Most cited article - PubMed ID 31671776
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors
A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 µM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.
- Keywords
- CoMSA, arginase inhibition, arylcinnamamides, lipophilicity, molecular docking, similarity-activity landscape index,
- MeSH
- Antimalarials * pharmacology MeSH
- Arginase pharmacology MeSH
- Chloroquine pharmacology MeSH
- Plasmodium falciparum MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antimalarials * MeSH
- Arginase MeSH
- Chloroquine MeSH
The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.
A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl-4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using 1H, 13C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain Staphylococcus aureus ATCC 29213, three clinical isolates of methicillin-resistant S. aureus (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends.
- Keywords
- antibacterial activity, antiproliferative activity, azaphenothiazines, lipophilicity, pharmacophore mapping, phenothiazine, similarity-activity landscape index,
- MeSH
- Anti-Bacterial Agents chemistry pharmacology MeSH
- Phenothiazines chemistry MeSH
- Heterocyclic Compounds chemistry MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Tumor Cells, Cultured MeSH
- Neoplasms drug therapy MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Staphylococcus aureus drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anti-Bacterial Agents MeSH
- Phenothiazines MeSH
- Heterocyclic Compounds MeSH
- Antineoplastic Agents MeSH
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.
- Keywords
- PET inhibition, hydroxynaphthalene-carboxamides, spinach chloroplasts, structure-activity relationships,
- MeSH
- Chloroplasts drug effects metabolism MeSH
- Photosynthesis drug effects MeSH
- Photosystem II Protein Complex antagonists & inhibitors metabolism MeSH
- Herbicides chemistry metabolism MeSH
- Naphthalenes chemistry metabolism MeSH
- Spinacia oleracea drug effects metabolism MeSH
- Electron Transport drug effects MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Photosystem II Protein Complex MeSH
- Herbicides MeSH
- Naphthalenes MeSH
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
