thiourea and coumarin

Hybrid drugs featuring two or more potentially bioactive pharmacophores have been recognized as advanced and superior chemical entities to simultaneously modulate multiple drug targets of multifactorial diseases, thus overcoming the severe side effects associated with a single drug molecule. The selection of these chemical moieties to produce hybrid structures with druggable properties is generally facilitated by the observed and/or anticipated synergistic pharmacological activities of the individual molecules. In this perspective, coumarin template has extensively been studied in pursuit of structurally diverse leads for drug development due to high affinity and specificity to different molecular targets. This review highlights the most commonly exploited approaches conceptualizing the design and construction of hybrid molecules by coupling two or more individual fragments with or without an appropriate linker. In addition to the design strategies, this review also summarizes and reflects on the therapeutic potential of these hybrid molecules for diverse enzyme inhibitory action as well as their observed structure-activity relationship (SAR). Several key features of the synthesized hybrid structures that assert a profound impact on the inhibitory function have also been discussed alongside computational investigations, inhibitor molecular diversity and selectivity toward multiple drug targets. Finally, these drug discovery and development efforts should serve as a handy reference aiming to provide a useful platform for the exploration of new coumarin-based compounds with enhanced enzyme inhibitory profile.

Topics: Aldehyde Reductase; Alkaline Phosphatase; Cholinesterases; Coumarins; Drug Design; Enzymes; Glucosidases; Humans; Molecular Docking Simulation; Monoamine Oxidase

The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets.. All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively.. In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier.. Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.

Topics: Animals; Blood-Brain Barrier; Cholinesterase Inhibitors; Coumarins; Humans; Kinetics; Models, Molecular; Molecular Docking Simulation; Permeability; Structure-Activity Relationship; Tacrine; Thiourea

A new method has been developed for the organocatalytic enantioselective benzylation and aldol-hemiacetalization of α,β-unsaturated trifluoromethyl ketones with toluene derivatives in the presence of a tertiary amine-thiourea catalyst. This method represents a facile and efficient strategy for the asymmetric synthesis of optically active 3,4-dihydroisocoumarins bearing a trifluoromethylated tetrasubstituted carbon stereocenter with high enantioselectivity. Notably, this strategy was used to synthesize several chiral trifluoromethylated analogues of typharin with high efficiency.

Topics: Aldehydes; Amines; Carbon; Catalysis; Coumarins; Crystallography, X-Ray; Isocoumarins; Ketones; Molecular Conformation; Stereoisomerism; Thiourea; Toluene

Mechanistic investigations of the intermolecular [2+2] photocycloaddition of coumarin with tetramethylethylene mediated by thiourea catalysts reveal that the reaction is enabled by a combination of minimized aggregation, enhanced intersystem crossing, and altered excited-state lifetime(s). These results clarify how the excited-state reactivity can be manipulated through catalyst-substrate interactions and reveal a third mechanistic pathway for thiourea-mediated organo-photocatalysis.

Topics: Alkenes; Catalysis; Coumarins; Cycloaddition Reaction; Light; Models, Molecular; Photochemical Processes; Thiourea

Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.

Topics: Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Thiourea

New coumarin-based chiral thiourea sensor 1 was found to be an enantioselective fluorescent chemosensor for N-Boc-protected proline. The chiral sensor shows lower background fluorescence, and higher fluorescence enhancement with 18 nm blue shifts. Job plot analysis result indicates that sensor 1 can form a 1 : 1 stoichiometric complex and it could be used as a fluorescence sensor for the determination of enantiomer composition of N-Boc-protected proline.

Topics: Coumarins; Fluorescent Dyes; Molecular Structure; Proline; Stereoisomerism; Thiourea

For detection of Hg(2+) and Ag(+), we have developed a coumarin-based probe with an N'-acetylthioureido group as a novel fluorescence switch, in which the hydrogen bond formation between the N-hydrogen and the acetyl O atom markedly increases the susceptibility of the probe toward desulfurization by Hg(2+) and Ag(+).

Topics: Acetylation; Acids; Buffers; Coumarins; Fluorescence; Fluorescent Dyes; Hydrogen Bonding; Hydrogen-Ion Concentration; Limit of Detection; Mercury; Sensitivity and Specificity; Silver; Spectrometry, Fluorescence; Sulfur; Thiourea; Water Pollutants, Chemical

Fluorescence enhancement by factors of 5-12 times 8-alkyl thiourido-7-ethoxy-4-methyl coumarin derivatives was observed upon complexation with Hg(2+), Ag(+), and Ag nanoparticles. The study reveals a chelation-enhanced fluorescence (CHEF) mechanism with the formation of 1:2 complexes in Hg(2+)/coumarin derivatives and 1:1 complexes in Ag(+)/coumarin derivatives. The activation parameters of the complexation processes were evaluated with energy of activation values in the case of Ag(+) being nearly twice those in the case of Hg(2+) complexation. Isokinetic studies indicate an enthalpy-controlled mechanism in the Hg(2+)/coumarin derivatives complex formation. No fluorescence enhancement was observed with Fe(3+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), La(3+), and Ce(3+), making the present coumarin thiourea derivatives selective chemosensors of both Hg(2+) and Ag(+) ions with different complexation time scales between these two ions. Fluorescence enhancement of the studied coumarin thiourea derivatives using silver nanomaterials occurs almost instantaneously and can be induced by silver nanoparticles in the picomolar (pM) concentration ranges.

Topics: Coumarins; Fluorescence; Mercury; Metal Nanoparticles; Molecular Structure; Silver; Thermodynamics; Thiourea

Topics: Catechol Oxidase; Coumarins; Humans; Lactuca; Oxidoreductases; Seeds; Thiourea; Vegetables

Topics: Coumarins; Thiourea