Antifungal activity of organobismuth compounds against the yeast Saccharomyces cerevisiae: structure-activity relationship

Antifungal activity of organobismuth(III) and (V) compounds 1-9 was examined against the yeast, Saccharomyces cerevisiae. A clear structure-activity relationship was observed in these compounds. Thus, triarylbismuth dichlorides 2 [(4-YC6H4)3BiCl2: Y=MeO, F, Cl, CF3, CN, NO2] and halobismuthanes 6 [2-(t)BuSO2C6H4(4-YC6H4)BiX: Y=MeO, Me, H, Cl; X=Cl, Br, I], 7 [Bi(X)(C6H4-2-SO2C6H4-1'-): X=Cl, Br, I], 8 [2-Me2NCH2C6H4(Ph)BiX: X=Cl, Br] and 9 [4-MeC6H4(8-Me2NC10H6-1-)BiCl] showed the growth inhibition effect, while triarylbismuth difluorides 3 [(4-YC6H4)3BiF2] and triarylbismuthanes 1 [(4-YC6H4)3Bi], 4 [2-(t)BuSO2C6H4(4-YC6H4)2Bi] and 5 [4-YC6H4Bi(C6H4-2-SO2C6H4-1'-)] were not active at all irrespective of the nature of the substituents. Generation of the inhibition effect is governed by the facility of nucleophilic reaction at the bismuth center and the Lewis acidic bismuth center is an active site. Of all the bismuth compounds attempted, halobismuthanes 7 derived from diphenyl sulfone exhibited the highest activities. An X-ray crystallographic study of 7a [Bi(Cl)(C6H4-2-SO2C6H4-1'-)] revealed that the bismuth center adopts a seven-coordinated geometry, which is unusual in organobismuth(III) compounds, through the intramolecular and intermolecular coordination between the bismuth and oxygen atoms. The marked inhibition effect of 7 may be attributed to such a highly coordinated geometry, which allows the bismuth center to bind tightly with some biomolecules playing important roles in the growth of S. cerevisiae.     

A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: Contribution of conformational flexibility to inhibitory activity

In this study, we investigated by linear regression model the SAR data of the 15 HIV-1 protease inhibitors possessing structurally diverse scaffolds. First, a regression model was developed only using the enzyme-inhibitor interaction energy as a term of the model, but did not provide a good correlation with the inhibitory activity (R2 = 0.580 and Q2 = 0.500). Then, we focused on the conformational flexibility of the inhibitors which may represent the diversity of the inhibitors, and added two conformational parameters into the model, respectively: the number of rotatable bonds of ligands (deltaSrot) and the distortion energy of ligands (deltaElig). The regression model by adding deltaElig successfully improved the quality of the model (R2 = 0.771 and Q2 = 0.713) while the model with deltaSrot was unsuccessful. The prediction for a training inhibitor by the deltaElig model also showed good agreement with experimental activity. These results suggest that the conformational flexibility of HIV-1 protease inhibitors directly contributes to the enzyme inhibition.     

A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: contribution of conformational flexibility to inhibitory activity

In this study, we investigated by linear regression model the SAR data of the 15 HIV-1 protease inhibitors possessing structurally diverse scaffolds. First, a regression model was developed only using the enzyme-inhibitor interaction energy as a term of the model, but did not provide a good correlation with the inhibitory activity (R² = 0.580 and Q² = 0.500). Then, we focused on the conformational flexibility of the inhibitors which may represent the diversity of the inhibitors, and added two conformational parameters into the model, respectively: the number of rotatable bonds of ligands (ΔSrot) and the distortion energy of ligands (ΔElig). The regression model by adding ΔElig successfully improved the quality of the model (R² = 0.771 and Q² = 0.713) while the model with ΔSrot was unsuccessful. The prediction for a training inhibitor by the ΔElig model also showed good agreement with experimental activity. These results suggest that the conformational flexibility of HIV-1 protease inhibitors directly contributes to the enzyme inhibition.     

Nitrosamine carcinogenicity: a quantitative Hansch-Taft structure-activity relationship

Statistically significant correlations have been demonstrated between carcinogenic activity, water-hexane partition coefficients and electronic factors for an extensive series of N-nitroso compounds. Electronic factors were expressed by the Taft sigma* values of substituents on the carbon atoms alpha to the N-nitroso group. Such correlations indicate that transport of the carcinogen to its active site has an important effect on its potency. The correlations also implicate reactivity at the alpha-carbon in the determination of carcinogenic activity and point out various structural types which do not follow the general rule.     

Synthetic peptides inducing metamorphosis in a tropical jellyfish: a quantitative structure-activity relationship study

Synthetic peptides are known to trigger metamorphosis to the polyp stage in larvae and larva-like buds of the jellyfish Cassiopea andromeda. Coupling of a hydrophobic moiety to the amino terminus of such peptides was found to increase their efficiency. Hydrophobicity can thus be considered an important factor in the biological activity of peptidic inducers. By establishing the n-octanol/water partition coefficient in order to characterize the hydrophobicity of bioactive peptides, we demonstrate that this parameter and efficiency are positively correlated in peptides of the same amino acid sequence. Hydrophobicity proved to be of much lesser importance than amino acid sequence when data of structurally disparate inducer peptides were considered.     

A quantitative structure-activity relationship study on some matrix metalloproteinase and collagenase inhibitors

A quantitative structure-activity relationship (QSAR) study is made on some hydroxamic acid-based inhibitors of matrix metalloproteinases (MMPs) and a bacterial collagenase, namely Clostridium histolyticum collagenase (ChC), that also belongs to an MMP family, M-31, using Kier's valence molecular connectivity index (1)chi(v) of the substituents and electrotopological state (E-state) indices of some atoms. The results indicate that out of the four MMPs (MMP-1, MMP-2, MMP-8, and MMP-9) studied, MMP-2 and MMP-9 can be structurally quite similar, but widely differing from MMP-1 and MMP-8 and ChC. For MMP-2 and MMP-9, the inhibition activity of compounds is shown to depend on both (1)chi(v )and E-state indices, while for MMP-1 and MMP-8 it is shown to depend only on E-state indices and for ChC only on (1)chi(v). However, in all the cases, an aromatic group like C(6)F(5) or 3-CF(3)-C(6)H(4) attached to SO(2) moiety in the compounds is indicated to be equally beneficial, due to probably the involvement of fluorine atom(s) in charge-charge interactions with the Zn(2+) ion of the enzymes or in the formation of the hydrogen bonds with some sites of the receptors.     

Oxidation of liposomal membrane suppressed by flavonoids: quantitative structure-activity relationship

Antioxidant activity of the set of 12 flavonoids in heterogeneous membrane system of dioleoyl phosphatidylcholine liposomes stressed by peroxidative damage induced by 2,2'-azobis-(2-amidinopropane)hydrochloride azoiniciator and evaluated by the thiocyanate method was assessed. Antioxidant activity (pIC(50)) was correlated with 19 molecule parameters calculated for the minimum energy conformers of the compounds tested. The linear regression analysis revealed that the parameter of hydration energy E(HYDR) (R = -0.747) was the best predictor of antioxidant activity in a liposomal system.     

A quantitative structure-activity relationship study on Clostridium histolyticum collagenase inhibitors: roles of electrotopological state indices

A quantitative structure-activity relationship (QSAR) study has been made on eight different series of Clostridium histolyticum collegenase (ChC) inhibitors. These series are comprised of four different groups of sulfonylated amino acids and their corresponding hydroxamates. In each series, the inhibition potency of the compounds has been found to be significantly correlated with the electrotopological state (E-state) indices of nitrogen and sulfur atoms of the sulfonylated amino group in the molecules, showing the importance of the electronic characterstics of these atoms in controlling the inhibition potency of the compounds.     

Simple criterion for selection of flavonoid compounds with anti-HIV activity

Flavonoid compounds represent an important natural source of antiretrovirals for AIDS therapy due to their significant anti-HIV-1 activity and low toxicity. Here we propose a simple theoretical criterion to discriminate active from inactive flavonoids that is suitable for rapid in silico screening of flavonoid libraries, and selection and optimization of lead compounds with anti-HIV-1 activity.     

A quantitative structure-activity relationship study on matrix metalloproteinase inhibitors: Piperidine sulfonamide aryl hydroxamic acid analogs

A quantitative structure-activity relationship (QSAR) study has been made on a series of piperidine sulfonamide aryl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibitory potencies of the compounds against two MMPs, MMP-2 and MMP-13, are found to be significantly correlated with the hydrophobic properties of the molecules, suggesting that in both enzymes the hydrophobic interaction is playing a dominant role.     

A quantitative structure-activity relationship study on matrix metalloproteinase inhibitors: piperidine sulfonamide aryl hydroxamic acid analogs

A quantitative structure-activity relationship (QSAR) study has been made on a series of piperidine sulfonamide aryl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibitory potencies of the compounds against two MMPs, MMP-2 and MMP-13, are found to be significantly correlated with the hydrophobic properties of the molecules, suggesting that in both enzymes the hydrophobic interaction is playing a dominant role.     

A quantitative structure-activity relationship study on some series of anthranilic acid-based matrix metalloproteinase inhibitors

A quantitative structure-activity relationship (QSAR) study has been made on four different series of anthranilic acid-based matrix metalloproteinase (MMP) inhibitors, in which two substituted aryl rings, one bearing the hydroxamic acid moiety that binds with the zinc atom of MMPs, are joined through a bridge group of sulfonamide. The QSAR results indicate that the sulfonamide group plays a very important role in the inhibition activity of the inhibitors and that the effectiveness of this sulfonamide group can be increased by the presence at the aryl rings or at the sulfonamide nitrogen itself of nitrogen-containing or some such substituents that can increase the electronic character of the sulfonamide group. The hydrophobic character of the molecules is not found to be of any advantage; rather in most of the cases it is shown to have detrimental effect, suggesting that MMPs provide little opportunity to the inhibitors to have a any hydrophobic interactions with them. On the other hand, polarizability of the molecules has been found to be conducive to activity in some cases. Thus the inhibition mechanism seems to predominantly involve the electronic interactions between the inhibitors and the enzymes.     

Comparative quantitative structure-activity study of radical scavengers

Classic and three-dimensional (3-D) QSAR analyses of 13 radical scavengers (1-13) were performed to derive two classic, two Apex-3-D and one comparative field analysis (CoMFA) models. Two classical models with predictive cross-validated r2 (Q2) over 0.96 indicated that the activity was attributed to the electronic COH and ELUMO, steric molar refractivity (MR) and lipophilic log P. Three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies were performed by 3-D pharmacophore generation (Apex-3-D) and CoMFA techniques. For Apex-3-D studies, two best models with high Q2 (0.94 and 0.97) were yielded. Structural properties contributing to the activity were not only lipophilic but also the optimum steric property and geometry of side-chain composition. For CoMFA studies, the sp3 C(+1) probe provided the best Q2 of 0.79 with steric and electrostatic contributions of 42.3 and 57.7%, respectively. The activity of four new compounds (14-17) not included in the derivation were predicted with these models. Although the derived models were from limited data, the statistic relation was predictive. The linear correlations between the experimental IC50 values and the predicted values from classical and Apex-3-D models were found to be high and significant. The predicted activity of 17 from CoMFA was much lower than the experimental value; this deviation occurred according to the missing of hydrophobic field in standard CoMFA study. In vitro and ex vivo antilipid peroxidation in mouse brain and ESR studies of 14-17 were investigated for the radical-scavenging ability. The difference between the in vitro results, antilipid peroxidation and electron spin resonance (ESR) and ex vivo results in coumarin series was found. Thus, other properties for good bioavailability besides log P should also be taken into consideration.     

Antinociceptive activity of structural analogues of rotundifolone: structure-activity relationship

Rotundifolone, a monoterpene isolated from the essential oil of the leaves of Mentha x villosa, is a constituent of several essential oils and known to have antinociceptive activity. Our recent study demonstrated that the analogues of rotundifolone showed also a significant antinociceptive effect. In the present report, to investigate the correlation between the structure and antinociceptive activity, rotundifolone and its analogues were evaluated in the acetic acid-induced writhing test in mice. All compounds showed to be more antinociceptive than rotundifolone against the pain response induced by acetic acid. Comparing the antinociceptive effect of rotundifolone with limonene oxide and (+)-pulegone, the results demonstrated that the epoxide group contributes as much as the ketone group to the antinociceptive activity of rotundifolone. Similarly, pulegone oxide and carvone epoxide were more antinociceptive than rotundifolone, thereby suggesting that the position of the functional group on the ring also influences the antinociceptive activity. (-)-Carvone produced maximal inhibition of the writhing response and was slightly more active than (+)-carvone. The study showed that by appropriate structural modification it may be possible to develop novel antinociceptive agents.     

Antiproliferative activity in HL60 cells by tetrasubstituted pyrroles: a structure-activity relationship study

A number of tetrasubstituted pyrrole derivatives have been synthesized and evaluated for their in vitro antiproliferative activities using the human promyelocytic leukemia cell line HL60. Tetrasubstituted pyrroles are obtained by irradiation of a silica gel absorbed mixture of a conjugated alkynoate and a primary amine. Active compounds exhibited GI50 values in the range 4-45 microM, and only six products showed TGI values within the evaluation range. A structure-activity relationship is also discussed.     

Synthesis of DL-standishinal and its related compounds for the studies on structure-activity relationship of inhibitory activity against aromatase

DL-Standishinal (1), an aromatase inhibitor isolated from Thuja standishii, was synthesized in 15 steps from p-formylanisole via aldol reaction of 12-hydroxy-6,7-secoabieta-8,11,13-trien-6,7-dial (2). In the present study, we found that the aldol condensation of 2 proceeded in excellent yield with the protonic catalyst such as d-camphorsulfonic acid in CH(2)Cl(2). Moreover, structure-activity relationship of 1 and its related compounds was studied and it was revealed that the isomers having cis-configuration on the A/B-ring generally exhibited more potent inhibitory activities against aromatase than those with trans-configuration.