ABSTRACT
A series of tetrahydropyrimidinethiones were synthesized from thiourea, ß-diketones and aromatic aldehydes, such as p-tolualdehyde, p-anisaldehyde, o-tolualdehyde, salicylaldehyde and benzaldehyde. These cyclic thioureas showed good inhibitory action against acetylcholine esterase (AChE), butyrylcholine esterase (BChE), and human (h) carbonic anhydrase (CA) isoforms I and II. AChE and BChE inhibitions were in the range of 6.11-16.13 and 6.76-15.68 nM, respectively. hCA I and II were effectively inhibited by these compounds, with Ki values in the range of 47.40-76.06 nM for hCA I, and of 30.63-76.06 nM for hCA II, respectively. The antioxidant activity of the cyclic thioureas was investigated by using different in vitro antioxidant assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging, Cu2+ and Fe3+ reducing, and Fe2+ chelating activities.
Subject(s)
Acetylcholinesterase/metabolism , Antioxidants/pharmacology , Butyrylcholinesterase/metabolism , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/pharmacology , Cholinesterase Inhibitors/pharmacology , Pyrimidines/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Carbonic Anhydrase I/metabolism , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
Rosmarinic acid (RA) is a natural polyphenol contained in many aromatic plants with promising biological activities. Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread and intensively studied metalloenzymes present in higher vertebrates. Acetylcholinesterase (AChE, E.C. 3.1.1.7) is intimately associated with the normal neurotransmission by catalysing the hydrolysis of acetylcholine to acetate and choline and acts in combination with butyrylcholinesterase (BChE) to remove acetylcholine from the synaptic cleft. Lactoperoxidase (LPO) is an enzyme involved in fighting pathogenic microorganisms, whereas glutathione S-transferases (GSTs) are dimeric proteins present both in prokaryotic and in eukaryotic organisms and involved in cellular detoxification mechanisms. In the present study, the inhibition effects of rosmarinic acid on tumour-associated carbonic anhydrase IX and XII isoenzymes, AChE, BChE, LPO and GST enzymes were evaluated. Rosmarinic acid inhibited these enzymes with Kis in the range between micromolar to picomolar. The best inhibitory effect of rosmarinic acid was observed against both AChE and BChE.
