Vladimír Pejchal

Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors

A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound.

1,3-substituted imidazolidine-2,4,5-triones: synthesis and inhibition of cholinergic enzymes.

A series of novel and highly active acetylcholinesterase and butyrylcholinesterase inhibitors derived from substituted benzothiazoles containing an imidazolidine-2,4,5-trione moiety were synthesized and characterized. The molecular structure of 1-(2,6-diisopropyl-phenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-imidazolidine-2,4,5-trione (3g) was determined by single-crystal X-ray diffraction. Both optical isomers are present as two independent molecules in the triclinic crystal system. The lipophilicity of the compounds was determined as the partition coefficient log Kow using the traditional shake-flask method. The in vitro inhibitory activity on acetylcholinesterase from electric eel and butyrylcholinesterase isolated from equine serum was determined. The inhibitory activity on acetylcholinesterase was significantly higher than that of the standard drug rivastigmine. The discussed compounds are also promising inhibitors of butyrylcholinesterase, as some of the prepared compounds inhibit butyrylcholinesterase better than the internal standards rivastigmine and galanthamine. The highest inhibitory activity (IC50 = 1.66 μmol/L) corresponds to the compound 1-(4-isopropylphenyl)-3-[(R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethyl]imidazolidine-2,4,5-trione (3d). For all the studied compounds, the relationships between the lipophilicity and the chemical structure as well as their structure-activity relationships are discussed.

Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors

In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, (1)H, (13)C, (19)F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimers disease.

Synthesis, structural characterization, antimicrobial and antifungal activity of substituted 6-fluorobenzo[d]thiazole amides

A series of novel 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl amides was synthesized by the condensation reaction of (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine with substituted benzoyl chlorides under mild conditions. Their structures were confirmed by 1H NMR, 13C NMR and 19F NMR spectra, elemental analyses and in three cases also by single-crystal X-ray diffraction techniques. The optical activities were confirmed by optical rotation measurements. All the synthesized compounds were screened for antibacterial and antifungal activity against a variety of bacterial and fungal strains. Some of the compounds reveal antibacterial and antifungal activity comparable or slightly better to that of chloramphenicol, cefoperazone and amphotericin B used as medicinal standards.

Salicylanilides and Their Derivates as Perspective Anti-tuberculosis Drugs: Synthetic Routes and Biological Evaluations

Abstract: Salicylanilides are a well-known family of pharmacological compounds, which are under renewed investigation because of the discovery of novel interesting biological activities and mechanisms of action over the last decade. This comprehensive mini-review de-scribes the biological and pharmacological properties of salicylanilides, their activity against atypical and multi-drug resist ant mycobacte-rial strains, and synthetic routes for their preparation. In particular, this review focuses on the synthesis and biological properties of sali-cylanilides and O -substituted derivates reported between 2000 and 2010, which have displayed the highest antituberculosis or antifungal activity. Keywords: Anti-MDR tuberculotics, anti-tuberculotic agents, hydroxybenzamides, salicylan ilides, salicylanilide derivates. 1. INTRODUCTION Salicylanilides ( N -substituted hydroxy benzamides) are well-known organic pharmacological compounds with numerous bio-logical activities, which were initially investigated for their antimi-crobial [1] and antifungal activities [2], as well as their usefulness as topical antimycotics and antiplaque agents [3]. Salicylanilides have also found use as molluscicidal [4] or anthelmintic agents [5] in human and veterinary practise. The most successful of these, 5,2´-dichloro-4´-nitrosalicylanilide (Niclosamide), is a member of a group of common molluscicides [6] with anthelmintic properties, and is also effective in the treatment of diphyllobothriasis and hy-menolepiasis [7]. Closantel is another broad-spectrum anthelmintic salicylanilide, which has been used as an anti-trematode, anti-nematode and anti-arthropod, in combination with benzimidazole anthelmintics such as Mebendazole [8]. Rafoxanide is highly active against

Triorganotin(IV) esters of 2-{[ N -(2-oxo-2H-naphthalene-1-yliden)hydrazo]}benzoic acid, instability of the cyclohexyl derivative

Three triorganotin(IV) esters of 2-{[N-(2-oxo-2H-naphthalene-1-yliden)hydrazo]}benzoic acid were prepared and studied by IR and NMR spectroscopy and X-ray crystallography for the tributyl- and triethyltin(IV)-2-{[N-(2-oxo-2H-naphthalene-1-yliden)hydrazo]}benzoates (2, 3). These compounds are monomeric in solution with four-coordinate tin. The hydrazo tautomeric forms are present in chloroform solution as well as in the solid state. The coordination geometries of tin in 2 and 3 are trigonal bipyramidal with all three carbons in equatorial positions, one carboxylic oxygen and the quinone-type oxygen from adjacent molecules are in axial positions forming centrosymmetric dimers with the ring containing 20 members. The yield of the tricyclohexyltin(IV) derivative (4) is much lower than 2 or 3, with instability towards moisture in solution. The product of the reaction with water is the bis(µ2-hydroxo)-bis{2-{[N-(2-oxo-2H-naphthalene-1-yliden)hydrazo]}benzoato}tetracyclohexylditin (4a) dimer. The tin is five-coordinate in the solid state by two cyclohexyl and two hydroxy groups, the last coordination site is occupied by a monodentate carboxy group. The dimeric form of this compound remains in chloroform solution.

Novel derivatives of substituted 6-fluorobenzothiazole diamides: synthesis, antifungal activity and cytotoxicity

A new series of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl diamides were synthesized in vitro as potential antifungal agents. Chemical structures of the synthesised compounds were substantiated by IR, 1H, 13C, 19F nuclear magnetic resonance spectra, high resolution mass spectrometry, elemental analysis and also by X-ray diffraction. In addition, the cytotoxicity of the most active compounds was investigated against cancer cell line (Jurkat) and one type of normal lung fibroblast cells (MRC-5) by (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) tetrazolium salt reduction assay, propidium iodide flow cytometry assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Compounds indicated as 11e, 11g, 11j, 11n and 11o, were the best of the series, showing minimum inhibitory concentration values of 6.25–50 μg/mL against pathogenic strains Candida albicans HE 169, Candida tropicalis 31/HK and Candida parapsilosis p69. Moreover compounds 11e, 11g, 11j and 11o did not show any cytotoxic effect against human Jurkat and MRC-5 cells.

Synthesis and characterization of pH-sensitive conjugate of isoniazid--methoxypoly(ethylene glycol)-b-poly(L-lysine).

The present paper deals with the preparation and characterization of a conjugate of isoniazid (INH) with the block copolymer methoxypoly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-PLL). The structure of the conjugate (mPEG-b-PLL-INH) was verified by means of (1)H NMR, GPC, infrared spectroscopy, elemental analysis and powder X-ray diffraction. The conjugate contains six l-lysine units with five INH molecules, which are attached by means of pH-sensitive amidine bond. Under in vitro conditions, the conjugate is hydrolyzed and isoniazid is released (pH 4; 37 °C; t(1/2) ≈ 10 h).

A Safe and Efficient Route for the Preparation of Nitro-, Dinitro-, and Trinitrophenyl Chloroformates

Abstract A safe and simple method has been developed for synthesis of chloroformates derived from 2-nitrophenol, 4-nitrophenol, 2,4-dinitrophenol, 2,4,6-trinitrophenol, and pentafluorophenol, the yields being in the range of 72–96%. The method is based on a heterogeneous reaction of the substituted phenol with phosgene dissolved in dichloromethane catalyzed with solid anhydrous potassium carbonate. The synthesis of 2,4,6-trinitrophenyl chloroformate takes place only in the presence of a phase-transfer catalyst, in this case the easily recovered α,ω-dimethoxy poly(ethylene glycol) (PEG; M = 2 kDa). The only waste products of the suggested synthesis of the mentioned esters are sodium chloride and potassium chloride. The method markedly reduces the explosion risk connected with drying and handling of salts of mono-, di-, and trinitrophenols and is much more environmentally friendly than the currently used methods. Supplemental materials are available for this article. Go to the publishers online edition of Synthetic Communications® to view the free supplemental file. GRAPHICAL ABSTRACT