Quantitative Structure-activity Relationship Investigations Research Articles

Antimicrobial Properties Of Pyrazolone Compounds With Their Qsar Investigations

The present paper reports the analysis and the antimicrobial activity viz. antifungal activity of some pyrazolone compounds which were performed against Alternaria solani using disc diffusion method on nutrient agar and nutrient broth media. The compounds were characterized by elemental analysis and spectral studies. Result of antimicrobial screening indicated that compounds 4-Amino antipyrine thiosemicarbazone, 1-(2-Chloro-5-sulfophenyl)-3-methyl-5-pyrazolone and 1-(4 -Sulfoamidophenyl)-3-methyl-5-pyrazolone were found to be the most potent/active against A. solani. Correlation studies between different computed properties of the compounds with their biological activity, QSAR (Quantitative Structure Activity Relationship) investigations with a stepwise linear regression analysis were conducted. The studies are carried out using Hyperchem 8.0 version software using AM1, PM3, MNDO and ZINDO methods. Selected QSAR/ 3D-QSAR equations including different physical parameters of these series are reported.

Acute toxicity of binary mixtures for quorum sensing inhibitors and sulfonamides against Aliivibrio fischeri: QSAR investigations and joint toxic actions

Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of Aliivibrio fischeri (A. fischeri) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in A. fischeri bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC50) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC50(QSI):EC50(SA) = 1:1) and non-equitoxic ratios (EC50(QSI):EC50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure–activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (Ebind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.

DESIGN OF POTENT ANTICANCER MOLECULES COMPRISING PYRAZOLYL-THIAZOLINONE ANALOGS USING MOLECULAR MODELLING STUDIES FOR PHARMACOPHORE OPTIMIZATION

Objectives: Numerous tiny receptor tyrosine kinase inhibitors have been reported as anticancer medications over the past 10 years. However, a lot of them lack effectiveness in vivo, selectivity, or do not last long before developing resistance. Methods: We used molecular modeling research to improve the pharmacophore to get beyond these limitations. For the purpose of linking the chemical makeup of pyrazolyl thiazolinone analogs with their anticancer activity, quantitative structure activity relationship (QSAR) investigations in two dimensions (2D) and three dimensions (3D) were carried out. Pyrazolyl thiazolinone pharmacophore’s stearic, electronic, and hydrophobic requirements were calculated using 3D QSAR. Results: By leveraging the findings of QSAR investigations, the pharmacophore was refined and new chemical entities (NCEs) were generated. The r2 and q2 values obtained for the best model No. 4 of 2D QSAR were 0.9244 and 0.8701, respectively. A drug-like pharmacokinetic profile was ensured by studying the binding affinities of proposed NCEs on epidermal growth factor receptor-TK using docking studies and estimating their absorption, distribution, metabolism, and excretion features. Conclusion: When statistical significance is closely examined, predictability of the model and its residuals (actual activity minus predicted activity) is found to be close to zero, leading us to draw the conclusion that the logic behind the design of NCEs was determined to be sound.

Benzo[g]quinazolines as antifungal against candidiasis: Screening, molecular docking, and QSAR investigations

Candida albicans, an opportunistic pathogen, is the most common type of fungus and represents a substantial source of human invasive disease (nosocomial infection). This category of fungi are part of our microbiota, and given the appropriate environmental conditions, it has the potential to cause both superficial and systemic infections. There is a soaring resistance against the available anticandidal agents. The purpose of this research is to investigate the activity of certain previously synthesized benzo[g]quinazolines against C. albicans in vitro by using the cup-plate diffusion method. There was a marked difference in the effectiveness of the target compounds 1–6 against the sample of C. albicans that was tested. Benzo[g]quinazolines 1 (inhibition zone = 20 mm) and 2 (inhibition zone = 22 mm) had good effects in comparison to fluconazole (inhibition zone = 26 mm). A docking study was conducted between benzo[g]quinazolines 1–6 and Candida spp. CYP51 to establish the binding mode compared with fluconazole and VT-1161 (oteseconazole) as reference medicines, and it was determined that binding at the active site of Candida spp. CYP51 occurred in the same manner. Quantitative structure–activity relationship (QSAR) investigation was performed to further characterize the identified anticandidal agents and recognize the major regulatory components governing such activity. In future studies, the benzo[g]quinazoline scaffold could serve as a model for the design and development of novel derivatives with antifungal potential.

New 1,2,3-Triazole Scaffold Schiff Bases as Potential Anti-COVID-19: Design, Synthesis, DFT-Molecular Docking, and Cytotoxicity Aspects.

Schiff bases encompassing a 1,2,3-triazole motif were synthesized using an efficient multi-step synthesis. The formations of targeted Schiff base ligands were confirmed by different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, and CHN analysis). The spectral data analysis revealed that the newly designed hydrazones exist as a mixture of trans-E and cis-E diastereomers. Densityfunctional theory calculations (DFT) for the Schiff bases showed that the trans-trans form has the lowest energy structure with maximum stability compared to the other possible geometrical isomers that could be present due to the orientation of the amidic NH–C=O group. The energy differences between the trans-trans on one side and syn-syn and syn-trans isomers on the other side were 9.26 and 5.56 kcal/mol, respectively. A quantitative structure-activity relationship investigation was also performed in terms of density functional theory. The binding affinities of the newly synthesized bases are, maybe, attributed to the presence of hydrogen bonds together with many hydrophobic interactions between the ligands and the active amino acid residue of the receptor. The superposition of the inhibitor N3 and an example ligand into the binding pocket of 7BQY is also presented. Further interesting comparative docking analyses were performed. Quantitative structure-activity relationship calculations are presented, illustrating possible inhibitory activity. Further computer-aided cytotoxicity analysis by Drug2Way and PASS online software was carried out for Schiff base ligands against various cancer cell lines. Overall, the results of this study suggest that these Schiff base derivatives may be considered for further investigation as possible therapeutic agents for COVID-19.

QSAR analysis of the acute toxicity of avermectins towards Tetrahymena pyriformis

ABSTRACT Avermectins have been effectively used in medicine, veterinary medicine, and agriculture as antiparasitic agents for many years. However, there are still no reliable data on the main ecotoxicological characteristics of most individual avermectins. Although many QSAR models have been proposed to describe the acute toxicity of organic compounds towards Tetrahymena pyriformis (T. pyriformis), avermectins are outside the applicability domain of these models. The influence of the molecular structures of various organic compounds on the acute toxicity towards T. pyriformis was studied using the OCHEM web platform (https://ochem.eu). A data set of 1792 toxicants was used to create models. The QSAR (Quantitative Structure-Activity Relationship) models were developed using the molecular descriptors Dragon, ISIDA, CDK, PyDescriptor, alvaDesc, and SIRMS and machine learning methods, such as Least Squares Support Vector Machine and Transformer Convolutional Neural Network. The HYBOT descriptors and Random Forest were used for a comparative QSAR investigation. Since the best predictive ability was demonstrated by the Transformer Convolutional Neural Network model, it was used to predict the toxicity of individual avermectins towards T. pyriformis. During a structural interpretation of the developed QSAR model, we determined the significant molecular transformations that increase and decrease the acute toxicity of organic compounds.

QSAR investigations and structure-based virtual screening on a series of nitrobenzoxadiazole derivatives targeting human glutathione-S-transferases

Quantitative structure-activity relationship (QSAR) models are useful tools for understanding the relation between biological activity and chemical structure, and for the design of new drugs. In this work, the performances of two QSAR approaches for modelling and predicting glutathione-S-transferases (GSTP1-1) inhibition are compared, namely Multiple Linear Regression (MLR) and Artificial Neural Network (ANN). These models are applied to 38 thiol substituted nitrobenzoxadiazole inhibitors. For these compounds, we found that the nonlinear model performs better than the linear one in terms of predictive ability, indicating a non-linear relation between the selected molecular descriptors and GSTP1-1 inhibition. The validity of the proposed models was established using the following techniques: separation of data into independent training and test sets, leave-one-out cross-validation, and Y-randomization. Otherwise, the domain of applicability indicating the area of reliable predictions was defined. Through the adopted QSAR model and in silico virtual screening, we identified 23 hits with good predictability. Our work should motivate future in vitro investigations on these compounds.

Quantitative structure-activity relationship (QSAR) investigation on 2-arylideneaminobenzimidazole derivatives as anti-proliferative activity against mv4-11 human leukaemia cells

This undertaking involves QSAR investigations on the use of 28 2-arylideneaminobenzimidazole derivatives, for curbing the proliferative activity of cells in the mv4-11 human leukaemia cell line. The geometries of the compounds under investigation were initially optimized at level (PM3) in accordance to the semi-empirical theory, and subsequently through the B3LYP procedure at the 6-31G(d) basis set in accordance to the DFT theory. The multiple regression procedure was employed for the construction of two QSAR equations, to assess the anti-proliferative activity of these compounds (Equations 1 and 2). The values of R2 extended from 0.792 to 0.812, those of S from 0.187 to 0.193, and those of F from 24.897 to 30.429. According to the results attained, the use of four parameters in Equation 2[(N5), (N10), r(C1=N2) andLUMO+4] led to raised R2 values and minimized S values. This suggests that these parameters are significant for identifying the anti-proliferative effectiveness of the compounds, in the context of mv4-11 human leukaemia cell line cells. This revelation is also an indication that QSAR can be successfully applied for a broad range of compounds.Â

QSAR investigation of acute toxicity of organic compounds during oral administration to mice

The effect of the structure of organic compounds on the acute toxicity upon oral injection in mice was studied using 2D simplex representation of the molecular structure and Random forest (RF) methods. Satisfactory quantitative structure-activity relationship (QSAR) models were constructed (R2 test = 0,61-0,62). The interpretation of the obtained QSAR models was carried out. The contributions of known toxicophores with established mechanisms of action were calculated in order to confirm the ability of the interpretation approach to correctly rank them relative to other structural fragments. The influence of the molecular surroundings of some toxicophores was analyzed. We analyzed the contributions of other highly ranked fragments from the list of common functional groups and ring systems in order to find new potential toxicophores. The on-line version of the expert system "OCHEM" (https://ochem.eu) and Arithmetic Mean Toxicity (AMT) approach were used for a comparative QSAR study.

Synthesis and evaluation of xanthone derivatives as acid sphingomyelinase inhibitors: potential treatment for UV-induced skin damage.

ASM, which hydrolyzes sphingomyelin into ceramide, is recognized as a therapeutic target for UV-induced skin damage. Direct inhibitors for this enzyme are rare. Here we synthesized several series of 1,3,6,7-tetrahydroxy-xanthone derivatives as novel ASM inhibitors. Several compounds were more potent than the lead compound, among which 5b was found competitively inhibiting the enzyme and dose-dependently reducing ceramide generation. Furthermore, 5b and 5c showed excellent protective effect to skin keratinocytes against UV. Quantitative structure-activity relationship investigation revealed detail relationships between molecular structure and biological activity. Insight into the binding mode was precisely illuminated by molecule docking. This work would provide fresh ideas and strong supports for further development of ASM inhibitors and drug candidates for skin damage.

Chromanyl–isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities.

QSAR Investigation of Acute Toxicity of Organic Acids and their Derivatives Upon Intraperitoneal Injection in Mice

The structure—acute-toxicity relationship of organic acids and their derivatives was studied. The effect of the structure of 88 organic compounds on the acute toxicity upon i.p. administration in mice was studied using 2D simplex representation of the molecular structure and partial least-squares methods. Satisfactory quantitative structure—activity relationship (QSAR) models were constructed and analyzed to reveal the structural fragments that enhance toxicity.

QSAR investigation of NaV1.7 active compounds using the SVM/Signature approach and the Bioclipse Modeling platform

A quantitative structure-activity relationship investigation of some NaV1.7 active compounds has been performed by repeated, random, external test set experiments employing structural descriptors (fingerprints) of signature type in combination with support vector machine (SVM) analysis using the radial basis function (RBF) kernel. The results from the investigation show remarkably stable performance from the derived in silico models in terms of statistical measures such as correlation coefficients as well as root mean squared errors (RMSEs) for the randomly selected external test sets. Also, the Bioclipse Modeling platform is utilized for introducing interpretation to the derived models.

Inhibition of leukemia-associated transcription factor c-Myb by sesquiterpene lactones and further natural products

The transcription factor c-Myb plays an important role in haematopoiesis, particularly during expansion and self-renewal of immature myeloid and lymphoid progenitor cells. Acute and chronic myeloid leukemia cells depend on the presence of c-Myb for their proliferation and viability and are more sensitive to c-Myb inhibition than their normal counterparts [1]. We recently reported the potential of sesquiterpene lactones (STLs) as first cell-permeable, low-weight inhibitors of the transcription factor c-Myb [2]. Currently, more than 90 different natural substances have been tested as possible c-Myb inhibitors in our GFP-based reporter gene assay. The most active compounds identified so far (two STLs, three Naphthoquinones and two quinone methide triterpenoids) displayed IC50 values <1µM. MTS-Assays were conducted to exclude unspecific cytotoxic effects as mere cause for the observed activity. Analysis of structure-activity relationships revealed alkylation as likely mechanism of action. However, it was shown that the mere capability to react covalently with biomolecules alone is not sufficient for c-Myb inhibition. An ongoing investigation of quantitative structure-activity relationships (QSAR) for more than 50 tested STLs gives insights into structural requirements for strong c-Myb inhibition.

Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

AbstractN‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas (CCNU) is an important alkylating agent used in the clinical treatment of cancer. The quantitative structure‐activity relationship (QSAR) of CCNU derivatives was investigated using the density functional theory (DFT)‐based descriptors and the n‐octanol/water partition coefficient (milogP). Geometry optimization was performed using the DFT/B3LYP method in conjunction with the 6‐311+G(d,p) basis set. Experimental data of anticancer activity, log(1/C), were used for the QSAR analysis. By stepwise multiple regressions, four optimum descriptors, (milog P)2, E1, EZ/E and BO1Cl8 were found for constructing the QSAR models. Two satisfied models were obtained by multiple linear regressions with the values of R2 higher than 0.9. The (milog P)2 descriptor has the highest correlation to the anticancer activity, indicating that similar improvements to hydrophilicity and lipophilicity are necessary for enhancing anticancer activity. The energy barriers for the decomposition of CCNU derivatives via a retro‐ene reaction (E1) and for the transformation from Z‐tautomers to E‐tautomers (EZ/E) are also considerable descriptors in the QSAR models. The anticancer activity is increased with the decrease of E1 and the increase of EZ/E. The BO1Cl8 descriptor, which requires the inclusion of the other three descriptors in the models, has positive correlation with the anticancer activity of CCNU derivatives. The results indicate that the introduction of the descriptors of activation energies (E1 and EZ/E) is a significant contribution to the methodology of QSAR investigations, because the dynamic descriptors may be more correlated with the biological activity of drugs and toxicants than the static descriptors. Our models shed light on the structure‐activity relationship of CCNU derivatives and may be useful in the development of more effective and less toxic nitrosoureas as anticancer agents. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

QSAR Investigation of New Cognition Enhancers

AbstractIncreasing longevity means that there is an increased likelihood of loss of cognitive functions and of incidence of dementias. There is thus a greater demand for cognition‐enhancing (noötropic) drugs. Some such drugs are already available, but many display serious side‐effects. We have designed, synthesized and tested a number of novel chemical entities that are predicted by the PASS software to be potential noötropic agents. The results have been subjected to QSAR (quantitative structure–activity relationship) analysis, and good QSAR correlations, with external validation, have been obtained, which can be used predictively to guide design of additional potential cognition‐enhancers.

A QSAR investigation of dermal and respiratory chemical sensitizers based on computational chemistry properties

A wide range of physicochemical properties based on molecular topology, size and shape, and semi-empirical molecular orbital theory were calculated for a variety of dermal and respiratory sensitizers, as well as some non-active substances. Compounds were randomly selected to belong to a training set of substances (approximately 90%) for development of quantitative structure–activity relationship (QSAR) models or to a test set (approximately 10%) for testing the models. A choice was made of those descriptors which were related to sensitization using standard statistics. Pattern recognition methods were then utilized to identify the combination of properties that provided the greatest contribution to the observed biological effect. Principal components (PC) analysis was then performed on the most important properties. The models derived were then applied to a test set of known sensitizers to predict their class. For dermal and respiratory sensitizers respectively, the PC model classified five (100%) of the R-43 active and two (100%) of the R42-active test set compounds correctly. Analysis of the PC loadings showed that the most useful properties distinguishing respiratory and/or dermal sensitizers from inactive substances were the molecular orbital-based terms.

Novel 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides: Synthesis, antimycobacterial activity and QSAR investigations

A series of 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides were synthesized using appropriate synthetic route. Antimycobacterial activity of the synthesized compounds ( 5a– 5j) was carried out and percentage reduction in relative light units (RLU) was calculated using luciferase reporter phages (LRP) assay. Percentage reduction in relative light units (RLU) for isoniazid was also calculated. The test compounds showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv and clinical isolates: S, H, R, and E resistant M. tuberculosis, when tested in vitro. Quantitative structure–activity relationship (QSAR) investigation with 2D-QSAR analysis was applied to find a correlation between different experimental or calculated physicochemical parameters of the compounds studied and 3D-QSAR analysis and to indicate the exact steric and electronic requirements in the ranges at various positions around pharmacophore. In general Schiff bases exhibit antimycobacterial activity and morpholine ring is important for antimicrobial activity. So we have synthesized 10 different 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides. The structures of new compounds were characterized by TLC, FTIR, 1H NMR, mass spectral data and elemental analysis. Amongst the compounds tested 5d and 5c were found to be the most potent, while 5i, 5e, and 5j were found to have an average activity against M. tuberculosis H37Rv and 5a, 5f, 5h, 5g, and 5b were found to have a greater activity against clinical isolates: S, H, R, and E resistant M. tuberculosis as compared to M. tuberculosis H37Rv.

QSAR analysis of 1,3-diaryl-4,5,6,7-tetrahydro-2 H-isoindole derivatives as selective COX-2 inhibitors

Quantitative structure–activity relationship (QSAR) analysis was performed on a series of 1,3-diaryl-4,5,6,7-tetrahydro-2 H-isoindole for their cyclooxygenase-2 (COX-2) inhibition. QSAR investigations were based on Hansch's extra thermodynamic multi-parameter approach and receptor surface analysis (RSA). QSAR investigations reveal that steric and electrostatic interactions are primarily responsible for COX-2 enzyme–ligand interaction. QSAR model derived from Hansch analysis demonstrated that COX-2 inhibitory activity is correlated with sum of atomic polarizability (Apol), number of hydrogen-bond donor groups (HBD), energy of the highest occupied molecular orbital (HOMO), desolvation free energy for water ( F H 2 O ) and fraction of areas of molecular shadow in the XY and ZX planes over area of enclosing rectangle (Sxyf and Sxzf) with r ranges 0.870–0.904. The best model was obtained from RSA model having r = 0.940 with good predictive ability (predicted compounds in training set and test set within ±1.0 unit of pIC 50) and can be used in designing better selective COX-2 inhibitors among the congeners in future.

Synthesis, antibacterial activity, and quantitative structure–activity relationships of new ( Z)-2-(nitroimidazolylmethylene)-3( [formula omitted])-benzofuranone derivatives

A new series of ( Z)-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3( 2 H )-benzofuranones ( 11a– p) and ( Z)-2-(1-methyl-4-nitroimidazole-5-ylmethylene)-3( 2 H )-benzofuranones ( 12a– m) were synthesized and assayed for their antibacterial activity against Gram-positive and Gram-negative bacteria. Most of the 5-nitroimidazole analogues ( 11a– p) showed a remarkable inhibition of a wide spectrum of Gram-positive bacteria ( Staphylococcus aureus, Streptococcus epidermidis, MRSA, and Bacillus subtilis) and Gram-negative Klebsiella pneumoniae, whereas 4-nitroimidazole analogues ( 12a– m) were not effective against selected bacteria. The quantitative structure–activity relationship investigations were applied to find out the correlation between the experimentally evaluated activities with various parameters of the compounds studied. The QSAR models built in this work had reasonable predictive power and could be explained by the observed trends in activities.