Impact of Topological and Electronic Descriptors in the QSAR of Pyrazine Containing Thiazolines and Thiazolidinones as Antitubercular and Antibacterial Agents
TL;DR: Quantitative structure activity relationships were developed relating the 14th and 21st day antituberculosis activity against H37Rv strain of Mycobacterium tuberculi and antibacterial activity against Staphylococcus aureus ATCC3750 and 55 pyrazine containing thiazolines and thiazolidinones, with the molecular descriptors.
Abstract: Quantitative structure activity relationships (QSAR) were developed relating the 14th and 21st day antituberculosis activity against H(37)Rv strain of Mycobacterium tuberculi and antibacterial activity against Staphylococcus aureus ATCC3750, Bacillus subtilis 6633, Escherichia coli ATCC3750, and Salmonella typhi NCTC786 of 55 pyrazine containing thiazolines and thiazolidinones, with the molecular descriptors. The developed models were able to fit the data well (r(2) = 0.69-0.87) and had reasonable predictive capability (q(2) > 0.62). The data were also divided into a training set and a test set, the former was used to develop the QSAR and the latter was used to evaluate the predictive capability of these developed models. In all the cases, the models were able to predict the test data set reasonably well. Predominantly, pyrazine ring is well-known for its antimycobacterial activity and hence these equation could be used to design newer analogues with higher activity. These compounds also possess both antitubercular and antibacterial activity. Descriptors pertaining to electronic, topology, and hydrophobicity of the molecules appear in the model equations.
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TL;DR: Topology, shape, charge distribution and hydrophobic nature of the molecules had pronounced effect on the antibacterial activity of these dispiropyrrolidines.
82 citations
TL;DR: Size, polarizability, electron‐donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram‐positive and Gram‐negative bacteria.
Abstract: Forty-eight chalcone analogs were synthesized and their in vitro antibacterial activity against Staphylococcus aureus NCIM 5021, Bacillus subtilis NCIM 2718, Phaseolus vulgaris NCIM 2813, Escherichia coli NCIM 2931, Salmonella typhi 2501 and Enterobacter aerogenes NCIM 5139 were evaluated by microdilution broth assay. Quantitative structure–activity relationships were developed for all the cases (r 2 = 0.68–0.79; = 0.58–0.78; q 2 = 0.51–0.68; F = 13.02–61.51). Size, polarizability, electron-donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram-positive and Gram-negative bacteria. Staphylococcus aureus was the most and S. typhi was the least hydrophobic of these organisms. These chalcones act better against more hydrophobic organisms. The more active chalcones have log P between 1.5 and 3. Compound 24, one of the most active compounds, was found to act by damaging the cell wall of S. aureus. Slimicidal activity of five of the most active compounds (24, 31, 32, 34 and 37) was found to be in the range of 48–60% against S. aureus and 40–54% against E. coli. A correlation was observed among the hydrophobicity of the compounds, hydrophobicity of the bacterial cell surface and the antibacterial activity of the compound.
60 citations
Cites background from "Impact of Topological and Electroni..."
...Electrons which occupy the high energy orbitals are less tightly bound, when compared with those which occupy the low energy orbital so the former are easily delocalizable, and hence they are highly reactive (46)....
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TL;DR: Since pyrazolines are reported to inhibit the activity of p-glycoprotein, they may prevent drug resistance developed by microorganism.
37 citations
TL;DR: Three‐dimensional quantitative structure–activity relationship studies indicated that electrostatic and steric field descriptors could explain the observed activity of quinoxaline derivatives with 2‐chloro, dimethylamino and nitro substitutions.
Abstract: Twenty new quinoxalines bearing azetidinone and thiazolidinone groups were synthesized by cyclocondensation of Schiff bases of quinoxaline-2, 3-dione and were characterized with several analytical tools. They were tested against Mycobacterium tuberculosis H37Rv at a concentration of 10 μg/mL by Microplate Alamar Blue Assay method. Quinoxaline derivatives with 2-chloro, dimethylamino and nitro substitutions exhibited in vitro activity, comparable to that of the drug, isoniazid. Three-dimensional quantitative structure-activity relationship studies indicated that electrostatic and steric field descriptors could explain the observed activity. The developed model fits the data well and has good predictive capability (r² = 0.81, q² = 0.71, F = 27.06, r² _pred = 0.84, r²(m) = 0.84, r² BS = 0.80). Electronegative groups play an important role in the antitubercular activity.
28 citations
Cites background or methods from "Impact of Topological and Electroni..."
...Similar descriptors have been identified while studying the antiTB activity of thiazolines and thiazolidinones (20)....
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...The structure of the 20 quinoxalines (Table 1) was drawn, and their minimum energy conformations were determined with MM+ force field using HYPERCHEM version 8 software (Molecular Modelling Tool, Hypercube Inc, Gainesville, FL, USA) (20)....
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...Quantitative structure–activity relationship The structure of the 20 quinoxalines (Table 1) was drawn, and their minimum energy conformations were determined with MM+ force field using HYPERCHEM version 8 software (Molecular Modelling Tool, Hypercube Inc, Gainesville, FL, USA) (20)....
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TL;DR: A series of structurally related Zn(II), Cu(II) and Ni(II)-clO4 complexes have been synthesized and characterized by spectroscopy, single crystal X-ray crystallography and density functional theory.
Abstract: A series of structurally related Zn(II), Cu(II) and Ni(II) complexes of 4-(2-(2-(1-(pyrazin-2-yl)ethylidene)hydrazinyl)-thiazol-4-yl)-benzonitrile (PyztbH) have been synthesized and characterized by spectroscopy, single crystal X-ray crystallography and density functional theory (DFT). All the complexes are mononuclear and the molecular composition of the complexes viz. [Zn(Pyztb)2] (1), [Zn(PyztbH)(SCN)2] (2), [Cu(Pyztb)(N3)(MeOH)] (3) and [Ni(Pyztb)(PyztbH)]ClO4 (4) is confirmed by single crystal X-ray crystallography. The interaction of the compounds with calf thymus DNA (CTDNA) was studied by various spectroscopic methods (UV-Vis and fluorescence) and molecular docking study. Both the binding constant (kb) and the Stern–Volmer dynamic quenching constant (KSV) values of the compounds are in the order of 104 indicating the intercalative binding mode of the compounds with CTDNA. The molecular docking study revealed that PyztbH, 1 and 3 are well fitted in the active sites of DNA having higher binding affinity than 2 and 4. All the synthesized compounds are assessed for anticancer activity towards different human cancer cell lines having different tissue origin e.g., U-937 (histiocytic lymphoma), HepG2 (hepatic carcinoma), HEK293T (embryonic kidney), U2OS (osteosarcoma), HeLa (cervical epithelium), A549 (lung carcinoma) and A431 (squamous carcinoma). The thiazole–pyrazine ligand shows relatively less cytotoxicity toward the tested cell lines than its metal derivatives. MTT assays reveal that 1 (IC50 values 1.5 to 21 μM) and 3 (IC50 values 1.0 to 15 μM) showed higher cytotoxicity than 2 (IC50 values 1.0 to 126 μM) and 4 (IC50 values 9 to 106 μM) across the cell types. Both 1 and 3 follow the necroptotic pathway of cell death, whereas 2 and 4 follow the apoptotic pathway. Peripheral blood mononuclear cell (PBMC) assay of 1, 2 and 4 revealed nontoxicity in normal blood cells.
22 citations
References
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4,724 citations
TL;DR: In this article, a method for the rapid calculation of atomic charges in σ-bonded and nonconjugated π-systems is presented, where only the connectivities of the atoms are considered.
3,640 citations
Book•
01 Jan 2002
TL;DR: This Users guide notations acronyms list of molecular descriptors contains abbreviations for molecular descriptor values that are useful for counting and topological descriptors calculation.
Abstract: Users guide notations acronyms list of molecular descriptors. Appendices: counting and topological descriptors calculation of descriptors tables of molecular descriptor values.
3,220 citations
2,920 citations
TL;DR: Differences in mycolic acid structure may affect the fluidity and permeability of the bilayer, and may explain the different sensitivity levels of various mycobacterial species to lipophilic inhibitors.
Abstract: Mycobacteria, members of which cause tuberculosis and leprosy, produce cell walls of unusually low permeability, which contribute to their resistance to therapeutic agents. Their cell walls contain large amounts of C60-C90 fatty acids, mycolic acids, that are covalently linked to arabinogalactan. Recent studies clarified the unusual structures of arabinogalactan as well as of extractable cell wall lipids, such as trehalose-based lipooligosaccharides, phenolic glycolipids, and glycopeptidolipids. Most of the hydrocarbon chains of these lipids assemble to produce an asymmetric bilayer of exceptional thickness. Structural considerations suggest that the fluidity is exceptionally low in the innermost part of bilayer, gradually increasing toward the outer surface. Differences in mycolic acid structure may affect the fluidity and permeability of the bilayer, and may explain the different sensitivity levels of various mycobacterial species to lipophilic inhibitors. Hydrophilic nutrients and inhibitors, in contra...
1,825 citations
"Impact of Topological and Electroni..." refers background in this paper
...In the case of Mycobacterium tuberculi, mycolic acid is the major component of the cell wall, which is responsible for its waxy nature affecting the diffusion of molecules into the cell (15)....
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