POM analysis and related approaches are significant tools based on calculating various physico-chemical properties and predicting biological activity, ADME parameters, and toxicity of a molecule. These methods are used to evaluate a molecule's potential to become a drug candidate. Avenanthramides (AVNs) are promising secondary metabolites specific to Avena spp. (oat). They comprise the amides of anthranilic acid linked to various polyphenolic acids with or without post-condensation molecule transformation. These natural compounds have been reported to exert numerous biological effects, including antioxidant, anti-inflammatory, hepatoprotective, antiatherogenic, and antiproliferative properties. To date, almost 50 various AVNs have been identified. We performed a modified POM analysis of 42 AVNs using MOLINSPIRATION, SWISSADME, and OSIRIS software. The evaluation of primary in silico parameters revealed significant differences among individual AVNs, highlighting the most promising candidates. These preliminary results may help coordinate and initiate other research projects focused on particular AVNs, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives.
- Publikační typ
- časopisecké články MeSH
Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC50 from 0.58 to 31 μM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC50 = 0.58 μM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) demonstrated efficacy in the IC50 range from 2.0 to 4.3 μM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-BlueTM NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising Plasmodium selective substances for further investigations.
- MeSH
- antagonisté kyseliny listové * MeSH
- antimalarika * farmakologie MeSH
- chlorochin farmakologie MeSH
- lidé MeSH
- tropická malárie * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Biogenic amines are low-molecular-weight nitrogen compounds that are formed primarily by the decarboxyla-tion of amino acids by microbial enzymes. These active substances are found mainly in various types of food or beverages. At certain concentrations, biogenic amines are essential for many physiological functions but toxic if consumed in large quantities. Therefore, the development and optimization of methods sensitive to determine these substances are very much needed. The determination of biogenic amines in food and beverages by the most com-monly used separation methods with different types of detection is covered in this review.
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.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- analýza hlavních komponent MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie MeSH
- inhibiční koncentrace 50 MeSH
- karbamáty farmakologie MeSH
- kyselina aminosalicylová chemie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- nádorové buněčné linie MeSH
- racionální návrh léčiv MeSH
- rozpouštědla MeSH
- shluková analýza MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu * MeSH
- THP-1 buňky MeSH
- viabilita buněk MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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-BlueTM 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.
- MeSH
- ampicilin farmakologie MeSH
- analýza hlavních komponent MeSH
- antiflogistika farmakologie MeSH
- cinnamáty chemická syntéza MeSH
- inhibiční koncentrace 50 MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků MeSH
- mikrobiální testy citlivosti MeSH
- mikrovlny MeSH
- molekulární modely MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- NF-kappa B metabolismus MeSH
- Staphylococcus aureus účinky léků MeSH
- THP-1 buňky MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
