A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

• Keywords
• 4-aminosalicylanilides, CoMSA, carbamate synthesis, cholinesterase inhibition, lipophilicity, molecular docking, similarity-activity landscape index,
• MeSH
• Acetylcholinesterase chemistry   metabolism   MeSH
• Principal Component Analysis MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   MeSH
• Inhibitory Concentration 50 MeSH
• Carbamates pharmacology   MeSH
• Aminosalicylic Acid chemistry   MeSH
• Humans MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Cell Line, Tumor MeSH
• Drug Design MeSH
• Solvents MeSH
• Cluster Analysis MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation * MeSH
• THP-1 Cells MeSH
• Cell Survival MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Carbamates MeSH
• Aminosalicylic Acid MeSH
• Ligands MeSH
• Solvents MeSH

A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 µM) against MRSA isolates than the commonly used ampicillin (MIC 45.8 µM). The screening of the cell viability was performed using THP1-Blue™ NF-κB cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)-3-phenylprop-2-enamide (IC50 6.5 µM), none of the discussed compounds showed any significant cytotoxic effect up to 20 μM. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pKa calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping.

• Keywords
• IVE-PLS, MTT assay, PCA, antistaphylococcal activity, cinnamamides, cytotoxicity, lipophilicity, quantitative structure-property relationships, synthesis,
• MeSH
• Ampicillin pharmacology   MeSH
• Principal Component Analysis MeSH
• Anti-Inflammatory Agents pharmacology   MeSH
• Cinnamates chemical synthesis   MeSH
• Inhibitory Concentration 50 MeSH
• Hydrogen-Ion Concentration MeSH
• Humans MeSH
• Methicillin-Resistant Staphylococcus aureus drug effects   MeSH
• Microbial Sensitivity Tests MeSH
• Microwaves MeSH
• Models, Molecular MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• NF-kappa B metabolism   MeSH
• Staphylococcus aureus drug effects   MeSH
• THP-1 Cells MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Inflammation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ampicillin MeSH
• Anti-Inflammatory Agents MeSH
• cinnamamide MeSH Browser
• Cinnamates MeSH
• NF-kappa B MeSH

A series of twenty-two novel N-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxy- naphthalene-2-carboxamide showed submicromolar (MICs 0.16-0.68 µM) activity against methicillin-resistant Staphylococcus aureus isolates. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against M. tuberculosis (both MICs 10 µM) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with N-[4-bromo-3-(trifluoromethyl)phenyl]- and N-(4-bromo-3-fluorophenyl)-3-hydroxynaphthalene-2-carboxamides against MRSA SA 630 isolate. The similarity-related property space assessment for the congeneric series of structurally related carboxamide derivatives was performed using the principal component analysis. Interestingly, different distribution of mono-halogenated carboxamide derivatives with the -CF3 substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coefficients indicated the structural dissimilarities of dichloro- and dimetoxy-substituted isomers from the remaining ones. Moreover, the quantitative sampling of similarity-related activity landscape provided a subtle picture of favorable and disallowed structural modifications that are valid for determining activity cliffs. Finally, the advanced method of neural network quantitative SAR was engaged to illustrate the key 3D steric/electronic/lipophilic features of the ligand-site composition by the systematic probing of the functional group.

• Keywords
• CoMSA, IVE-PLS, MIC, MTT assay, antistaphylococcal activity, antitubercular activity, hydroxynaphthalenecarboxamides, lipophilicity, similarity-activity landscape index,
• MeSH
• Anti-Infective Agents chemical synthesis   MeSH
• Methicillin-Resistant Staphylococcus aureus * MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis * MeSH
• Naphthalenes chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Infective Agents MeSH
• Naphthalenes MeSH
• naphthalene-2-carboxamide MeSH Browser

A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The 'indirect' ligand-based and 'direct' protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an 'average' 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).

• Keywords
• CoMSA, IVE-PLS, in vitro cholinesterase inhibition, molecular docking, silicon-based carbamates, similarity-activity landscape index,
• MeSH
• Butyrylcholinesterase MeSH
• Chloroplasts MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Photosystem II Protein Complex MeSH
• Inhibitory Concentration 50 MeSH
• Carbamates chemistry   pharmacology   MeSH
• Silicon chemistry   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Docking Simulation MeSH
• Spinacia oleracea MeSH
• THP-1 Cells drug effects   MeSH
• Electron Transport drug effects   MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Photosystem II Protein Complex MeSH
• Carbamates MeSH
• Silicon MeSH
• Ligands MeSH

A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action.

• MeSH
• Apoptosis drug effects   MeSH
• DNA metabolism   MeSH
• Doxorubicin pharmacology   MeSH
• HCT116 Cells MeSH
• Intercalating Agents pharmacology   MeSH
• Small Molecule Libraries chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Naphthols chemical synthesis   chemistry   pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Design * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-naphthol MeSH Browser
• calf thymus DNA MeSH Browser
• DNA MeSH
• Doxorubicin MeSH
• Intercalating Agents MeSH
• Small Molecule Libraries MeSH
• Tumor Suppressor Protein p53 MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure⁻activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host⁻target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

• Keywords
• CoMSA, IVE-PLS, benzene-based carbamates, in vitro cholinesterase inhibition, molecular docking study,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Principal Component Analysis MeSH
• Benzene chemical synthesis   chemistry   pharmacology   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Electrophorus MeSH
• Inhibitory Concentration 50 MeSH
• Carbamates chemical synthesis   chemistry   pharmacology   MeSH
• Horses MeSH
• Ligands MeSH
• Probability MeSH
• Drug Design MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Benzene MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Carbamates MeSH
• Ligands MeSH

Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.

• Keywords
• Franz diffusion cell, HPLC determination, cytotoxicity, permeation, piperazine-2,5-diones, skin, theophylline,
• MeSH
• Skin Absorption * MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Permeability MeSH
• Piperazine chemistry   pharmacokinetics   MeSH
• Theophylline chemistry   pharmacokinetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Piperazine MeSH
• Theophylline MeSH