• Bulletin of the Korean Chemical Society
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• v.26 no.12
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• pp.1941-1945
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• 2005

To raises the possibility of designing effective inhibitors, 3D-QSAR for the inhibition of calcineurin-NFAT signaling by new N-(4-oxo-1(4H)-naphthalenylidene benzenesulfonamide derivatives as inhibitors of intracellular protein-protein interactions were studied using CoMFA and CoMSIA methodology. The three templates, N-(4-oxo-1(4H)-naphthalenylidene)benzenesulfonamide (A), benzenesulfonamide (B) and 4-oxo-1(4H)-naphthalenylidene (C) were selected to improve the statistic of the present 3D-QSAR models. The best models with combination of standard field in CoMFA, and steric field and electrostatic field in CoMSIA derived from the template, B and C, because most of the compounds tend not to be aligned in template A. From the based on the CoMFA and CoMSIA contour maps, the $R_1$ and $R_2$ groups on 4-oxo-1(4H) naphthalenylidene ring are steric favor. The ortho position on the benzenesulfonyl ring is steric disfavor and the meta position is steric favor. In addition, the oxygene atom of carbonyl group will have better inhibition activities as it has a negative charge favor. From these findings, we can conclude that the analyses of the contour maps provided insight into possible modification of molecules for effective inhibitiors.

• Bulletin of the Korean Chemical Society
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• v.33 no.9
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• pp.2971-2975
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• 2012

Second-order rate constants $k_N$ have been measured spectrophotometrically for nucleophilic substitution reactions of t-butyl 4-pyridyl carbonate 8 with a series of alicyclic secondary amines in $H_2O$ at $25.0{\pm}0.1^{\circ}C$. The Br${\emptyset}$nsted-type plot for the reactions of 8 is linear with ${\beta}_{nuc}$ = 0.84. The ${\beta}_{nuc}$ value obtained for the reactions of 8 is much larger than that reported for the corresponding reactions of t-butyl 2-pyridyl carbonate 6 (i.e., ${\beta}_{nuc}$ = 0.44), which was proposed to proceed through a forced concerted mechanism. Thus, the aminolysis of 8 has been concluded to proceed through a stepwise mechanism with a zwitterionic tetrahedral intermediate $T^{\pm}$, in which expulsion of the leaving-group from $T^{\pm}$ occurs at the rate-determining step (RDS). In contrast, aminolysis of benzyl 4-pyridyl carbonate 7 has been reported to proceed through two intermediates, $T^{\pm}$ and its deprotonated form $T^-$ on the basis of the fact that the plots of pseudo-first-order rate constant $k_{obsd}$ vs. amine concentration curve upward. The current study has demonstrated convincingly that the nature of the leaving and nonleaving groups governs the reaction mechanism. The contrasting reaction mechanisms have been rationalized in terms of an intramolecular H-bonding interaction, steric acceleration, and steric inhibition.

• Archives of Pharmacal Research
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• v.21 no.5
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• pp.595-598
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• 1998

The rate of the GSH conjugate formation, the inhibition of DNA topoisomerase-I and the cytotoxic activity against L1210 cells of the naphthoquinones showed the same order; 5,8-dimethoxy-1,4-naphthoquinone (DMNQ)>6-(1-hydroxyethyl)-DMNQ>2-(1-hydroxyethyl)-DMNQ; the steric hindrance of the substituents, particularly 2-substutuent, in reacting with cellular nucleophiles must be the main cause for lowering the bioactivities. Acetylation of 2-(1-hydroxyethyl)-DMNQ producing 2-(acetyloxyethyl)-DMNQ potentiated the bioactivities; 2-(-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed $ED_{50}$ of 0.146 mg/ml for the cytotoxcity. Furthermore, the acetylation 2-(1-hydroxyethyl)-DMNQ(T/C, 119%) enhanced the T/C values for the mice bearing S-180 tumor {T/C of 2-(1-acetyloxyethyl)-DMNQ, 276%]. It was assumed that the difference in bioactivities ensued by acetylation was based on the mechanism of the so-called bioreductive alkylation.

• Archives of Pharmacal Research
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• v.13 no.1
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• pp.82-96
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• 1990

Ten (E)-and (Z)-isomers of 2-phenylcyclopropylamine (PCA), 1-Me PCA, 2-Me-PCA, N-Me-PCA, and N, N-diMe PCA and fifteen o-. m-, p- isomers of (E) PCA with substituents of Me, Cl, F, OMe, OH were synthesized in this laboratory and tested for the inhibition of rat brain mitochondrial MAO-A and MAO-B. The effects of substituents, their positions, and stereochemistry on the inhibition were assessed for the compounds with substituents at cyclopropyl and amino groups and QSAR analyses were performed using the potency data of ring-substituted compounds. The best correlated QSAR equations are as follows : pI$_{50}$ = 0.804 $\pi^2$-0.834 Blo-1.069 Blm + 0.334 Lp-1.709 HDp +7.897 (r = 0.945, s =0.211, F = 16.691, p = 0.000) for the inhibition of MAO-A;PI$_{50}$= 1.815$\pi$-0.825 $\pi^2$-1.203R + 0.900 Es$^2$ + 0.869 Es$^3$ + 0.796 Es$^4$-0.992 HDp + 0.562 HAo + 3.893 (r = 0.982, s =0.178, F = 23.351, p = 0.000) for the inhibition of MAO-B. Based on the potency difference between stereoisomers of cyclopropylamine-modified compounds and an QSAR cavity near para position, two hydrophobic carities interacting with Me group, a hydrophobic site near para position, and an amino group binding site and that in addition to the same two hydrophotic cavities, hydrophotic area, steric boundaries, hydrogen-acceptor site, and amino group binding site, another steric boundary near para position and a hydrogen donating site near ortho position constitute active sites of MAO-B.

• Applied Biological Chemistry
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• v.47 no.4
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• pp.414-421
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• 2004

3D QSAR studies for protox inhibition activities against root and shoot of the rice plant (Orysa sativa L.) and barnyardgrass (Echinochloa crus-galli) by a series of new 1-(5-methyl-3-phenylisoxazolin-5-yl)methoxy-2-chloro-4-fluorobenzene derivatives were conducted based on the results (Sung, N. D. et al.'s, (2004) J. Korean Soc. Appl. Biol. Chem. 47(3), 351-356) using comparative molecular similarity indices analysis (CoMSIA) methodology. Four CoMSIA models, without hydrogen bond donor field for the protox inhibition activities against root and shoot of the two plants, were derived from the combination of several fields using steric field, hydrophobic field, hydrogen bond acceptor field, LUMO molecular orbital field, dipole moment (DM) and molar refractivity (MR) as additional descriptors. The predictabilities and fitness of CoMSIA models for protox inhibition activities against barnyard-grass were higher than that of rice plant. The statistical results of these models showed the best predictability of the protox inhibition activities against barnyard-grass based on the cross-validated value $r^2\;_{cv}\;(q^2=0.635{\sim}0.924)$, non cross-validated, conventional coefficient $r^2\;_{ncv.}$ value $(r^2=0.928{\sim}0.977)$ and PRESS value $(0.255{\sim}0.273)$. The protox inhibition activities exhibited a strong correlation with the steric $(5.4{\sim}15.7%)$ and hydrophobic $(68.0{\sim}84.3%)$ factors of the molecules. Particularly, the CoMSIA models indicated that the groups of increasing steric bulk at ortho-position on the C-phenyl ring will enhance the protox inhibition activities against barnyard-grass and subsequently increase the selectivity.

• Bulletin of the Korean Chemical Society
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• v.30 no.3
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• pp.613-617
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• 2009

3D-QSARs for the inhibition activities against protox by herbicidal 2-N-phenylisoindolin-1-one derivatives were studied quantitatively using CoMFA and CoMSIA methods. The result of the statistical quality of optimized CoMSIA model 2 ($FF:\;{r^2}_{cv.};\;0.973\;&\;{r^2}_{ncv.};\;0.612$) was higher than that of CoMFA model 1 ($AF:\;{r^2}_{cv.};\;0.414\;&\;{r^2}_{ncv.};\;0.909$). Also, the relative contribution of the optimized CoMSIA model 2 showed the steric (24.6%), electrostatic (31.0%), hydrophobic (ClogP, 23.4%) and H-bond acceptor field (21.0%), respectively. From the results of the contour maps, the protox inhibition activities are expected to increase when steric favor and H-bond acceptor favor groups are substituted on $R_2$ position and positive favor group are substituted on $C_2,\;C_3,\;and\;C_5$ atom in phenyl ring of $R_2$ position. And the inhibition activities are expected to increase when hydrophobic favor group is substituted on $C_1,\;C_3$ atom in phenyl ring of $R_2$ position and $C_1$ atom of $R_2$ position and hydrophilic favor groups are substituted on $C_4$ atom in phenyl ring of $R_1$ position and the terminal group of $R_1$ position.

• Journal of Pharmaceutical Investigation
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• v.36 no.2
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• pp.103-107
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• 2006

In order to develop hydroquinone analogues for topical delivery, a structure-activity relationship study has been performed. A series of 2-substituted hydroquinones were tested for their ability to inhibit mushroom tyrosinase, alter melanin release and exert cytotoxicity in B6-F10 melanocytes. The electronic property of the 2-substituents did not affect the tyrosinase inhibition nor melanocyte toxicity. However, lipophilicity did affect to some degree the tyrosinase inhibition. The discrepancy in the structure-activity relationship may be due to the poor aqueous solubility of select analogues. Compounds with steric bulk at the 2-position seems to be less soluble, not enabling the analogue to interact effectively with the tyrosinase enzyme. Among the analogues tested, 2-isopropyl hydroquinone seems to be the most promising candidate for topical delivery, being the least toxic analogue with moderate melanin release inhibition.

• Corrosion Science and Technology
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• v.16 no.4
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• pp.187-193
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• 2017

Polymer amines are found to show distinct corrosion inhibition effects in acidic media. The functional groups of organic compounds have a wide role in the physical and chemical properties, for the inhibition efficiency with respect to steric factors, aromaticity, and electron density. The influence of $H^+$ ions and $Cl^-$ ions on the corrosion inhibitive effect of poly(p-aminophenol) for iron in hydrochloric acid was studied using electrochemical methods such as impedance, linear polarization, and Tafel polarization techniques. The experiments were conducted with and without the inhibitor, poly(p-aminophenol). The concentration range of $H^+$ ions and $Cl^-$ ions are from 1 M to 0.05 M and 1 M to 0.1 M, respectively. With the inhibitor poly(p-aminophenol), this study shows that inhibition efficiency decreases with the reduction of $H^+$ ion and $Cl^-$ ion concentrations in aqueous solution. Further, it reveals that the adsorption of an inhibitor on the surface of iron is dependent on the concentrations of $H^+$ and $Cl^-$ ions in the solution and the adsorption of inhibitor on the iron surface through the cationic form of amine.

• Molecular & Cellular Toxicology
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• v.2 no.3
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• pp.216-221
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• 2006

The cholinesterase-inhibiting organophosphorous (OP) compounds known as nerve agents are highly toxic. The principal toxic mechanism of OP compounds is the inhibition of acethylcholine esterase (AChE) by phosphorylation of its catalytic site. The reversible competitive inhibition of AChE may prevent the subsequent OP intoxication. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) was performed to investigate the relationship between the 29 compounds with structural diversity and their bioactivities against AChE. In particular, predictive models were constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results indicate reasonable model for CoMFA ($q^{2}=0.453,\;r^{2}=0.697$) and CoMSIA ($q^{2}=0.518,\;r^{2}=0.696$). The presence of steric and hydophobic group at naphtyl moiety of the model may lead to the design of improved competitive inhibitors for organophosphorous intoxication.

• Archives of Pharmacal Research
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• v.22 no.5
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• pp.507-514
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• 1999

6-(1-azidoalkyl)-DMNQ derivatives compared to 2-(1-azidoalkyl)-DMNQ isomers, exhibited higher cytotoxic activity against L1210 mouse leukemia cells and stronger inhibition of DNA topoisomerase-I (TOPO-I), suggesting involvement of steric hindrance. However, similar antitumor activity against mice bearing S-180 cell was shown by 2-an 6-(1-azidoalkyl)-DMNQ derivatives.