bluuebunny/crossref_metadata_2025 huggingface dataset:
Antigastric ulcer effects in rats of Aloe arborescens Miller var. natalensis Berger extract
Authors: Teradaira R. , Shinzato M. , Beppu H. , Fujita K.
Published: October 2006

The antigastric effects of Aloe arborescens Miller var. natalensis Berger extract with high molecular weight components ((A) MW over 5000 and (B) MW over 50 000)) were examined by changes of ulcer index with three different experimental models in rats. The suppressive effects were evaluated under (1) stress (immobilization in water) and (2) ligation of pylorus, and the healing effects were likewise examined with the (3) acetic acid test. Both fractions showed a slight suppressive effect on the stressed animals. However, in the groups with pylorus ligation, Aloe extract (A) significantly disclosed suppressive effects. Furthermore, the same Aloe fraction heated at 100°C for 15 min also demonstrated a significant effect on animals with pylorus ligation. Rats induced with acetic acid exhibited a significant healing effect. However, fraction (B) produced only a slight beneficial effect.

These results suggest the existence of both suppressive and healing substances on gastric ulcer in the Aloe extract within the range of MW 5000–50 000. These effects were confirmed by micro‐ and macroscopic findings.
Antitrichomonal activity of matrine, an active substance from Sophora flavescens
Authors: Wang Hwang‐Huei , Cheng Juei‐Tang
Published: October 2006

In an attempt to develop an antitrichomonal agent, the present study investigated the effect of matrine, one of the active principles isolated from the root of Sophora flavescens Ait. (Leguminoae), on the pathogenicity of Trichomonas vaginalis in two model system. First, it reduced the cytotoxic effect of this parasite towards mammalian cells in culture: at concentration lower than 1 mM it prevented the decrease of rate astrocytic cells in mixed culture with trichomonads. Second, it delayed the development of subcutaneous abscesses due to this parasite infection. It cured the intravaginal infection of trichomonads in mice. However, the antitrichomonal action of matrine was observed only with a combined intravaginal suppository and subcutanmeous injection, and it failed to produce the same activity through oral administration. The results suggest a potential for matrine as an antitrichomonal drug.
Hypotensive and spasmolytic activities of ethanolic extract of Capparis cartilaginea
Authors: Gilani Anwar‐Ul Hassan , Aftab Khalid
Published: October 2006

An ethanolic extract of Capparis cartilaginea (CC) at a dose of 1–10 mg/kg caused a dose‐dependent fall in blood pressure and heart rate in anaesthetized rats. These effects were not blocked by atropine (1 mg/kg) and pretreatment with CC did not alter the pressor response to norepinephrine, indicating that the cardiovascular effects of CC are independent of cholinergic or adrenergic receptor involvement. In spontaneously beating guinea‐pig atria, CC induced a concentration‐dependent (0.1–1 mg/mL) decrease in force and rate of atrial contractions. In rabbit thoracic aorta, CC caused inhibition of norepinephrine or K+‐induced contractions. In guinea‐pig ileum, CC (1 mg/mL) inhibited submaximal contractions induced by acetylcholine, histamine or 5‐HT. Spontaneous contractions of rat uterus were also abolished when CC was added to the tissue bath at similar concentrations. These results suggest that the direct relaxant action of CC on myocardium and blood vessels may be responsible for its hypotensive and bradycardiac effects observed in the in vivo studies. Moreover, CC exhibits general spasmolytic activity in different smooth muscle preparations.
Toxicological evaluation of Nerium oleander on isolated preparations
Authors: Mazumder P. K. , Rao P. V. Lakshmana , Kumar Deo , Dube S. N. , Gupta S. Das
Published: October 2006

In vitro toxicological evaluation of Nerium oleander was carried out using different isolated preparations. The methanolic leaf extract potentiated both spontaneous and electrically evoked contractions of vas deferens of rats and guinea‐pig ileum in a concentration dependent manner. The effect was not antagonized by the adrenergic blocker, tolazoline. The extract inhibited electrically stimulated neurogenic twitch responses of rat phrenic nerve diaphragm preparation. The dose dependent inhibition of twitch response in this preparation could not be reversed by the anticholinesterase drug, neostigmine. The extract evoked a persistent depolarizing effect on the phrenic nerve diaphragm preparation. The extract exhibited its most potent action on the isolated right atrial preparation of rat. It inhibited the rate of spontaneously beating atria in a concentration dependent manner. The negative chronotropic effect was not antagonized either by antimuscarinic drug or adrenergic agonist.
Toxicity testing of organic solvent extracts from Annona squamosa: Effects on rabbit eyes and ear skin
Authors: Sookvanichsilp Nongluck , Gritsanapan Wandee , Somanabandhu Aim‐On , Lekcharoen Khanong , Tiankrop Pongkrit
Published: October 2006

Some organic solvent extracts of seeds and leaves from Annona squamosa exhibit insecticidal activity. They were studied for the management of human lice. However, toxicological data of these extracts have not yet been widely reported. In this experiment, the extracts of active compounds of leaves and seeds from A. squamosa in four organic solvents, i.e. petroleum ether, ether, chloroform and ethanol were tested for toxicity to the eyes and ear skin of rabbits, using 1:10 (w/v) dilutions of dried extracts in propylene glycol as test substances. The results revealed that some extracts caused conjunctival redness, chemosis, rugged cornea, skin erythema and oedema. The organic solvent extracts that produced adverse effects on rabbit eyes were in the following order of severity: ether > petroleum ether > chloroform > ethanol, and those on rabbit ear skin were petroleum ether > ether > chloroform > ethanol. Ethanol extracts of leaves and seeds seemed to produce mildest toxicity to rabbit eyes and no toxicity to rabbit ear skin.
Analgesic antiinflammatory action of Pfaffia paniculata (Martius) kuntze
Authors: Mazzanti G. , Braghiroli L.
Published: October 2006

The alcoholic extract of Pfaffia paniculata dried roots was studied for analgesic antiinflammatory activity in the rat paw oedema test, writhing test, hot plate test and increased vascular permeability. Pfaffia paniculata inhibited the carrageenin‐induced rat paw oedema and increased vascular permeability and showed analgesic activity on inflammatory pain but not on noninflammatory pain. Moreover the extract was devoid of local irritant action.
Aloe vera: Antiulcer and antidiabetic effects
Authors: Koo M. W. L.
Published: October 2006

A health product containing aloe vera gel was examined for its effects on gastric mucosal lesions induced by cold‐restraint or by oral administration of 70% v/v ethanol (2 mL/kg), and on plasma glucose levels in alloxan‐induced diabetic rats. Pretreatment with the preparation orally did not protect against lesion formation. There was no beneficial effect on the healing of ethanol‐induced gastric mucosal damage when the preparation was given twice daily for 3 days. The plasma glucose level of alloxan‐injected rats (120 mg/kg, s.c.) was about twice as high as that of their controls. It was further elevated by a single oral dose of the preparation. Chronic treatment with the preparation, given twice daily for 10 days, produced a sustained increase in the plasma glucose levels. The findings do not support the claimed efficacy of the preparation in treating gastric ulceration and diabetes mellitus.
Contraceptive efficacy of Carica papaya seed extract in male mice (Mus musculus)
Authors: Chinoy N. J. , D'Souza J. M. , Padman Priya
Published: October 2006

The effects of an aqueous extract of Carica papaya seeds (20 mg/kg body weight/animal/day orally and 5 mg/kg body weight/animal/day i.m. for 60 days) were investigated for contraceptive efficacy and other related side effects in male albino mice, Mus musculus. The data revealed that the extract might be causing an androgen deprived effect to target organs resulting in alterations in the internal milieu of the cauda epididymis especially. The treatment did not, however, affect the testicular sperm count suggesting that it acted at the post‐testicular level which lead to a reduction of cauda epididymal sperm motility and thus the treatment brought about a significant reduction in fertility rate. The induced effects were transient and reversible upon withdrawal of the treatment, elucidating that functional sterility could be induced by the aqueous papaya seed extract in rodents.
Cardiovascular active substances from the straw mushroom, Volvariella volvacea
Authors: Chiu K. W. , Lam A. H. W. , Pang P. K. T.
Published: October 2006

The straw mushroom Volvariella volvacea is one of the common edible mushrooms in Hong Kong and is widely cultivated in Southeast Asian countries. It has been reported to produce a hypotensive response in animals including humans. An aqueous extract of the mushroom (SME) was prepared and given through intravenous injections to normotensive rats. The blood pressure changes produced by SME alone or in the presence of various drugs were studied. The effects of SME on the kidney function of water‐loaded rats and on isolated tissue preparations of the tail artery and right atrium were examined. An i.v. injection of SME produced a hypotensive effect in rats with an ED50 of 25 mg dry weight/kg body weight. This hypotensive effect of SME was attenuated or blunted in the presence of hexamethonium, phentolamine, pyrilamine and cimetidine suggesting the involvement of the α‐adrenergic component of the autonomic system and/or histamineergic stimulation. SME did not increase urinary excretion nor sodium diuresis. It produced positive chronotropic and inotropic effects on isolated right atria and induced contraction of isolated tail artery strips. This latter contractile response was inhibited by antagonists of serotonin and α‐adrenoceptor, ketanserin and phentolamine respectively. Partial purification using dialysis and liquid chromatography revealed that the hypotensive active substances had molecular masses between 8000 and 12000 dalton. These substances were heat stable and resistant to trypsin digestion. In view of the similarity in blood pressure and cardiovascular response, SME might contain serotonin‐like substances.
Evaluation of oestrogenicity and pregnancy interceptory efficacy of lapachol (2‐hydroxy‐3‐(3‐methyl‐2‐butenyl)‐1,4‐naphthoquinone) in the mouse
Authors: Sareen Vineeta , Jain Sunita , Narula Anita
Published: October 2006

Lapachol, a naphthoquinone isolated from Tectona grandis was evaluated for its oestrogenicity and antinidational activity in the mouse and was found to possess a statistically significant (p < 0.001) uterotrophic effect after administration of the drug at a dose of 20 mg/kg body weight/day/mouse, intramuscularly. However, in comparison with conjugated oestrogen, the drug proved to be a relatively weak oestrogenic. Lapachol when administered at the same dose level exhibited interceptory activity at all stages of early pregnancy.
Screening of various plant extracts used in ayurvedic medicine for inhibitory effects on human immunodeficiency virus type 1 (HIV‐1) protease
Authors: Kusumoto Ines Tomoco , Nakabayashi Takeshi , Kida Hiroaki , Miyashiro Hirotsugu , Hattori Masao , Namba Tsuneo , Shimotohno Kunitada
Published: October 2006

To identify substances with anti‐human immunodeficiency virus (HIV) activity in traditional medicines, water and methanol extracts of crude drugs used in Indian traditional medicine (Ayurveda) were subjected to screening for their inhibitory effects on HIV type 1 protease (PR). The enzyme activity was determined by HPLC and of the 39 crude drugs tested, the extracts of the seeds of Areca catechu, the bark of Eugenia jambolana, the bark of Saraca indica and the stem bark of Terminalia arjuna inhibited the HIV‐1 PR activity by more than 70% at a concentration of 0.2 mg/mL. The most potent inhibition was shown by the A. catechu extract, from which some procyanidins were isolated. One of them, arecatannin B1 showed significant HIV‐1‐PR inhibitory activity.
Shilajit induced morphometric and functional changes in mouse peritoneal macrophages
Authors: Ghosal Shibnath , Baumik Sraboni , Chattopadhyay Sukumar
Published: October 2006

The dose‐ and time‐dependent effects of processed shilajit (SJP) on morphometric and functional changes of mouse peritoneal macrophages were evaluated. Several dynamic aspects of cellular modulations were observed in response to SJP treatment (0.025–900 mcg per mouse, i.p.) for different periods of time (0 min to several hours). A plausible mechanism of drug‐receptor interactions, involving different types of transition states, is postulated. Dose and time dependent bond formation‐deformation in the complex transitions were reflected in the morphometric and functional manifestations of the adherent cells. These findings suggest the necessity of carefully determining the dose and period of administration of shilajit even when accepted as a panacea.
Isolation and partial characterization of biologically active polysaccharides from Plantago major L.
Authors: Samuelsen Anne Berit , Paulsen Berit Smestad , Wold Jens Kristian , Otsuka Hanako , Yamada Haruki , Espevik Terje
Published: October 2006

Polysaccharide fractions were isolated from Plantago Major L. leaves by extraction with cold water, hot water and with dimethylsulphoxide (DMSO). Each of the three crude extracts obtained was further separated by ionexchange chromatography. Only the two acidic fractions from the 50°C crude extract were biologically active, demonstrated by in vitro testing of activation of the complement system and induction of tumour necrosis factor alpha (TNF‐α) production from human monocytes. One of the fractions, PM I50, contains polysaccharide material comprising arabinose, galactose and xylose with smaller proportions of galacturonic acid, glucose, mannose and rhamnose. This fraction was further fractionated by size exclusion chromatography to give three fractions PM Ia, PM Ib and PM Ic. PM Ia is probably an arabinogalactan and PM Ib is mainly a 1,4‐linked xylan. The other biologically active fraction, PM II50 is composed of 75% galacturonic acid, 3% rhamnose, 6% arabinose and 8% galactose. Structure analysis indicates that PM II50 is a pectin type polysaccharide.
Studies on the antiulcer activity of Moringa oleifera leaf extract on gastric ulcer models in rats
Authors: Pal Saroj K. , Mukherjee Pulok K. , Saha B. P.
Published: October 2006

The methanol fraction of M. oleifera leaf extract was found to possess significant protective actions in acetylsalicylic acid, serotonin and indomethacin induced gastric lesions in experimental rats. A significant enhancement of the healing process in acetic acid—induced chronic gastric lesions was also observed with the extract‐treated animals.
Medicinal plants of euphorbiaceae occurring and utilized in thailand. V. Skin irritants of the daphnane and tigliane type in latex of Excoecaria bicolor and the uterotonic activity of the leaves of the tree
Authors: Karalai C. , Wiriyachitra P. , Sorg B. , Hecker E.
Published: October 2006

From latex of Excoecaria bicolor (Euphorbiaceae) four TLC‐homogeneous fractions highly enriched in diterpene esters were obtained (F1–F4). Fraction F3 by NMR was found to be a mixture of 9,13,14‐orthoester‐20‐esters (1a) of 5β‐hydroxyresiniferonol‐6α,7α‐epoxide (1). Alkaline transesterification yielded from 1a a mixture of 5β‐hydroxyresiniferonol‐6α,7β‐epoxide‐9,13‐14‐orthoesters (1f) carrying unsaturated orthoester groups as a TLC‐homogeneous material (final isolation of Excoecaria factors B1/B2, B3 and B4). The transesterification mixture also contained, according to GC‐MS, methyl n‐carboxylates corresponding to the even numbered C22−C30 acids from 20‐positions in 1a. Fraction F4 by NMR contained molecular species (2a) structurally closely related to 1a, carrying 5β,12β‐dihydroxyresiniferonol‐6α, 7α‐epoxide (2) as the parent alcohol. From 2a, by alkaline transesterification, a two‐component mixture of Excoecaria factors B5/B6, i.e. 5β,12β‐dihydroxy‐resiniferonol‐6α,7α‐epoxide‐9,13,14‐ortho(2,4,6‐hexadecatrienoate)/‐(2,4,6,8‐hexadecatetraenoate) (2b/2c) was obtained. GC‐MS of the transesterification mixture revealed methyl n‐carboxylates corresponding to even numbered C16‐C16 acids from 20‐positions in 2a (omitting C18 and C20). Fractions F1 and F2 by alkaline transesterifications yielded 12‐deoxyphorbol (3) and its 13‐(3,5‐tetradecadienoate) 3b (Excoecaria factor B7). Moreover 4,12‐dideoxy(4α)phorbol (4), its 13‐(3,5‐tetradecadienoate) 4b and the natural 4‐epimer of 4b 4,12‐dideoxyphorbol‐13‐(3,5‐tetradecadienoate) (5a) (new Excoecaria factor B8) were obtained. GC‐MS of the transesterification mixtures revealed mainly methyl n‐carboxylates corresponding to even numbered C16‐C30 acids. Thus the latex and the fractions F1 and F2 contain 13,20‐diesters of the parent alcohols 12‐deoxyphorbol (3) and 4,12‐dideoxyphorbol (5). 4,12‐dideoxy(4α)phorbol (4) and its derivatives may be considered artifacts from alkaline epimerization of 5. The daphnane type Excoecaria factors B1‐B6 are structurally very closely related to diterpenes such as yuanhuacine occurring in certain Daphne and Wikstroemia species. Daphnane type esters of this kind are currently used routinely in China for fertility regulation. Similarly, daphnane and tigliane type Excoecaria factors present in the latex of E. bicolor may be responsible for the uterotonic activity of its leaves utilized in Thai herbal medicine.
Preventive and curative effects of Berberis aristata Fruit extract on paracetamol‐ and CCl4‐induced hepatotoxicity
Authors: Gilani Anwar‐Ul Hassan , Janbaz Khalid Hussain
Published: October 2006

The effect of an aqueous‐methanol extract of Berberis aristata fruits (Berberidaceae) was investigated against paracetamol‐ and CCl4‐induced hepatic damage. Paracetamol produced 100% mortality at a dose of 1 g/kg in mice while pre‐treatment of animals with crude extract (500 mg/kg) reduced the death rate to 10%. Pre‐treatment of rats with fruit extract (500 mg/kg, orally twice daily for 2 days) prevented (p<0.05) the paracetamol (640 mg/kg) as well as CCl4 (1.5 mL/kg)‐induced rise in serum transaminases (GOT and GPT). Post‐treatment with three successive doses of extract (500 mg/kg, 6h) restricted the hepatic damage induced by acetaminophen (p<0.01) but CCl4‐induced hepatotoxicity was not altered (p>0.05). Plant extract (500 mg/kg) caused significant prolongation (p<0.01) in pentobarbital (75 mg/kg)‐induced sleep as well as increased strychnine‐induced lethality in mice suggestive of inhibitory effect on microsomal drug metabolizing enzymes (MDME). These results indicate that the crude extract of Berberis aristata fruits exhibits hepatoprotective action partly through MDME inhibitory action.
Tanzanian medicinal plants used traditionally for the treatment of malaria: In vivo antimalarial and in vitro cytotoxic activities
Authors: Gessler M. C. , Tanner M. , Chollet J. , Nkunya M. H. H. , Heinrich M.
Published: October 2006

Seventeen fractions of extracts obtained from 11 Tanzanian medicinal plants, which had previously been shown to possess a high antimalarial activity in vitro were submitted to the 4‐day suppressive test in Plasmodium berghei‐infected mice, and were investigated for cytotoxic activity in human carcinoma cell lines in vitro. Several fractions administered orally to the mice (500 mg/kg body weight/day) produced a significant reduction of parasitaemia. The most effective plant fractions investigated were those of the root and stem bark of Maytenus senegalensis (90% and 63% suppression of parasitaemia, respectively) and of the roots of Cissampelos mucronata (59% suppression). Highest cytotoxic activities were found with all fractions of Maytenus senegalensis (IC50 1 μg/mL) and with the PE fraction of the roots of Salacia madagascariensis (median IC50=1.2 μg/mL for HT 29 and 2.3 μg/mL for KB).
Computer‐Assisted Structure‐Activity Relationship Analysis: Pattern Recognition Studies on Hypolipidemic Arylpropionic Acid Derivatives
Authors: Gombar Vijay K. , Jaeger Edward P. , Jurs Peter C.
Published: October 2006

Pattern recognition techniques are applied to analyze the structure‐activity relationships (SAR) among α‐substituted‐β‐arylpropionic acid derivatives possessing hypolipidemic properties. The triglyceride lowering activity of 116 such compounds is investigated. Twelve structural descriptors are identified which can discriminate derivatives more active than clofibrate from those which have activity to or less than that of clofibrate with a success rate greater than 97%. Among the 12 descriptors selected out of a total of about 70, three are electronic and two are geometric. In addition, certain chemical substructures and their environments have been found to be important in determining the activity class.
Quantitative Structure‐Activity Relationship (QSAR) Analysis Using the Partial Least Squares (PLS) Method: The Binding of Polycyclic Aromatic Hydrocarbons (PAH) to the Rat Liver 2,3,7,8‐Tetrachlorodibenzo‐P‐Dioxin (TCDD) Receptor
Authors: Johnels Dan , Gillner Mikael , Nordén Bo , Toftgård Rune , Gustafsson Jan‐åke
Published: October 2006

It is demonstrated that it is possible to obtain quantitative structure‐activity relationships from different molecular descriptors for the binding affinity of ten polycyclic aromatic hydrocarbons (PAH) for the rat liver 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) receptor, by the use of the partial least squares method. The variables used as descriptors range from theoretical and measured electronic properties to simple descriptors of the molecular geometry. A two component model, explaining 85% of the variance of the binding affinity of the ten PAH for the TCDD receptor is obtained when all descriptor variables are included in the analysis. When only molecular geometry descriptors are utilized in the modelling, a one component model explaining 75% of the variance is obtained.
Rationalisations among Heterocyclic Partition Coefficients. Part 3: π‐Excessive Heterocycles. Some Comments on the CLOGP Algorithm
Authors: Bradshaw John , Taylor Peter J.
Published: October 2006

The partition coefficients for 123 furans, thiophenes, pyrroles and their benzofused derivatives are listed and the results discussed in terms of Δπ, i.e. the difference in π‐value from that expected for benzene. The smaller internal bond angle of 5‐membered rings leads to characteristically larger π‐values for some bulky groups, notably tertiary amide, since these can approach planarity more closely than in benzene. By contrast, lone pair repulsion lowers π for some 2‐substituted furans. Otherwise, π is very slight in furans and thiophenes, demonstrating the absence of appreciable electronic interactions. Because pyrroles and indoles are proton donors, they superficially show electronic effects similar to anilines. Closer analysis, based partly on the existence of anomalous negative Δπ values, demonstrates complications which the CLOGP algorithm does not consider. The rationale of electronic interaction and its effect on log P is discussed in terms of the need to consider (a) separate proton donor and acceptor terms, (b) rises as well as falls in lone pair electron density. It is pointed out, inter alia, that π‐donor ring hetero‐atoms are not proton acceptors, and that aromatic ring hetero‐atoms in general do not behave like ring substituents. While no attempt is made to construct an alternative algorithm, various suggestions are made concerning the lines along which CLOGP might be modified.
Wiener Indices and Partition Coefficients of Unsaturated Hydrocarbons
Authors: Lukovits I.
Published: October 2006

The Wiener index W was defined originally for saturated hydrocarbons. In this work the definition of W was extended for unsaturated hydrocarbons: W = Ws + Wd + Wt + Wa, where s, d, t, and a refer to the contributions of single, double, triple and aromatic bonds, respectively. Good correlation (r = 0.95) could be demonstrated between the logarithms of n‐octanol‐water partition coefficients of the molecules and the components Ws, Wd, Wt and Wa.
Model‐based LFER Parameters and QSAR of Ligand‐β‐Adrenoceptor Interactions I. Equlibrium Models and Parameters of β‐Adrenergic Effectuation
Authors: Dove Stefan , Franke Rainer
Published: October 2006

A separate consideration of ligand‐β‐adrenoceptor interactions responsible for affinity (recognition, binding) and agonistic activity, respectively, is very important for the explanation of molecular events eliciting the activating conformational change of the receptor. Equilibrium models of β‐adrenergic effectuation including receptor activation by agonists and partial agonists, receptor‐effector (G‐protein) coupling, and adenylate cyclase stimulation allow to obtain LFER‐related parameters of both interaction components from apparent dissociation constants and intrinsic activities. Two models, both containing “precoupling” of non‐activated receptor and effector molecules, are derived: a ternary complex model for the interaction of ligands, receptor, and effector in the absence, and an adenylate cyclase activation model for enzyme activation in the presence of GTP. Agonistic activity is represented by the equilibrium constant K* reflecting the concentration ratio of activated and non‐activated agonist‐receptor complexes. KD, the dissociation constant of non‐activated complexes, represents ligand‐receptor recognition and binding. K* can be estimated either from using ratios KL/KH of apparent low‐ and high affinity dissociation constants in GTP absence, or from using intrinsic activities of adenylate cyclase activation. According to our models, KL, which also describes apparent dissociation in binding assays with GTP, is related to KD and K* with KL = KD/(1 + K*). In terms of the free energy of ligand binding and receptor activation. ΔG° = RT ln KL, this corresponds to a decomposition of pKL into pKL = pKD + log (1 + K*). In QSAR, thus, log (1 + K*) is the parameter of choice for LFER‐related description of ligand‐receptor interactions eliciting agonistic activity.
QSAR of Some Antifungal Benzoxazoles and Oxazolo(4,5‐b)pyridines against C. albicans
Authors: Şener Esin , Yalçin I̊smail , Sungur Engin
Published: October 2006

A congeneric set of 2,5‐disubstituted benzoxazole (III) and 2‐substituted oxazolo(4,5‐b)pyridine (IV) derivatives 1–46, previously tested for their antifungal activity against C. albicans, were analyzed by quantitative structure‐activity relationship (QSAR) techniques. The activity contributions for either ring system or substituent effects were determined from the correlation equations, and the predictions of the potent antifungally active derivatives were described by the results obtained from the computer‐assisted stepwise regression procedure. The resulting QSAR revealed that oxazolo(4,5‐b) pyridine ring system was more preferable than benzoxazole and the benzyl group at position 2 was more significant than the corresponding phenyl substituent. Although the para substitution of benzyl or phenyl moiety with electron donating/withdrawing groups was neglectable, the nature of the substituents at the 5th position (R1) of the fused ring system was important for the potency. Substituting this position with electron withdrawing groups like nitro produces an increase in the antifungal activity.
A Quantitative Structure‐ Activity Relationship (QSAR) for Prediction of α‐2μ‐Globulin Nephropathy
Authors: Barratt Martin D.
Published: October 2006

A number of chemicals induce a toxic syndrome in male rats – referred to as α‐2‐μ‐globulin nephropathy – which is characterized by an accumulation of the urinary protein α‐2‐μ‐globulin in renal lysosomes, subsequent cytotoxicity and cell death. Borghoff et al. [1] measured the binding affinities to α‐2μ‐globulin for a number of molecules and metabolites recognised as causing α‐2μ‐nephropathy and suggested that binding is dependent on both hydrophobic interactions and hydrogen bonding. Binding affinity to α‐2μ‐globulin has been identified as one of the determinants for α‐2μ‐globulin nephropathy. A QSAR based on these data has been derived by multiple regression analysis relating the binding to negative charge density of the binding molecule and its molecular volume. Data of Bomhard et al. [2] correlating aliphatic and alicyclic hydrocarbon structures with ability to induce renal lysosome accumulation in male rats, were analysed by the technique of principal components analysis applied to the molecular volumes and principal inertial axes of alcohols predicted to be derived from the hydrocarbons. Mapping of the first and second principal components showed clustering of molecules relative to their biological activity. A combination of the two QSARs is useful in identifying molecules with a potential to cause α‐2μ‐globulin nephropathy.
Variable Selection in QSAR Studies. II. A Highly Efficient Combination of Systematic Search and Evolution
Authors: Kubinyi Hugo
Published: October 2006

Recently two evolutionary strategies for the derivation of regression models, a genetic function approximation and the mutation/ selection algorithm MUSEUM have been described. The MUSEUM (Mutation and Selection Uncover Models) algorithm starts from a model containing randomly chosen variables. Random mutation, first by addition or elimination of only one or very few variables, afterwards by simultaneous random additions, eliminations and/or exchanges of several variables at a time, leads to new models which are evaluated by an appropriate fitness function. Only the “fittest” model is stored and used for further mutation and selection, leading to better and better models. However, the fitness of all models with up to three X variables can be determined much faster by calculation of the correlation coefficients ry.ij and ry.ijk from the partial correlation coefficients ryi, rij, ryj.j, rjk.i and ryk.ij. Using the Selwood data set (n = 31 compounds, k = 53 variables), it is demonstrated that systematic search is the best strategy for regression models with two or three X variables. The variables contained in the best three‐variable models can be selected for further investigation, using the evolutionary approach. With the exception of complex models, containing six and more variables, nearly all relevant regression models are found by this combination of systematic search with the mutation/selection algorithm MUSEUM; the results are obtained in considerably shorter time than by including all variables in the calculations. In addition, systematic search is also a valuable tool for variable selection prior to stepwise regression and PLS analyses.
QSAR in Toxicology. 2. Prediction of Acute Mammalian Toxicity and Interspecies Correlations
Authors: Cronin Mark T. D. , Dearden John C.
Published: October 2006

A critical review is given of quantitative structure‐activity relationships (QSAR) for the prediction of mammalian toxicological endpoints. QSAR predictions for mammalian toxicity are generally poorly developed although hydrophobicity correlates well with the toxicity of unreactive chemicals. Interspecies correlations of acute toxicity are discussed and when the mode of toxic action is taken into account these may provide a valuable source of information for comparative toxicity and the potential use of surrogate species for testing.
Application of Alternating Conditional Expectations Method to Quantitative Electronic Structure‐Activity Relationships (QESAR)
Authors: Nguyen‐Cong Vu , Rode Bernd M.
Published: October 2006

The Alternating Conditional Expectations (ACE) algorithm for nonlinear dependence of cytotoxicity on atomic net charges evaluated on the basis of semiempirical SCF‐MO calculations has been applied to a series of 28 quassinoids. The best ACE model found from investigating all possible subsets of electronic descriptors has shown that ACE is a useful tool in quantitative structure‐activity relationship studies.
QSAR in Toxicology. 4. Prediction of Non‐lethal Mammalian Toxicological Endpoints, and Expert Systems for Toxicity Prediction
Authors: Cronin Mark T. D. , Dearden John C.
Published: October 2006

A critical review is given of quantitative and qualitative structure‐activity relationships (QSAR) for the prediction of some non‐lethal mammalian toxicological endpoints required for regulatory purposes. QSAR in these areas of toxicology, such as irritation and respiratory allergy, is hindered by a lack of quality in vivo toxicity data to model, and by the mechanisms of action not being fully understood. Much progress has been made though into the prediction of skin sensitisation. Commercially available expert systems based on QSAR for toxicity prediction are also described and evaluated critically. Generally it is considered although some systems are well advanced in particular areas, more work is required to make expert systems sufficiently accurate for reliable toxicity prediction.
Conformational Analysis and 3D QSAR Study on Novel Partial Agonists of 5‐HT3 Receptors
Authors: Bureau R. , Lancelot J. C. , Prunier H. , Rault S.
Published: October 2006

A conformational analysis which was carried out by molecular dynamics on novel selective and partial agonists of the 5‐HT3 receptor, led to the definition of the partial agonist pharmacophore for 5‐HT3 receptor. Comparative molecular field analysis was carried out on thirty‐nine piperazino pyrrolo thieno pyrazines. The correlation between steric and electrostatic interactions with biological affinities was observed only when electrostatic partial charges were considered. The generated contour maps particulary defined the importance of two groups: a basic nitrogen and a π system.
Molecular Similarity Determination of Heteroaromatic Ring Fragments Using GRID and Multivariate Data Analysis
Authors: Langer Thierry
Published: October 2006

This study reports on molecular similarity determination for heteroaromatic ring fragments permitting to take into account differences in anchoring positions of such substructures in a given molecule. A total of 72 aromatic moieties (five‐ and six‐membered monocyclic and fused benzoannelated heteroaromatics containing one or two heteroatoms) was characterized by interaction energy calculations using a total of 6 multi atom probes within the GRID program and new QSAR descriptors were generated from principal component analysis of the interaction energy matrices thus obtained. A hierarchical clustering procedure of the obtained principal components as well as applying factorial design criteria allowed partitioning of the heteroaromatic substituents into similar families and permitted a classification of structures according to their molecular similarity. The descriptors now obtained were tested for their prediction capacity using different previously reported datasets of biologically active compounds. The results obtained hereby clearly demonstrate the usefulness of 3D derived descriptors.
QSAR and Molecular Modelling of Catamphiphilic Drugs Able to Modulate Multidrug Resistance in Tumors
Authors: Pajeva Ilza K. , Wiese Michael
Published: October 2006

The Free‐Wilson approach was applied to two groups of catamphiphilic multidrug resistance (MDR) modifiers using classical multiple linear regression (MLR) and genetic algorithms (GA) for feature selection. In the first group (17 thioxanthenes) the side chain length between the ring system and tertiary nitrogen, the type of the tertiary nitrogen substituent and the stereoisomery were found to be significant for anti‐MDR activity both by MLR and GA (r2 = 0.803, predictive power Q2 = 0.652). In the second data set (17 phenothiazines and related drugs) the ring system type, the stereoisomery, the side chain type, and the ring substituent kind in position two contributed significantly (r2 = 0.938 and Q2 = 0.908). The QSAR studies showed a thioxanthene ring with a ‐CF3 substituent in position two, a piperazine moiety with a 4‐bond distance from the ring system and trans‐isomery to be optimal for MDR reversal. Based on these results molecular modeling of trans‐(T) and cis‐flupentixol (C) was performed assuming that the 2 to 3‐fold difference in MDR reversing activity of T compared to C might be related to different preferable conformations in the membrane lipid environment. Among all conformations generated by the SYBYL systematic search routine those comprising local energy minima were selected and optimized with semiempirical quantum chemistry methods. The optimized conformations were compared with 1H‐NMR analysis results on drug conformations in lipid environment, some of them corresponded excellently. The electrostatic and lipophilic fields of T and C were compared to identify molecular properties related to the activity difference. The results demonstrated that T and C could have a different (mirror‐like) orientation entering the lipid bilayer by the ring system suggesting much better fitting of T compared to C to the lipid “MDR‐reversal receptor”.
Correspondence Analysis of the Skin Sensitization Potential of Organic Chemicals
Authors: Cronin Mark T. D. , Dearden John C.
Published: October 2006

Correspondence analysis is a variant of principal component analysis for use with categoric data. It has been applied to structural information describing the frequencies of certain molecular features and the skin sensitization potential of a database of organic compounds. Correspondence analysis allows the graphical study of the interrelationship between the relative frequency of structural features of non, weak, moderate and strong sensitizers and the individual class membership. Structural features resulting in protein reactivity are shown to be strongly associated with strong sensitizers; other features, not related to reactivity, are associated with non, or weak, sensitizers. The analysis also indicates structural features whose description is too vague and needs more refinement.
QSARs with Orthogonal Descriptors on Psychotomimetic Phenylalkylamines
Authors: Mracec Maria , Muresan Sorel , Mracec Mircea , Simon Zeno , Náray‐Szabó Gábor
Published: October 2006

Multiple linear regressions have been obtained for 49 psychotomimetic phenylalkylamines. The MTD method has been applied and the MTD parameter was used as steric descriptor. The energy of the lowest unoccupied molecular orbital and the net charges on the phenyl ring atoms (from AMI calculations) have been used as electronic descriptors and logPow, or average electrostatic field as lipophilicity descriptor. Hall and Kier electrotopological state indices were also tested. The descriptors have been scaled to unit and orthogonalized by Randic method. The predictability of the regressions obtained from MTD method have been checked by a method similar to cross‐validation from CoMFA method. MTD has been identified as the dominant descriptor by Randic orthogonalization. The best model has been obtained with MTD and electrotopological state indices, showing the importance of the steric and electronic properties for the interaction at the receptor site level.
Structure‐Activity Relationships of a Steroid Family using Quantum Similarity Measures and Topological Quantum Similarity Indices
Authors: Lobato Miquel , Amat Lluís , Besalú Emili , Carbó‐Dorca Ramon
Published: October 2006

This work will try to study an application example of quantum similarity measures, in order to determine quantitative relationships between the structure and biological activity for a family of steroids. The studied family is composed of 31 molecules, and the property analyzed is the affinity to the corticosteroid binding globulin receptor. Two methodologies have been chosen to perform QSAR on the mentioned steroid set. Both methodological frameworks are based on quantum similarity measures, the first one is based on the use of similarity indices as molecular descriptors and the second methodology uses quantum similarity topological indices for the same purpose. The use of molecular descriptors, obtained from quantum similarity topological indices constructs, constitutes a new technique developed recently in our laboratory to be used in QSAR in close relationship with the already explored field of quantum similarity measures. Results become comparable to other 3D‐QSAR techniques.
On Flexible Fitting Using The Molecular Similarity Index. A neural network analysis for antileishmaniasis compounds
Authors: Montanari Carlos A. , Tute Michael S.
Published: October 2006

Pentamidine analogues bind to the minor groove by using the pharmacophoric conformation as being isohelical do DNA. A QSAR model has disclosed three physiochemical descriptors as being important for such compounds against Leishmania mexicana amazonensis: Clog P, electrotopological index and Carbo similarity index. A comparison of the QSAR equation derived from multiple regression analysis, MRA, and the one from neural network analysis, NN, shows the latter to be of higher significance.
ToF‐SIMS imaging of lipids in cell membranes
Authors: Johansson Björn
Published: October 2006

Secondary ion mass spectrometry (SIMS) has been in use in biomedical imaging for more than three decades and has resulted in some important biomedical discoveries. However, SIMS has not become a part of most biologists' instrumentarium, even though this method enables chemical analysis in the context of anatomical regions and even subcellular structures. Secondary ions characteristic of a range of important lipids can now be efficiently produced from cell membranes and imaged by SIMS. Recently developed ion sources producing cluster primary ions, in combination with modern, sensitive time‐of‐flight (ToF) mass analyzers, have enabled this new bioimaging method. This article briefly describes cell membranes and their lipids as well as the new primary ion sources, and moves on to review recent biomembrane studies by time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) and related methods. Further refinements in equipment and other methodology that will facilitate the use of SIMS in biomembrane studies are suggested. It is concluded that ToF‐SIMS mass spectrometry for membrane and other biology applications is definitely on the rise. Copyright © 2006 John Wiley & Sons, Ltd.
Rapid radiation degradation in the XPS analysis of antibacterial coatings of brominated furanones
Authors: Al‐Bataineh Sameer A. , Britcher Leanne G. , Griesser Hans J.
Published: October 2006

Brominated furanones are promising antibacterial compounds, both in solution and immobilized on solid surfaces, and there is interest in their utilization as protective coatings on biomedical devices to combat device‐centered infections. The rational design and optimization of antibacterial furanone coatings requires detailed spectroscopic surface characterization of the coatings produced and correlation of surface analysis data with antibacterial performance. However, as reported in this study, the extreme sensitivity of brominated furanones to radiation damage in the course of XPS analysis greatly complicates characterization. Our data show that rapid degradation occurs, as shown by the emergence of a signal assignable to Br− ion in the Br 3d spectrum. This Br− is water soluble as shown by washing experiments, whereas the CBr signal does not become reduced during washing, consistent with covalent interfacial immobilization of the furanone molecules. Furanone molecules were immobilized onto two different hydrogel interlayers (polyacrylic acid and polyethylene oxide (PEO)), and XPS analyses show that the interlayers did not suffer significant radiation degradation; the damage is limited to the furanone molecules. The results of this study may assist in XPS analyses of other brominated compounds on surfaces; the possibility of Br− ions deriving from XPS analysis–damage must be investigated before assigning their generation to side reactions in the coating or surface‐modification procedure. Copyright © 2006 John Wiley & Sons, Ltd.
The application of atomic force microscopy force measurements to the characterisation of microbial surfaces
Authors: Wright Chris J. , Armstrong Ian
Published: October 2006

The interaction of microbes and subsequent development of biofilms at surfaces has far‐reaching consequences in bioprocess engineering, agriculture, medicine and dentistry. Thus, the microbial surface has been the focus of wide scientific investigation. However, only recently has technology permitted quantitative study of the molecular interactions that govern the interactions of microbes. One such technology is atomic force microscopy (AFM) that not only permits the high resolution imaging of microbial surfaces but also the direct measurement of molecular forces and physical properties found at the microbial surface. This review highlights the current development of AFM force measurements and how these may be applied to microbial cell surfaces. The refinement of the AFM force measurement technique for characterising microbial surfaces will be discussed with reference to selected studies from the author's laboratory and key results from other research teams. The review will demonstrate how the application of the AFM techniques of single‐molecule force spectroscopy, functionalised tips, cell probes and lateral force measurement to microbial surfaces has provided exciting and unique insights into the microbial surface and its interactions. Copyright © 2006 John Wiley & Sons, Ltd.
Acute toxicity tests using rotifers. III. Effects of temperature, strain, and exposure time on the sensitivity of Brachionus plicatilis
Authors: Snell Terry W. , Moffat Brian D. , Janssen Colin , Persoone Guido
Published: October 2006

As part of the development of a standardized acute toxicity test, the effect of cyst age, strain, temperature, and exposure time on the toxicity of 21 chemicals to the estuarine rotifer Brachionus plicatilis was investigated. Toxicity was chemical specific, with LC50s ranging from 0.061 mg · L−1 for mecury to 598 mg · L−1 for 2,4‐dichlorophenoxyacetic acid. Intralaboratory coefficients of variation averaged 11%, at least three times lower than for other aquatic invertebrate acute tests. The age of rotifer cysts stored up to 27 months had no effect on the sensitivity of test animals, but significant differences in sensitivity were detected among rotifer strains. Test temperatures of 25, 30, and 35°C generally yielded lower LC50s than at 20°C. LC50s decreased by 80–90% for cadmium and pentachlorophenol when toxicant exposure time was increased from 24 to 72 h. Life table analysis of rotifer survival in the controls revealed that 72 h is the longest acute test possible without feeding. A comparison of the sensitivity of the rotifer test to that of sea urchin (Arabacia punctulata) early embryo, sea urchin sperm cell, Microtox®, and Mysidopsis bahia tests revealed comparability for several compounds. However, no species is consistently the most sensitive to all compounds.