Hansch Approach Research Articles

Molecular Mechanics-Based Quantitative Structure-Activity Relationship Study on the Inhibitory Activity of Some Schiff Bases against Escherichia coli

Due to their high inhibitory action against Escherichia coli (E. coli), the rise of multidrug-resistant strains of the bacteria necessitates the testing and development of a new set of Schiff bases as anti-E. coli agents worldwide. In this study, the Genetic function approximation (GFA) Quantitative structure-activity relationship (QSAR) analyzes selected Schiff bases with anti-E. coli activity. This was done using different molecular descriptors and Hansch's approach, which results in the production of one statistically significant hepta parameter model as the strongest model with a squared correlation coefficient (R2) = 0.828, adjusted squared correlation coefficient (R2adj) = 0.775, cross-validated correlation coefficient (Q2) = 0.691, Difference between R2 and Q2, Q2 (R2 - Q2) = 0.137, external prediction (R2pred.) = 0.751 and lack of fit (LOF) of 0.067 value were selected as the best model based on its sound statistical parameters. The development model demonstrated the predominance of the descriptors Minimum H E State (Hmin) and Valence path order 6 (VP-6) in influencing the observed anti-E. coli activity of Schiff bases. Insilico techniques can certainly provide a quick, inexpensive and safe quantitative risk assessment for this class of compounds. It is envisaged that the QSAR results discovered in this work will provide crucial structural insights towards the design of effective anti-E. coli drugs based on Schiff bases

Evaluation of contribution of different molecular fragments on antibacterial activity of Schiff bases of indole-3-aldehyde based on QSAR study

The paper describes the QSAR analysis of a series of 22 Schiff bases of indole-3-aldehyde employing the Hansch approach. Various physicochemical and steric parameters were calculated using the Chem 3D package of molecular modeling Software Chemoffice 2004. QSAR models were generated employing the sequential multiple regression method. Models were validated using leave-one-out and bootstrapping methods. Results obtained show that dipole–dipole energy, LUMO, and total energy play an important role, as their positive contribution is seen in the models. Findings of the present study reveal that substituents that cause increase in flexibility, a decrease in polarity, and electron withdrawing in nature are favorable for antibacterial activity of Schiff bases.

Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents

A set of substituted-[N′-(benzofuroxan-5-yl)methylene]benzohydrazides (4a–t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases. Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents. The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0.11; F = 42.19; R2 = 0.90 and Q2 = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R2 = 0.98, Q2 = 0.93 (SDEP = 0.08)], three latent variables explained 62% of the total variance from original data. Steric and hydrophobic properties were pointed out as the key for biological activity. Based upon the findings, six novel benzofuroxan derivatives (4u–z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction. Then, the predictability for the both models, 2D-QSAR (Rpred2 = 0.91) and 3D-QSAR (Rpred2 = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 μM).

2‐(pyrazin‐2‐yloxy)acetohydrazide Analogs QSAR Study: An Insight into the Structural Basis of Antimycobacterial Activity

Quantitative structure activity relationship analysis based on classical Hansch approach was adopted on reported novel series of 2-(pyrazin-2-yloxy)acetohydrazide analogs. Various types of descriptors like topological, spatial, thermodynamic, and electronic were used to derive a quantitative relationship between the antitubercular activity and structural properties. The consensus scoring function showed a significant statistics of training and test set. Coefficient of determination (r²) of consensus model and predictive squared correlation coefficient (r²(pred)) were found to be 0.889 and 0.782, respectively. The model is not only able to predict the activity of test compounds but also explained the important structural features of the molecules in a quantitative manner. The study revealed that antimycobacterium activity is predominantly explained by the molecular connectivity indices of length 6, hydrogen donor feature of the analogs, and shape factors of the substituent. The comparative investigation of antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhi provided structural insights on how modulation of the molecular connectivity indices, energy of lowest unoccupied molecular orbital, accessible surface area, and moment of inertia of the analogs could be usefully made to optimize the antibacterial activity.

QSAR Investigations on Benzylideneamino and Phenyliminomethyl Scaffolds for Selective COX-2 Inhibition: A Hansch Approach

Cyclooxygenase inhibitory and selectivity profile of a combined series of thirty one aryl sulphonamide compounds possessing 4-benzylideneamino or 4-phenyliminomethyl scaffolds were subjected to QSAR study using Hansch approach. The compounds in the selected series were characterized using classical aromatic substituent constants like hydrophobicity (pi), molar refractivity (MR), Hammett electronic (sigma), electronic field effect (F), resonance effect (R), and some indicator variables encoding molecular group contributions. Statistically significant QSAR models were generated using multiple regression analysis and cross-validation tools. The derived QSAR models demonstrated that the COX-2 selectivity over COX-1 is predominantly influenced by the central core -N=C- of the diaryl system. Further, the study also indicated that the electronic properties and structural variation in the para position of the phenyl ring (B) governs the COX-2 selectivity of the title compounds. The derived results reveal the important structural features significant for improved COX-2 inhibitory activity and selectivity of these novel aryl sulfonamides.

Modeling of the growth hormone secretagogue receptor antagonistic activity using chemometric tools

A quantitative structure-activity relationship (QSAR) study has been carried out on growth hormone secretagogue receptor antagonistic activity of the derivatives of 2,4-diaminopyrimidine. To obtain significant QSARs, the approaches involving the non-parametric such as Fujita-Ban, and the parametric based on physicochemical and DRAGON descriptors in Hansch type of analysis have been employed. The Fujita-Ban approach, however, was constrained to 18 compounds only due to a limited number of substituents appeared at varying positions. The derived contributions of different substituents and the parent moiety were used to identify the potential congeners. The physicochemical model of Hansch was subsequently used to interpret the type of interactions involved between the receptor sites and varying positions of these compounds. The study, employing DRAGON descriptors in Hansch approach was also carried out on this data set to discuss the prevailing interactions in terms of topological descriptors. The derived highest significant model was discussed to delineate the type of interactions involved and suggestions have been made for different alterations to lead to further potential compounds of the series.

Exploration of QSAR modelling techniques and their combination to rationalize the physicochemical characters of nitrophenyl derivatives towards aldose reductase inhibition

The quantitative structure–activity relationship (QSAR) analysis of nitrophenyls active as aldose reductase inhibitors (ARIs) has been performed employing Fujita-Ban, classical Hansch approach and physicochemical properties. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) techniques considering adjustable correlation coefficient (r2adj). The statistical quality of SEQ-MLR equations were evaluated considering parameters like correlation coefficient (r), standard error of estimation (SEE), and variance ratio (F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF).The QSAR analysis gave insight to some common important structural feature i.e. the hydroxyl group is crucial for hydrogen bond interaction with the receptor. Similarly electro-negative substitution is essential for polar interaction with charge region of the receptor. Moreover analysis inferred that diarylsulphides can be explored for optimization of the analogs.

Insights through AM1 calculations into the structural requirement of N-hydroxythiosemicarbazone analogs as anti-tubercular agents

Fujita-Ban, Hansch substituent constants, topological descriptors and conformational dependent descriptors were explored for quantification of anti-tubercular activity of N-hydroxythiosemicarbazone analogs. All the approaches gave statistically sound model which accounts for more than 88% of the explain variance against anti-tubercular activity except Fujita-Ban (∼75%). Fujita-Ban & Hansch approaches having certain limitation, however, another approache showed their significant role in explaining activity of the modified scaffolds. QSAR study of N-Hydroxythiosemicarbazone analogs furnished some important structural insights i.e., the R position is more prone for improving inhibitory activity and the R1 position play a decisive role in the ionic interaction of the ligand with macromolecules. On the basis of findings, N-hydroxythiosemicarbazones interaction model with macromolecule of M. Tuberculosis has been proposed. These interactions might be helpful in further development of potent anti-tubercular agents.

SARs of the antiprotozoal action of 6,7-diaryl-bicyclo[2.2.2]octan-2-ols

Several 4-amino-6,7-diarylbicyclo[2.2.2]octan-2-ols bearing varying substituents on the aromatic rings were synthesized following a manual method for applying the Hansch approach. All new compounds were tested for their activity against the causative organisms of East African sleeping sickness and malaria tropica. Structure activity relationships are discussed.

Structure–Antioxidant Activity Relationships in a Series of NO‐Donor Phenols

Recently we reported a new class of NO-donor phenols that could be of interest in the treatment of many forms of cardiovascular disease (CD). Their potencies as inhibitors of ferrous salt/ascorbate-induced peroxidation of membrane lipids of rat hepatocytes were assessed as pIC(50) values through the TBARS assay. In this work we aimed to find quantitative relationships between the antioxidant activity of these compounds and appropriate molecular descriptors. In particular, we determined their log P(oct), their reactivity (log Z) in reaction with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(.)), and the theoretical parameter DeltaH(abs), which describes the enthalpy of homolytic O--H bond cleavage. The QSAR equations found through the classical Hansch approach allowed us to draw interesting conclusions on the possible mechanisms of reaction with radicals in the various environments, while underlining the role of lipophilicity in antioxidant activity.

Novel Azabicyclo[3.2.2]nonane derivatives and their activities against Plasmodium falciparum K 1 and Trypanosoma brucei rhodesiense

New diaryl substituted 2-azabicyclo[3.2.2]nonane derivatives have been synthesized in order to investigate the influence of the aromatic substitution and of N substitution on the antiprotozoal activities of those compounds. Following a manual method for the Hansch approach, different 4-substituted aryl rings were systematically inserted, and moieties with varying basicity and polarity were attached to the ring nitrogen. All compounds were investigated for their activities against Trypanosoma brucei rhodesiense (STIB 900) and the K 1 strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) and for their cytotoxicity using microplate assays. Some of the new compounds are amongst the most active antitrypanosomal agents in this series, and the selectivity index of a single derivative is superior in the 2-azabicyclo-nonane series.

Quantitative Structure Activity Analysis of 2-Alkoxydihydrocinnamates as PPARα /γ Dual Agonist

To optimize the physiochemical properties of 2-alkoxydihydrocinnamates as PPARalpha/gamma dual agonist, a quantitative structure activity relationship, Hansch approach was made using combination of various thermodynamic, electronic and spatial descriptors. Several regression expressions are obtained using multiple linear regression analysis. The best QSAR model is further validated by leave-one-out cross validation method. Analyses of results from the present QSAR study suggest that for favorable dual PPARalpha/gamma agonist activity electronic property of the substituents in hydrophobic tail phenyl ring plays a key role. The contribution of Hammett constant and dipole moment in the models deduced the importance of electron withdrawing substituents for dual activity. Additionally the study also indicates that bulky substituents in head acid moiety not confer selectivity towards the PPAR activity. Thus the QSAR study brings important structural insight to aid the design of dual PPARalpha/gamma receptor agonist.

3,4‐Disubstituted‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thiones: Synthesis, Antimicrobial Evaluation and QSAR Investigations Using Hansch Analysis

The 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives were synthesized and characterized by physicochemical and spectral means, and the results of antimicrobial study of these compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans by tube dilution method indicated that 4-(4-chlorophenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 6 and 4-(4-fluorophenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 12 were the most potential ones. Further, the QSAR studies by Hansch analysis applied to find out the correlation between physicochemical characteristics of synthesized compounds with antimicrobial activity demonstrated the contribution of electronic parameter, total energy (Te) and the topological parameter (valence second order molecular connectivity index (2 chi v). Excellent statistically significant models were developed by Hansch approach (r2 = 0.828-0.898) for the three microorganisms under study. The cross-validated r2 (q2), which is an indication of the predictive capability of the model for all cases was also very good (q2 = 0.776-0.875).

Quantitative structure-activity relationship study of novel rhinacanthins and related naphthoquinone esters as anticancer agents

The anticancer activity of rhinacanthins and related naphthoquinone esters is quantitatively analyzed through Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds. From both approaches it appeared that naphthalene ring instead of benzene ring, dimethyl substitution at R1 and R2, and hydrogen-bond acceptor substituents at R3 (Figure ) are advantageous to improve the activity of a compound against KB cell lines. This in turn leads to the suggestion that the rhinacanthin-N scaffold is the structural entity that needs exploration for new potential compounds. Further, in the Fujita-Ban analysis, it is observed that the compounds bearing a OMe substitution, relative to H, at R4 have a slight positive contribution to pIC50 (KB) whereas the substituents H or OMe at R5, relative to OH, have negative contributions. In conformity with these findings, the Hansch approach revealed that a more hydrophobic group at R4 and a more hydrophilic group at R5 positions are beneficial in raising the activity. The two quantitative structure-activity relationship (QSAR) analyses, differing in parametric approach, therefore, provided the grounds for rationalizing the substituent selection to design more potent compounds of the series.Figure 1 Structures of rhinacanthin–M (1), –N (14), –Q (15) and related naphthoquinone esters (2–13, 16–42).

QSAR study of 5-arylidene-2,4-thiazolidinediones as aldose reductase inhibitors

The shortage of drugs currently available for the treatment of diabetic complications has aroused our interest for the search of new aldose reductase inhibitors (ARIs) endowed with more favorable biological properties. In response, quantitative structure–activity relationship (QSAR) study has been performed on a series of 5-arylidene-2,4-thiazolidinediones using the Fujita-Ban and the classical Hansch approach and molecular modeling studies employing AM1 calculations to gain structural insight into the binding mode of these molecules to the aldose reductase enzyme. The QSAR models were generated using 18 compounds. The predictive ability of the resulting QSAR models was evaluated employing the leave-one-out method of cross validation. Remarkably, the results obtained from the Fujita-Ban and Hansch approaches were in agreement with the molecular modeling studies. The QSAR analysis reported herein confirms that the presence of the carboxylic anionic head of the N-3 acetic chain is an important, albeit not essential, structural requisite to produce high levels of enzyme inhibition. Furthermore, the hydrophobic substitutions are conducive to this activity.

QSAR as a Tool for the Development of Potent Antiproliferative Agents by Inhibition of Choline Kinase

The identification of the molecular components involved in the aberrant processes that control proliferation, differentiation and apoptosis, is necessary for the development of chemotherapeutic interventions to restore or to destroy selectively the transformed cells. The discovery of new chemotherapeutic agents is probably one of the most reliable ways to improve our success against cancer, and intelligent drug design is a key factor to achieve this goal. Thus, the identification of novel targets for anticancer drug discovery is needed. Here we provide evidence that choline kinase (ChoK) is a novel target for the design of antitumor drugs. In this review we present the evolution of ChoK inhibitors by using the Hansch approach, starting from hemicholinium-3 (HC-3) as a lead compound. To start with we synthesized and evaluated ten bis-quaternary derivatives, in which the modifications affect both the spacer and the two cationic heads of the prototype. In the second phase 56 biscationic dibromides with distinct polar heads [bis(4-substituted)pyridinium, bis(4-substituted)quinolinium, and bisisoquinolinium moieties] and several spacers were synthesized and assayed for biological activity. This oriented synthesis produced 45 inhibitors of ChoK with antitumor activity against the HT-29 cell line. Finally, 40 bisquinolinium compounds were prepared and the corresponding QSAR equation was obtained for the whole set of compounds for the antiproliferative activity, the electronic parameter R of R4, the molar refractivity of R8, and the lipophilic parameters clog P and πlinker. The most potent antiproliferative agent so far described shows IC50 = 0.20 μM, while its theoretical value is 0.45 μM.

Encoding Type and Position in Peptide QSAR: Application to Peptides Binding to Class I MHC Molecule HLA‐A*0201

AbstractVarious QSAR approaches have evolved over time to find a relationship between chemical structure and biological response by translating the information in the chemical structure into a quantitative (Hansch approach) or qualitative (Free–Wilson approach) description followed by a statistical modeling. The nature and position of every amino acid in the peptide sequence dictate its binding to the receptor. We have investigated an approach to peptide QSAR where the position and type of every amino acid in the sequence are encoded in the QSAR paradigm, and along with the principles of the Hansch (descriptor QSAR) and the Free–Wilson (binary QSAR) methodologies we were able to arrive at the optimal sequence of amino acids in the peptide. As an example, we illustrate the procedure on two datasets of nonamer peptides that bind to the class I major histocompatibility complex molecule HLA‐A*0201. The models generated have statistically significant co‐relation coefficient (r2) and predictive r2 (r2pred). The cross‐validated r2 (q2) for “descriptor QSAR” approach and the “binary QSAR” approach are in an acceptable range. The QSAR analysis is able to identify the preferential and detrimental amino acids at every position of the nonamer peptide. This QSAR formalism as applied to peptides is a simple and effective way to explain structure–activity relationships as well as to optimize the binding affinity.

Rationalization of physicochemical characters of oxazolyl thiosemicarbazone analogs towards multi-drug resistant tuberculosis: A QSAR approach

The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis and the continuing pandemic of tuberculosis emphasizes the urgent need for the development of new and potent anti-tubercular agents. In an effort to develop new and more effective agents to treat tuberculosis emphasis was focused on quantification of structure–activity relationship of oxazolyl thiosemicarbazone derivatives. The de novo analysis gave insight to some important structural features i.e. nitro group on phenyl ring at R 1 position is optimal for the activity and might be responsible for electronic interaction, while phenyl ring at R position interact with the hydrophobic pocket more effectively as compared to unsubstituted or methyl substituted analogs. Hansch approach offered the understanding and parameterization of interactions of the inhibitor with receptor. Similarly QSAR analysis gave some important physicochemical properties, i.e. empirical aromatic index (ARR) and 3D-MoRSE code value of scattering angle at 8Å −1. These two physicochemical properties shall be helpful in the development of more potent analogs.

Exploring Structural Feature of Aldose-Reductase Inhibition by 5-[[2-(.OMEGA.-Carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine Derivatives Employing Fujita-Ban and Hansch Approach

Designing of a highly selective, potent and safe inhibitor of aldose reductase (ALR) capable of potentially blocking the excess glucose flux through the polyol pathway that prevails under diabetic condition has been a long standing challenge. In our study, we did quantitative structure-activity relationship (QSAR) analysis, based on Fujita-Ban and classical Hansch approach, on 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives. Study gave structural insight into the binding mode of the molecules to the aldose reductase enzyme. The Fujita-Ban approach revealed that benzylidene thiazolidine nucleus is more potent as compare to naphthyl-methylene thiazolidine analogs. The bulkierness of naphthyl-methylene might be inquisitive with receptor. Hansch approach suggested that electron-withdrawing groups are conducive to aldose reductase inhibitory activity.

Quantitative Structure Activity Relationships of Some Selective Inhibitors of Glucagon Receptor: A Hansch Approach

Quantitative Structure Activity Relationships of Some Selective Inhibitors of Glucagon Receptor: A Hansch Approach