Reversed-phase thin-layer chromatography with different stationary phases in studies of quantitative structure-biological activity relationship of new antimycotic compounds

Reversed-phase thin-layer chromatography with RP-8, RP-18, and RP-18W stationary phases was used in quantitative structure-activity relationship (QSAR) studies of new antimycotic compounds. The retention behavior of 10 dihydroxythiobenzanilides was examined for acquisition of log k' data. With water-acetone mixtures as the mobile phases, the concentration range for which the correlation between log k' and acetone concentration is linear was established for each stationary phase and used to determine hydrophobicity parameters log k'w by linear extrapolation. The effect of substituents on retention constants was quantitated by using the group contribution parameters tau W. On the basis of QSAR equations obtained from these studies, log k'w data can be used to predict antifungal activities of dihydroxythiobenzanilides with satisfactory accuracy.     

硝基苯类化合物的FMO位电荷密度能S_(Ei)~(HO) 与生物毒性的QSAR研究

应用简易的量化方法计算了20多种硝基苯衍生物中的64个芳环FMO位电荷密度能S_(Ei)~(HO),用回归法建立一个新的生物毒性评价方程,-lgLC_(50)=0.6191log K_(ow)+0.1881S_(Ei)~(HO)+4.0894,应用所得方程,预测有机物的生物毒性,方程对大多数化合物拟和很好。结果表明,所研究的有机物生物毒性同S_(Ei)~(HO)和log K_(ow)密切相关,同化合物与酶的活性点复合或反应是生物中毒的主要因素。     

固相微萃取技术在估算多环芳烃的辛醇-水分配系数中的应用

采用固相微萃取 气相色谱／质谱联用技术分析了水中１１种多环芳烃,并获得其平衡时的分配系数。当固相微萃取纤维上涂渍的固定液被视为一种有机溶剂时,根据萃取系统间线性的自由能关系,建立了聚二甲基硅氧烷 水分配系数（Ｋｓｗ）与正辛醇 水分配系数（Ｋｏｗ）间的关系式,并将其应用于估算其它多环芳烃的未知的醇 水分配系数。所建立的方法简单、快速,与Ｌｅｏ碎片法相比,可以更精确地估算取代基位置不同的同分异构体的Ｋｏｗ。     

Non-linear modeling of bioconcentration using partition coefficients for narcotic chemicals

Bioconcentration factors (BCFs) have traditionally been used to describe the tendency of chemicals to concentrate in aquatic organisms. A reexamination of the log-log QSAR between the BCF and Kow for non-congener narcotic chemicals is presented on the basis of recommended data for fish. The model is extended to give a simple correlation between BCF and the toxicity of highly, moderately and weakly hydrophilic chemicals. For the first time, in this study an equation for calculating BCF was applied in a QSAR model for predicting the acute toxicity of chemicals to aquatic organisms.     

Validity and validation of expert (Q)SAR systems

At a recent workshop in Setubal (Portugal) principles were drafted to assess the suitability of (quantitative) structure-activity relationships ((Q)SARs) for assessing the hazards and risks of chemicals. In the present study we applied some of the Setubal principles to test the validity of three (Q)SAR expert systems and validate the results. These principles include a mechanistic basis, the availability of a training set and validation. ECOSAR, BIOWIN and DEREK for Windows have a mechanistic or empirical basis. ECOSAR has a training set for each QSAR. For half of the structural fragments the number of chemicals in the training set is >4. Based on structural fragments and log Kow, ECOSAR uses linear regression to predict ecotoxicity. Validating ECOSAR for three 'valid' classes results in predictivity of > or = 64%. BIOWIN uses (non-)linear regressions to predict the probability of biodegradability based on fragments and molecular weight. It has a large training set and predicts non-ready biodegradability well. DEREK for Windows predictions are supported by a mechanistic rationale and literature references. The structural alerts in this program have been developed with a training set of positive and negative toxicity data. However, to support the prediction only a limited number of chemicals in the training set is presented to the user. DEREK for Windows predicts effects by 'if-then' reasoning. The program predicts best for mutagenicity and carcinogenicity. Each structural fragment in ECOSAR and DEREK for Windows needs to be evaluated and validated separately.     

Joint QSAR analysis using the Free-Wilson approach and quantum chemical parameters

A new quantitative structure-activity relationship (QSAR) technique combining the Free-Wilson method and constructed quantum chemical parameters was used to simulate the aqueous solubility (Sw), 1-octanol/water partition coefficient (Kow) of 14 new synthesized benzanilide derivatives and their 96 h acute toxicity (EC50) to Daphnia magna. The mode of action of the 14 selected compounds to Daphnia magna was shown to be a complex process involving a physical partition stage and a bio-chemical reaction stage. The results also indicated that the joint (QSAR) analysis was much effective than the original Free-Wilson method and Hansch method not only in predicting properties/toxicity, but also in investigating the mode of action of chemicals.     

Validity and validation of expert (Q)SAR systems

At a recent workshop in Setubal (Portugal) principles were drafted to assess the suitability of (quantitative) structure–activity relationships ((Q)SARs) for assessing the hazards and risks of chemicals. In the present study we applied some of the Setubal principles to test the validity of three (Q)SAR expert systems and validate the results. These principles include a mechanistic basis, the availability of a training set and validation. ECOSAR, BIOWIN and DEREK for Windows have a mechanistic or empirical basis. ECOSAR has a training set for each QSAR. For half of the structural fragments the number of chemicals in the training set is >4. Based on structural fragments and log Kow, ECOSAR uses linear regression to predict ecotoxicity. Validating ECOSAR for three ‘valid’ classes results in predictivity of ?≥?64%. BIOWIN uses (non-)linear regressions to predict the probability of biodegradability based on fragments and molecular weight. It has a large training set and predicts non-ready biodegradability well. DEREK for Windows predictions are supported by a mechanistic rationale and literature references. The structural alerts in this program have been developed with a training set of positive and negative toxicity data. However, to support the prediction only a limited number of chemicals in the training set is presented to the user. DEREK for Windows predicts effects by ‘if-then’ reasoning. The program predicts best for mutagenicity and carcinogenicity. Each structural fragment in ECOSAR and DEREK for Windows needs to be evaluated and validated separately.     

硝基苯类化合物的FMO位电荷密度能S_(Ei)~(HO)与生物毒性的QSAR研究

应用简易的量化方法计算了20多种硝基苯衍生物中的64个芳环FMO位电荷密度 能S_(Ei)~(HO)，用回归法建立了一个新的生物毒性评价方程，-lg LC_(50)=0. 6191log K_(ow)+0.1881S_(Ei)~(HO)+4.0894，应用所得方程，预测有机物的生物 毒性，方程对大多数化合物拟和很好。结果表明，所研究的有机物生物毒性同S_ (Ei)~(HO)和log K_(ow)密切相关，同化合物与酶的活性点复合或反应是生物中毒 的主要因素。     

Modelling bioconcentration of pesticides in fish using biopartitioning micellar chromatography

Ecotoxicity assessment is essential before placing new chemical substances on the market. An investigation of the use of the chromatographic retention (log k) in biopartitioning micellar chromatography (BMC) as an in vitro approach to evaluate the bioconcentration factor (BCF) of pesticides in fish is proposed. A heterogeneous set of 85 pesticides from six chemical families was used. For pesticides exhibiting bioconcentration in fish (experimental log BCF > 2), a quantitative retention-activity relationships (QRAR) model is able to perform precise log BCF estimations of new pesticides. Considering the present data, the results based on log k seem to be more reliable than those from available software (BCFWIN and KOWWIN) and from log P (quantitative structure-activity relationships (QSAR)). It is also possible to perform risk assessment tasks fixing a threshold value for log k, which substitute two common threshold values, log P and experimental log BCF, avoiding the experimental problems related with these two parameters.     

氯代苯、醇、酯气相色谱保留指数与其正辛醇-水分配系数相关性

报道了氯代苯、醇、酯类化合物气相色谱保留指数与其正辛醇－水分配系数的相关性，研究了固定相极性对相关性影响，得出弱极性柱上测得的化合物保留指数能更准确地预测其分配系数，从而为极性化合物氯代苯、醇、酯分配系数的测定和预测提供了一种简便易行的新方法。     

Response-surface analyses for toxicity to Tetrahymena pyriformis: reactive carbonyl-containing aliphatic chemicals

A response-plane has been developed with Tetrahymena pyriformis population growth impairment toxicity data [log 1/50% growth inhibitory concentration (IGC50)], the 1-octanol/water partition coefficient (log Kow), and the energy of the lowest unoccupied molecular orbital (Elumo). A statistically robust plane [log 1/IGC50 = 0.530 (log Kow) -0.890 (Elumo) -0.271, n = 50, s = 0.295, r2 = 0.855, F = 145] was found for reactive carbonyl-containing aliphatic chemicals. These compounds had a variety of electrophilic mechanisms of action and included aldehydes acting as Schiff-base formers, alpha,beta-unsaturated aldehydes and alpha,beta-unsaturated ketones acting as Michael-type acceptors, and selected alpha-diones acting as selective binders to arganine residues; gamma-diones acting as selective binders to tubulin; and beta-diones with unknown mechanisms of action. Outliers to this model broadly fell into two groups: small reactive molecules (e.g., acrolein) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., 2,4-dimethyl-2,6-heptadienal) that were less toxic than predicted.     

Retention behavior of o-phthalic, 3-nitrophthalic, and 4-nitrophthalic acids in ion-suppression reversed-phase high performance liquid chromatography using acids instead of buffers as ion-suppressors

In reversed-phase high performance liquid chromatography, the logarithm of the retention factor, log k, is usually correlated with the logarithm of the octanol-water partition coefficient, log Kow. The k and Kow of an ionizable analyte are greatly influenced by the mobile phase pH. In this paper, log kw of diprotic o-phthalic, 3-nitrophthalic, and 4-nitrophthalic acids, are obtained by extrapolation to pure aqueous fraction of mobile phase in ion-suppression reversed-phase high performance liquid chromatography with acetic acid and perchloric acid as the ion-suppressors. The Kow values of the three analytes are calibrated according to the apparent octanol-water partition coefficient, Kow, under different pH conditions, and the log K"ow values show a much better correlation with log kw than do log Kow. The influences of two ion-suppressors, acetic and perchloric acids, on the retention behavior of these diprotic acids at different pH are contrasted. An abnormal trend is found in the k vs. pHw plot of the acetic acid system when the methanol content is low. A possible reason is that acetic acid is an even stronger organic modifier than methanol, besides being an ion-suppressor. The results make the selection of mobile phase for the separation of acidic compounds by ion-suppression reversed-phase high performance liquid chromatography direct, accurate, and practical.