Investigating spectrum of biological activity of 4- and 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides

In this study, a series of twenty-two 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides and ten 4-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides is described. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against mycobacterial, bacterial and fungal strains. They were also evaluated for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The compounds showed biological activity comparable with or higher than the standards isoniazid, fluconazole, penicillin G or ciprofloxacin. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.     

Photosynthesis-Inhibiting Activity of N-(Disubstituted-phenyl)-3-hydroxynaphthalene-2-carboxamides

A set of twenty-four 3-hydroxynaphthalene-2-carboxanilides, disubstituted on the anilide ring by combinations of methoxy/methyl/fluoro/chloro/bromo and ditrifluoromethyl groups at different positions, was prepared. The compounds were tested for their ability to inhibit photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. N-(3,5-Difluorophenyl)-, N-(3,5-dimethylphenyl)-, N-(2,5-difluorophenyl)- and N-(2,5-dimethylphenyl)-3-hydroxynaphthalene-2-carboxamides showed the highest PET-inhibiting activity (IC₅₀ ~ 10 µM) within the series. These compounds were able to inhibit PET in photosystem II. It has been found that PET-inhibiting activity strongly depends on the position of the individual substituents on the anilide ring and on the lipophilicity of the compounds. The electron-withdrawing properties of the substituents contribute towards the PET activity of these compounds.     

Synthesis and characterization of (Z)-5-arylmethylidene-rhodanines with photosynthesis-inhibiting properties

A series of rhodanine derivatives was prepared. The synthetic approach, analytical and spectroscopic data of all synthesized compounds are presented. Lipophilicity of all the discussed rhodanine derivatives was analyzed using the RP-HPLC method. The compounds were tested for their ability to inhibit photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and reduce chlorophyll content in freshwater alga Chlorella vulgaris. Structure-activity relationships between the chemical structure, physical properties and biological activities of the evaluated compounds are discussed. For majority of the tested compounds the lipophilicity of the compound and not electronic properties of the R1 substituent were decisive for PET-inhibiting activity. The most potent PET inhibitor was (5Z)-5-(4-bromobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (IC(50) = 3.0 μmol/L) and the highest antialgal activity was exhibited by (5Z)-5-(4-chlorobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (IC(50) = 1.3 μmol/L).     

5-Bromo- and 3,5-dibromo-2-hydroxy-N-phenylbenzamides — inhibitors of photosynthesis

5-Bromo-(Br-PBA) and 3,5-dibromo-2-hydroxy-N-phenylbenzamides (Br₂-PBA) inhibited photosynthetic electron transport (PET) and their inhibitory efficiency depended on the compound lipophilicity as well as on the electronic properties of the R substituent in the N-phenyl moiety. Br-PBA showed higher PET inhibiting activity than Br₂-PBA with the same R substituent. The most effective inhibitors in the tested series were the derivatives with R = 3-F (Br-PBA; IC₅₀ = 4.3 μmol dm^?3) and R = 3-Cl (Br₂-PBA; IC₅₀ = 8.6 μmol dm^?3). Bilinear dependence of the PET inhibiting activity on the lipophilicity of the compounds as well as on the Hammett constant, σ, of the R substituent was observed for both investigated series. Using EPR spectroscopy it was found that the site of action of the tested compounds in the photosynthetic apparatus is situated on the donor side of PS 2, in D^· or in the Z^·/D^· intermediates. Interaction of the studied compounds with chlorophyll a and aromatic amino acids present in the pigment-protein complexes mainly in photosystem 2 was documented by fluorescence spectroscopy.     

Synthesis, antimycobacterial, antifungal and photosynthesis-inhibiting activity of chlorinated N-phenylpyrazine-2-carboxamides

A series of sixteen pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings was synthesized by the condensation of chlorides of substituted pyrazinecarboxylic acids with ring-substituted (chlorine) anilines. The prepared compounds were characterized and evaluated for their antimycobacterial and antifungal activity, and for their ability to inhibit photosynthetic electron transport (PET). 6-Chloro-N-(4-chlorophenyl)pyrazine-2-carboxamide manifested the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 6-chloro-5-tert-butyl-N-(3,4-dichlorophenyl)pyrazine-2-carboxamide (MIC=62.5 μmol/L). 6-chloro-5-tert-butyl-N-(4-chlorophenyl)pyrazine-2-carboxamide showed the highest PET inhibition in spinach chloroplasts (Spinacia oleracea L.) chloroplasts (IC50=43.0 μmol/L). For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.     

Lipophilicity analysis of newly synthetized quinobenzothiazines by use of TLC

Lipophilicity is a very important property of chemical compound taking into consideration in drugs design. Relationships between biological activity, among others lipophilicity, and chemical structure (QSAR) of the compound are very often used by researches. Especially important is the kind of substituents connected to the basic structural fragment and how it changes the lipophilicity of the compound. The aim of this study was to determine the parameters of lipophilicity of quinobenzothiazine derivatives using reversed phase - thin-layer chromatography (RP-TLC), which would enable one to determine the structure–activity relationship. The objective of our work is a series of 15 newly synthetized quinobenzothiazines. They were analyzed by thin-layer chromatography (TLC) with the use of two different mobile phases consisting of methanol or acetone as organic modifiers. For all compounds investigated, the values of lipophilicity obtained from computational method were also determined. Cluster analysis was carried out too for all data of lipophilicity obtained. Low correlation was found between values of experimental lipophilicity and lipophilicity from computational methods for newly synthetized compounds.     

Relationships between structure, retention and biological activity of some Schiff base ligands and their complexes

The lipophilicity of a series of Schiff base ligands and their complexes with nickel(II) and copper(II) has been determined by reversed-phase thin-layer chromatography using binary dioxane-water mobile phase. Chelate ligands were prepared by condensation of diamine and the corresponding beta-diketone. Copper(II) and nickel(II) complexes with chelate ligands containing ethane-1,2-diamine or propane-1,2-diamine as the amine part and pentane-2,4-dione and/or 1-phenylbutane-1,3-dione, pentane-2,4-dione and/or 1,1,1-trifluoropentane-2,4-dione, or 1,1,1-trifluoropentane-2,4-dione and/or 1-phenylbutane-1,3-dione as the beta-diketone part were synthesized. Some of investigated compounds were screened for their in vitro antifungal activity against Sacharomyces cerevisiae and antibacterial activity against Escherichia coli. Chromatographically obtained lipophilicity parameters were correlated both with calculated n-octanol-water partition coefficient C log P and antimicrobial activities. Satisfactory correlations were obtained. Chromatographic data proved to be reliable parameters for describing the lipophilic properties of the investigated compounds. Additionally, the principal components analysis was performed on the data chromatographically obtained. This statistical method was useful for distinguishing compounds and objective comparison of their lipophilicity parameters.     

Studies on 8-methoxyquinolones: synthesis and antibacterial activity of 7-(3-amino-4-substituted)pyrrolidinyl derivatives

A series of 8-methoxyquinolones bearing 3-amino-4-methylpyrrolidines or 3-amino-4-fluoromethylpyrrolidines at the C-7 position was synthesized and their physicochemical and biological properties were evaluated. All of the compounds synthesized showed more potent activity than LVFX (3) against both gram-positive and negative bacteria. Increases in lipophilicity of these compounds had desirable effects on their potency of single intravenous toxicity and pharmacokinetic profiles in animals. Among the compounds synthesized, 1-fluorocyclopropyl derivatives 17 and 20, and 7-(cis-3-amino-4-fluoromethylpyrrolidinyl) derivative 19 (DC-756h) showed negative responses in the micronucleus test in mice while 1-cyclopropyl-7-(3-aminopyrrolidinyl) derivative 16 showed a positive response. These results suggested that the introduction of a fluorine atom into the 3-aminopyrrolidinyl substituent resulted in favorable influence on genetic toxicity as well as into the N-1 cyclopropyl substituent.     

Relationships between LC retention, octanol-water partition coefficient, and fungistatic properties of 2-(2,4-dihydroxyphenyl)benzothiazoles

The retention behavior of newly synthesized compounds with antimycotic activity from the 2-(2,4-dihydroxyphenyl)benzothiazole group by high-performance liquid chromatography has been investigated. RP-18 stationary phase and methanol-acetate buffer aqueous mobile phases at pH 4 and 7.4 have been used. In the case of the mobile phase at pH 7.4, higher concentrations of water can be applied than at pH 4. The studied compounds showed regular retention behavior, their log k values decreasing linearly with an increasing concentration of methanol in the mobile phase. On the basis of these relationships, the lipophilicity (log kw), specific hydrophobic surface area (S), and isocratic chromatographic hydrophobicity index (psi0) were determined. Similar log kw values and sensitivity to changes in the structure of compounds studied for both mobile phases have been found. Moderate correlations between the chromatographic parameters and the calculated octanol-water log P values were found. Finally, the lipophilicity parameters were compared with the fungistatic properties of compounds expressed by log MIC (minimum inhibitory concentration) values to find quantitative structure activity relationship equations.     

Synthesis and characterization of two homologous series of diastereomeric 2-alkoxyphenylcarbamates

Two homologous series of racemic diastereomeric cis- and trans-(2-dimethylaminomethylcycloheptyl)-2-alkoxyphenylcarbamates with alkyl chain lengths ranging from C? to C? were synthesized by stereoselective reactions. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR and IR spectroscopy and their physico-chemical properties were characterized. The two new series of diastereomeric compounds were tested for their local anesthetic activity and parabolic relationship between the local anesthetic activity and lipophilicity was found for both cis- and trans-series. Interestingly, cis-stereoisomers exhibited higher local anesthetic activity.     

Investigating the spectrum of biological activity of substituted quinoline-2-carboxamides and their isosteres

In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethyl)quinoline-2-carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonyl)quinoline and 1-(2-naphthoyl)pyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC(50) value of the most active compound N-benzyl-2-naphthamide was 7.5 μmol/L. For all compounds, the structure-activity relationships are discussed.     

A novel series of thromboxane A2 synthetase inhibitors with free radical scavenging and anti-peroxidative activities

A novel series of indoline derivatives with imidazole and carboxyl moieties were synthesized and evaluated for their thromboxane A2 (TXA2) synthetase inhibiting, radical scavenging and anti-peroxidative activities. Among the compounds synthesized, 3-[5-substituted-3-[2-(imidazol-1-yl)ethyl]indolin-1-yl]propionic acids showed free radical scavenging activity and inhibitory effects on lipid-peroxidation of rat brain homogenate and on arachidonate-induced TXA2-dependent aggregation of rabbit platelets. The anti-platelet and anti-peroxidative activities were related to the lipophilicity of the 5-substituent. The 5-hexyloxy derivative (13) showed about 35-fold higher inhibitory activity on TXA2 synthesis than that of ozagrel and about 100-fold higher activity on lipid peroxidation than that of alpha-tocopherol. Compound 13 showed in vivo anti-thrombotic effect in mice and ex vivo anti-peroxidative activity in rats.     

叔丁氧羰基二肽胺磷酸对碘苯酚酯的生物性质研究

采用细胞结合实验对配合物叔丁氧羰基二肽胺磷酸对碘(131I)苯酚酯的体外生物活性进行了评价,结果表明标记抗原保持了原来的亲和力,在标记等操作过程中未受到明显损伤;对配合物进行了稳定性、亲脂性、急性毒性的考察,结果显示配合物的结构和性能比较稳定,三天后的脱碘率为12%左右、是亲脂性的、毒性低;成功建立了VX2肝癌单发肿瘤动物模型,得到了配合物在正常小鼠和肿瘤大白兔体内的分布结果.     

Acetylcholinesterase-Inhibiting Activity of Salicylanilide <em>N</em>-Alkylcarbamates and Their Molecular Docking

A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'_(3,4) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'₍₄₎ exhibited slightly more effective AChE inhibitors than in C'₍₃₎. Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.     

A new group of potential antituberculotics: <Emphasis Type="Italic">N</Emphasis>-(2-pyridylmethyl)salicylamides and <Emphasis Type="Italic">N</Emphasis>-(3-pyridylmethyl)salicylamides

As a part of our systematic study of antimycobacterially active derivatives of salicylamides, a series of nineteen derivatives of N-(2-pyridylmethyl)salicylamides and N-(3-pyridylmethyl)salicylamides was synthesised. The compounds exhibited in vitro activity against Mycobacterium tuberculosis and M. avium. Their lipophilicity, R _M, was measured by thin layer chromatography on silica gel impregnated with trioctadecylsilane and the logarithm of the partition coefficient (octanol-water), logP, was calculated. Both the parameters of lipophilicity correlated. The quantitative relationship between the structure and antimycobacterial activity was calculated. Antimycobacterial activity increased with an increase in lipophilicity. The N-(2-pyridylmethyl)salicylamide derivatives were more active than the derivatives of isomeric N-(3-pyridylmethyl)salicylamides. The geometry of compounds was calculated and the calculation was verified by measuring the length of the hydrogen bond between hydroxyl and carbonyl groups on the salicylic moiety.     

Novel 4-substituted 2-piperazinylquinazolines as potent anticonvulsive and antihypoxic agents

Several types of quinazoline derivatives were prepared and examined for anticonvulsive and antihypoxic activities. Many compounds showed potent anticonvulsive activity, and their anticonvulsive profile is similar to that of phenytoin. The analysis of quantitative structure-activity relationships indicated that the anticonvulsive activity was parabolically related to the lipophilicity of the compounds. Most of the 4-alkoxyquinazolines showed potent anticonvulsive and antihypoxic activities. It is confirmed that there is a good correlation between the potencies of these activities.     

Estimation of the lipophilicity of antiarrhythmic and antihypertensive active 1-substituted pyrrolidin-2-one and pyrrolidine derivatives

The lipophilicity of some antiarrhythmic and antihypertensive active 1-[2-hydroxy- or 1-[2-acetoxy-3-(4-aryl-1-piperazinyl)propyl]pyrrolidin-2-one derivatives (1-12) has been investigated. Their lipophilicity (R(MO) and log k') was determined by reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography with mixtures of acetonitrile and Tris buffer as mobile phases. The partition coefficients of compounds 1-12 (log P(ScilogP)) were also calculated with the ScilogP program. Comparison of R(MO), log k' and calculated log D(7.0 ScilogP) values enabled calculation of clog D(7.0 TLC) and clog D(7.0 HPLC) values. Preliminary quantitative structure-activity relationship studies indicated that for active compounds there is a dependence between affinity for alpha(2)-adrenoceptors and their clog D(7.0 HPLC) values.     

Synthesis and photosynthetic inhibition activity of substituted 5-(bis-trifluoromethyl)methyl)-2-aminothiazoles

The reaction of 5,5,5-trifluoro-4-trifluoromethyl-pent-3-en-2-one with aminothiocarbonyls yielded aminothiourea precursors which readily cyclised to the corresponding thiazole derivatives, 5-(bis-trifluoromethyl)methyl)-2-aminothiazoles. The inhibitory potency of photosystem II activity of these thiazoles was evaluated using fluorescence measurement techniques. Two of the compounds showed a good activity in comparison with the reference compound DCMU, 3-(3,4-dichlorophenol)-1,1-dimethylurea. Calculation of lipophilicity according to Rekker and Frey, and a corresponding experimental determination are reported.     

Application of thin-layer chromatographic data in quantitative structure-activity relationship assay of thiazole and benzothiazole derivatives with H1-antihistamine activity. II

Quantitative structure-activity relationship (QSAR) analysis of H1-antihistamine activity was carried out and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine, 2-(2-benzyl-4-thiazolyl)ethanamine, 2-(2-benzhydrylthiazol-4-yl)ethylamine derivative, and 2-(1-piperazinyl- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives were obtained. Normal-phase (NP) TLC plates (silica gel 60F254), impregnated with solutions of selected amino acid mixtures (L-Asp, L-Asn, L-Thr and L-Lys) were used in two developing solvents as human histamine H1-receptor (hH1R) antagonistic interaction models. The lipophilicity data of the examined compounds were obtained and used in the QSAR assay. Using regression analysis, relationships between chromatographic and biological activity data were found. The correlations obtained in the present experiment with NP-TLC are more significant that those obtained in the experiment with RP2 TLC, because of the optimal fitting of the chromatographic system conditions to the lipophilicity of solutes. All proposed chromatographic models should facilitate pre-selection of the new drug candidates. The correlations of calculated pA2(H1) values of the tested compounds predicted by the use of the best equations versus their pA2(H1) obtained from the biological tests were significant (R2 = 0.91-0.94).     

Preparation and antiplatelet activity of glycidic acid derivatives

Arylalkanoic acid derivatives exhibit a variety of biological effects. In the current publication some of new glycidic acid derivatives were prepared via the Darzens condensation. The synthetic approach, analytical and spectroscopic data of all newly synthesized compounds are presented. The prepared compounds were evaluated as potential inhibitors of arachidonic acid-induced platelet aggregation and their activity was compared with that of acetylsalicylic acid as the standard. (±)-Ethyl 3-{4-[(4-methoxyphenyl)sulfanyl]phenyl}-3-methyl-cis-oxirane-2-carboxylate (IC₅₀ = 0.07 mmol L⁻¹) and (±)-3-{4-[(4-methoxyphenyl)sulfanyl]phenyl}-3-methyl-cis-oxirane-2-carboxylic acid (IC₅₀ = 0.06 mmol L⁻¹) showed the highest antiplatelet activity against arachidonic acid-induced platelet aggregation comparable with the standard. Structure-activity relationships between the chemical structure, lipophilicity, and the antiplatelet activity of the evaluated compounds are discussed.