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).     

Atomic property fields: generalized 3D pharmacophoric potential for automated ligand superposition, pharmacophore elucidation and 3D QSAR

The atomic property fields (APF) concept is introduced as a continuous, multi-component 3D potential that reflects preferences for various atomic properties at each point in space. Atomic property field-based approaches to several key problems in the field of ligand structure-based rational drug discovery and design are investigated. The superposition of ligands on one or multiple molecular templates is performed by Monte-Carlo minimization in the atomic property fields potentials combined with standard force-field energy. The approach is extended to multiple flexible ligand alignments using an iterative procedure, Self-Consistent atomic Property Fields by Optimization (SCAPFOld). The application of atomic property fields and SCAPFOld for virtual ligand screening and 3D Quantitive Structure-Activity Relationship (QSAR) is tested on published benchmarks. The new methods are shown to perform competitively in comparison to current state-of-the-art methods.     

Exploring QSARs for antiviral activity of 4-alkylamino-6-(2-hydroxyethyl)-2-methylthiopyrimidines by support vector machine

The support vector machine, which is a novel algorithm from the machine learning community, was used to develop quantitative structure activity relationship models to predict the antiviral activity of 4-alkylamino-6-(2-hydroxyethyl)-2-methylthiopyrimidines. The genetic algorithm was employed to select the variables that resulted in the best-fitted models. A comparison between the obtained results using support vector machine with those of multiple linear regression revealed that support vector machine model was much better than multiple linear regression. The root mean square errors of the training set and the test set for support vector machine model were calculated to be 0.102 and 0.205, and the correlation coefficients (r2) were 0.956 and 0.852, respectively. Furthermore, the obtained statistical parameter of leave-one-out (LOO) and leave-group-out (LGO) cross-validation test on support vector machine model were 0.893 and 0.881, respectively, which prove the reliability of this model. The results suggest that branching, volume and lipophilicity are the main independent factors contributing to the antiviral activities of the studied compounds.     

Cytotoxic Activity and Quantitative Structure Activity Relationships of Arylpropyl Sulfonamides

B13 is a ceramide analogue and apoptosis inducer with potent cytotoxic activity. A series of arylpropyl sulfonamide analogues of B13 were evaluated for their cytotoxicity using MTT assays in prostate cancer PC-3 and leukemia HL-60 cell lines. Some compounds (4, 9, 13, 14, 15, and 20) showed stronger activities than B13 in both tumor cell lines, and compound (15) gave the most potent activity with IC₅₀ values of 29.2 and 20.7 µM, for PC-3and HL-60 cells, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed to build highly reliable and predictive CoMSIA models with cross-validated q² values of 0.816 and 0.702, respectively. Our results suggest that long alkyl chains and a 1R, 2R configuration of the propyl group are important for the cytotoxic activities of arylpropyl sulfonamides. Moreover, the introduction of small hydrophobic groups in the phenyl ring and sulfonamide group could increase biological activity.     

Pharmacophore, 3D‐QSAR,and Bayesian Model Analysis for Ligands Binding at the Benzodiazepine Site of GABAA Receptors: the Key Roles of Amino Group and Hydrophobic Sites

Ligands binding at the benzodiazepine site of GABA_A receptor play important pharmacological roles in clinical application. In this study, ligand‐based pharmacophore modeling, 3D‐QSAR analysis, and Bayesian model studies have been performed on a set of 84 diverse ligands binding at the benzodiazepine site. The results showed the best pharmacophore hypothesis AADHR.4, which included two hydrogen acceptors (A), one hydrogen donor (D), one hydrophobic group (H), and one aromatic ring (R). Atom‐based 3D‐QSAR model was built, and it showed good statistical significance (R² = 0.936) and excellent predictive ability (Q² = 0.821). Moreover, Bayesian model was developed and used to identify the key molecular features which are good or bad for the ligand binding activity. All the results from the pharmacophore, 3D‐QSAR, and Bayesian modeling studies revealed that a hydrogen‐bond donor (e.g., N‐H) and a hydrophobic group (e.g., Br) are critical structural features for the ligands binding at the benzodiazepine site.     

Synthesis,Antibacterial Activities,and 3D‐QSAR of Sulfone Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

A series of sulfone derivatives containing 1, 3, 4‐oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC₅₀ values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b , and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC₅₀ values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC₅₀ values of 45.91 and 216.70 μg/mL, respectively. The structure–activity relationship (SAR) of compounds was studied using three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D‐QSAR models effectively predicted the correlation between inhibitory activity and steric–electrostatic properties of compounds.