Diethyl 2-(Phenylcarbamoyl)phenyl Phosphorothioates: Synthesis, Antimycobacterial Activity and  Cholinesterase Inhibition

Vinšová, Jarmila; Komloova, Marketa; Dadapeer, E.; Štěpánková, Šárka; Vorčáková, Katarína; Stolaříková, Jiřina

doi:10.3390/molecules19067152

Cited by 12 publications

(13 citation statements)

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“…Salicylanilide derivatives exhibit a wide range of interesting biological properties including inhibition of various enzymes [16,17,18,19,20,21,22]. Previously, we identified salicylanilide O , O -diethyl thiophosphates (phosphorothioates) [23] and their oxo analogues (diethyl phosphates) [24] as pseudo-irreversible inhibitors of both AChE and BChE with low micromolar IC 50 values. Interestingly, thiophosphates exhibited the balanced activity against both cholinesterases [23] whereas phosphates showed more effective inhibition of BChE [24].…”

Section: Introductionmentioning

confidence: 99%

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

et al. 2016

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Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2- [(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,Ndiphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

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Section: Introductionmentioning

confidence: 99%

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

et al. 2016

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“…Surprisingly, salicylanilide diethyl phosphates 1-27 showed significantly weaker inhibition of AChE than their sulphur isosters, salicylanilide diethyl thiophosphates (phosphorothioates). For BChE, the average activity was higher in the case of thiophosphates, but six phosphates (19,20,22,24,25, and 26) exhibited lower IC 50 values than all thiophosphates [22].…”

Section: In Vitro Cholinesterases Inhibitionmentioning

confidence: 92%

“…Previously, two groups of salicylanilide derivatives have been reported as cholinesterases inhibitors -salicylanilide N-alkyl carbamates [21] and, more importantly, O,O-diethyl thiophosphates (phosphorothioates) which were described as potent inhibitors of both AChE and BChE with IC 50 values in the micromolar range [22]. The fact that organophosphate pesticides acting via ChE inhibition are more toxic than their thioforms [3] inspired us to the evaluation of salicylanilide diethyl phosphates (oxygen-isosteres of salicylanilide diethyl thiophosphates [22]) against both AChE a BChE.…”

Section: Introductionmentioning

confidence: 99%

“…All tested compounds 1-27 showed greater inhibition of AChE than rivastigmine but not galantamine, and six of them(19,20,22,(24)(25)(26) inhibited BChE more effectively than both drugs.Members of Group 2 (5-chloro derivatives synthesized from 4-chlorosalicylic acid) are more effective inhibitors of BChE (IC 50 s form 0.9 to 11.5 lM) than derivatives of Group 1 (10.3-68.3 lM).…”

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Salicylanilide diethyl phosphates as cholinesterases inhibitors

Krátký

Štěpánková

Vorčáková

2015

Bioorganic Chemistry

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“…Experiments were repeated at least two times [2,5,12,13,38,39]. All experiments with virulent human pathogen M. tuberculosis H 37 Rv were carried out in a bio-safety level 3 (BL-3) containment area at Korányi National Tuberculosis Hospital (Budapest, Hungary).…”

Section: Evaluation Of In Vitro Antimycobacterial Activity On Mycobacmentioning

confidence: 99%

Comparative analysis of new peptide conjugates of antitubercular drug candidates—Model membrane and in vitro studies

Ábrahám

Baranyai²,

Gyulai

et al. 2016

Colloids and Surfaces B: Biointerfaces

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Novel peptide conjugates of two antitubercular drug ca ndidates were s ynthesi s ed a nd cha ra cteri s ed us i ng new tufts i n peptide derivatives (OT14) as carrier moiety. As antitubercular drug ca ndidates two pyridopyrimidine derivatives, TB803 (2-a l lylamino-4-oxopyrido[1,2-a]pyrimidine-3-carbaldehyde) a nd TB820 (4-oxo-2-(pyrroli di n-1-yl )-pyri do[1,2-a ]pyri mi di n-3-ca rba ldehyde) inhibiting vi tal enzyme of Mycobacterium tuberculosis were applied. Membrane affini ty of the compounds TB803 a nd TB820 a nd their peptide conjugates wa s eva l ua ted us i ng experi menta l l i pi d mono -a nd bi l a yer model s . Penetration ability was assessed tensiometrically from La ngmuir monolayer study a nd a pplying quartz crys tal microbalance for the s upported l ipid bilayer (SLB) system. Mi nimal inhibitory concentration (MIC) values remained in a similar micromolar ra nge for both of the conjugates whi l e thei r cel l ul a r upta k e ra te wa s i mproved s i gni fi ca ntl y compa red to the drug ca ndidates. A correlation was found between membrane affinity properties a nd results of in vitro bi ological i nvestiga ti ons . Ana l ysis of physical/structural properties of SLB in contact with bioactive components and vi s ua l i za ti on of the s tructura l cha nge by a tomic-force microscopy (AFM) provi ded i nformation on the type and route of mol ecul a r i ntera cti on of drug cons truction with lipid l ayers. The possible role of electrostatic i nteractions between lipid layer a nd drug ca ndi da tes wa s tes ted in Langmuir-balance experiments using nega ti vel y cha rged l i pi d mi xture (DPPC+DPPG). Es peci a l l y the pepti de conjugates presented i ncreased membrane affinity due to ca tionic cha ra cter of the pepti de s equence s el ected for the conjugate formation. That is supposed to be one reason for the enhanced cellular uptake observed in vitro for MonoMa c6 cel l line. The conjugation of a ntitubercular a gents to a peptidic ca rrier i s a promi s i ng a pproa ch to enha nce membra ne a ffi ni ty, cel l ul a r upta ke ra te a nd in vitro s el ecti vi ty.

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Diethyl 2-(Phenylcarbamoyl)phenyl Phosphorothioates: Synthesis, Antimycobacterial Activity and Cholinesterase Inhibition

Cited by 12 publications

References 15 publications

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

Salicylanilide diethyl phosphates as cholinesterases inhibitors

Comparative analysis of new peptide conjugates of antitubercular drug candidates—Model membrane and in vitro studies

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