported to lysosomes and the accumulation of gentamicin in lysosome causes its rupture. Among other nephrotoxic antibiotics belong -lactams, which are transported by membrane transporters to proximal tubule where -lactams cause acute necrosis. The last chapter of the thesis deals with antitumor drugs, especially with cisplatin. Cisplatin is a frequently used drug reacting with thiol groups through catalysis by glutathione-S-transferases and this reaction is a principle of ischemic renal disease.Fakulta chemicko-technologick

Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators

Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy

International audienceIn this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation

Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease