25 research outputs found
Bioactivity of Methoxylated and Methylated 1-Hydroxynaphthalene-2-Carboxanilides: Comparative Molecular Surface Analysis
A series of twenty-six methoxylated and methylated N-aryl-1-hydroxynaphthalene-
2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular
structure of N-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound
was determined by single-crystal X-ray di raction. All the analysed compounds were tested against
the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S. aureus
as well as against Mycobacterium tuberculosis and M. kansasii. In addition, the inhibitory profile
of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts was specified.
In vitro cytotoxicity of the most e ective compounds was tested on the human monocytic leukaemia
THP-1 cell line. The activities of N-(3,5-dimethylphenyl)-, N-(3-fluoro-5-methoxy-phenyl)- and
N-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even
better than the commonly used standards ampicillin and isoniazid. All promising compounds
did not show any cytotoxic e ect at the concentration >30 M. Moreover, an in silico evaluation
of clogP features was performed for the entire set of the carboxamides using a range of software
lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity
(log k), in consensus lipophilicity estimation, was conducted as well. Principal component
analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity
(theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the
assessment of the three-dimensional quantitative structure–activity relationship profile were carried
out with the comparative molecular surface analysis to determine electron and/or steric factors that
potentially contribute to the biological activities of the investigated compounds
Towards intelligent drug design system: Application of artificial dipeptide receptor library in QSAR-oriented studies
The pharmacophore properties of a new series of potential purinoreceptor (P2X) inhibitors determined using a coupled neural network and the partial least squares method with iterative variable elimination (IVE-PLS) are presented in a ligand-based comparative study of the molecular surface by comparative molecular surface analysis (CoMSA). Moreover, we focused on the interpretation of noticeable variations in the potential selectiveness of interactions of individual inhibitor-receptors due to their physicochemical properties; therefore, the library of artificial dipeptide receptors (ADP) was designed and examined. The resulting library response to individual inhibitors was arranged in the array, preprocessed and transformed by the principal component analysis (PCA) and PLS procedures. A dominant absolute contribution to PC1 of the Glu attached to heptanoic gating acid and Phe bonded to the linker m-phenylenediamine/triazine scaffold was revealed by the PCA. The IVE-PLS procedure indicated the receptor systems with predominant Pro bonded to the linker and Glu, Gln, Cys and Val directly attached to the gating acid. The proposed comprehensive ligand-based and simplified structure-based methodology allows the in-depth study of the performance of peptide receptors against the tested set of compounds.NC
Two Decades of 4D-QSAR: A Dying Art or Staging a Comeback?
A key question confronting computational chemists concerns the preferable ligand geometry
that fits complementarily into the receptor pocket. Typically, the postulated ‘bioactive’ 3D
ligand conformation is constructed as a ‘sophisticated guess’ (unnecessarily geometry-optimized)
mirroring the pharmacophore hypothesis—sometimes based on an erroneous prerequisite. Hence,
4D-QSAR scheme and its ‘dialects’ have been practically implemented as higher level of model
abstraction that allows the examination of the multiple molecular conformation, orientation and
protonation representation, respectively. Nearly a quarter of a century has passed since the eminent
work of Hopfinger appeared on the stage; therefore the natural question occurs whether 4D-QSAR
approach is still appealing to the scientific community? With no intention to be comprehensive, a
review of the current state of art in the field of receptor-independent (RI) and receptor-dependent
(RD) 4D-QSAR methodology is provided with a brief examination of the ‘mainstream’ algorithms. In
fact, a myriad of 4D-QSAR methods have been implemented and applied practically for a diverse
range of molecules. It seems that, 4D-QSAR approach has been experiencing a promising renaissance
of interests that might be fuelled by the rising power of the graphics processing unit (GPU) clusters
applied to full-atom MD-based simulations of the protein-ligand complexes
Unsupervised Learning in Drug Design from Self-Organization to Deep Chemistry
The availability of computers has brought novel prospects in drug design. Neural networks
(NN) were an early tool that cheminformatics tested for converting data into drugs. However, the
initial interest faded for almost two decades. The recent success of Deep Learning (DL) has inspired a
renaissance of neural networks for their potential application in deep chemistry. DL targets direct
data analysis without any human intervention. Although back-propagation NN is the main algorithm
in the DL that is currently being used, unsupervised learning can be even more efficient. We review
self-organizing maps (SOM) in mapping molecular representations from the 1990s to the current
deep chemistry. We discovered the enormous efficiency of SOM not only for features that could be
expected by humans, but also for those that are not trivial to human chemists. We reviewed the DL
projects in the current literature, especially unsupervised architectures. DL appears to be efficient in
pattern recognition (Deep Face) or chess (Deep Blue). However, an efficient deep chemistry is still
a matter for the future. This is because the availability of measured property data in chemistry is
still limited
Proline-based carbamates as cholinesterase inhibitors
Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared
and completely characterized. All the compounds were tested for their in vitro ability to
inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of
compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all
the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the
compounds demonstrated insignificant toxicity. All the compounds showed rather moderate
inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate
(IC50 = 46.35 M) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and
benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity
(IC50 = 28.21 and 27.38 M, respectively) comparable with that of rivastigmine. The ortho-brominated
compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate
demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory
potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties
was provided using comparative molecular surface analysis (CoMSA) and principal component
analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test
subset was performed to monitor the statistical estimators performance in the effort to map the
probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile
revealed potentially relevant structural and physicochemical features that might be essential for
mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the
reaction site by the substituent in the 30-/40-position of the phenyl ring. In addition, the investigation
was completed by a molecular docking study of recombinant human AChE
Sektorowy formalizm porównawczej analizy powierzchni cząsteczkowej (s-CoMSA) - zastosowanie do modelowania zależności struktura-aktywność
Celem pracy jest: Opracowanie nowej metody obliczania deskryptorów cząsteczkowych s-CoMSA
(ang. sector-comparative molecular surface analysis); w metodzie tej przestrzeń
cząsteczkowa jest dzielona za zbiór sześciennych sektorów,
● Szeroko rozumiana optymalizacja metody s-CoMSA,
● Analiza QSAR oraz SAR wybranych szeregów związków aktywnych biologicznie z
wykorzystaniem metody s-CoMSA oraz innych metod 3D-QSAR.
W zakres pracy wchodzi: Opracowanie formalizmu metody s-CoMSA,
● Zaprogramowanie procedur analizy s-CoMSA,
● Badanie modeli s-CoMSA aktywności biologicznej wybranych szeregów związków
organicznych, w tym:
• szeregu steroidów o powinowactwie do globuliny wiążącej kortykosteroidy
(ang. corticosteroid-binding globulin – CBG),
• inhibitorów wirusa HIV,
• inhibitorów reduktazy kwasu dihydrofoliowego
Consensus-based pharmacophore mapping for new set of N-(disubstitutedphenyl)- 3-hydroxyl-naphthalene-2-carboxamides
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-hydroxynaphthalene-
2-carboxamide showed submicromolar (MICs 0.16–0.68 M) 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 M) 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,
di erent distribution of mono-halogenated carboxamide derivatives with the –CF3 substituent is
accompanied by the increased activity profile. A symmetric matrix of Tanimoto coe cients 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 cli s.
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
Investigation of hydro-lipophilic properties of n-alkoxyphenylhydroxynaphthalenecarboxamides
The evaluation of the lipophilic characteristics of biologically active agents is indispensable for the rational design of ADMET-tailored structure–activity models. N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides, and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently reported as a series of compounds with antimycobacterial, antibacterial, and herbicidal activity. As it was found that the lipophilicity of these biologically active agents determines their activity, the hydro-lipophilic properties of all three series were investigated in this study. All 57 anilides were analyzed using the reversed-phase high-performance liquid chromatography method for the measurement of lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, a range of software lipophilicity predictors for the estimation of clogP values of a set of N-alkoxyphenylhydroxynaphthalenecarboxamides was employed and subsequently cross-compared with experimental parameters. Thus, the empirical values of lipophilicity (logk) and the distributive parameters (π) were compared with the corresponding in silico characteristics that were calculated using alternative methods for deducing the lipophilic features. To scrutinize (dis)similarities between the derivatives, a PCA procedure was applied to visualize the major differences in the performance of molecules with respect to their lipophilic profile, molecular weight, and violations of Lipinski’s Rule of Five
Synthesis and hybrid SAR property modeling of novel cholinesterase inhibitors
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 Min the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)
carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 M) 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. -
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 grou
Towards property profiling: SYNTHESIS and SAR probing of new tetracyclic diazaphenothiazine analogues
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