Abstract
Electronic structures, the effect of the substitution, structure physicochemical property/activity relationships and drug-likeness applied in pyrazine derivatives, have been studied at ab initio (HF, MP2) and B3LYP/DFT (density functional theory) levels. In the paper, the calculated values, i.e., NBO (natural bond orbitals) charges, bond lengths, dipole moments, electron affinities, heats of formation and quantitative structure-activity relationships (QSAR) properties are presented. For the QSAR studies, we used multiple linear regression (MLR) and artificial neural network (ANN) statistical modeling. The results show a high correlation between experimental and predicted activity values, indicating the validation and the good quality of the derived QSAR models. In addition, statistical analysis reveals that the ANN technique with (9-4-1) architecture is more significant than the MLR model. The virtual screening based on the molecular similarity method and applicability domain of QSAR allowed the discovery of novel anti-proliferative activity candidates with improved activity.
Highlights
Pyrazine is a heterocyclic compound containing two nitrogen atoms in its aromatic ring with molecular formula C4H4N2.1 it is a symmetrical molecule with point group D2h.Pyrazine is less basic than pyridine, pyridazine and pyrimidine
The goal of the present study is to validate a suitable methodology for the accurate prediction of molecular geometries and energetic properties of potentially active compounds, and to determine the best molecular descriptors to be used in conjunction with linear (MLR) and nonlinear (ANN) quantitative structure-activity relationships (QSAR) models to identify the best candidates for antiproliferative agents against the BGC823
The geometries of pyrazine and their methyl, ethyl, bromo, fluoro derivatives were fully optimized with ab initio/HF, MP2 and DFT/B3LYP methods, using both basis set 6-311G ++(d,p) and cc-pVDZ integrated with Gaussian 09 program package
Summary
Pyrazine is a heterocyclic compound containing two nitrogen atoms in its aromatic ring with molecular formula C4H4N2.1 it is a symmetrical molecule with point group D2h.Pyrazine is less basic than pyridine, pyridazine and pyrimidine. Pyrazine is a heterocyclic compound containing two nitrogen atoms in its aromatic ring with molecular formula C4H4N2.1 it is a symmetrical molecule with point group D2h. Some pyrazine derivatives contain various pharmacological effects: anti-cancer, antidepressant and anxiolytic, tuberculosis, an anti-diabetic drug and pulmonary hypertension and cardiac valve.[2,3,4,5,6,7]. Quantum chemistry methods play an important role in obtaining molecular structures and predicting various properties. To obtain highly accurate geometries and physical properties for molecules that are built from electronegative elements, expensive Ab initio/MP2 electron correlation methods are required.[8] Density functional theory methods[9,10,11,12,13,14] offer an alternative use of inexpensive computational methods which could handle relatively large molecules.[15,16,17,18,19,20]
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