Evaluation of the non-clinical toxicity of an antiparasitic agent: diminazene aceturate.

The diminazene aceturate (C14H15N7.2C4H7NO3) is a chemotherapeutic agent with more than six decades of use, however more studies regarding its toxicity still need to be performed. Thus, the present study determined the acute toxicity (14 days) of diminazene acetate (DIZE) in male and female swiss mice by changes in body mass, food consumption, biochemical and hematological parameters, locomotor activity and motor coordination. DIZE was administered at a single dose (1000 and 2000 mg/kg) orally. In addition, in vitro antioxidant capacity, hemolytic activity, toxicity in Artemia salina and in silico evaluation were also performed. The results obtained include several signs of toxicity (hypoactivity, loss of the straightening reflex and tachycardia), reduction of behavioral activity (locomotor activity and motor coordination) and significant changes (p < 0.05) in biochemical and hematological parameters. According to the in silico study, the DIZE can be classified based on the mean lethal dose (LD50) in category 4 (300 mg/kg < LD50 ≤ 2000 mg/kg, ProTox-II) or 3 (50 mg/kg < LD50 ≤ 300 mg/kg, AdmetSAR 1.0). Additionally, DIZE (30.3-969.9 nM) was not toxic to A. salina in the first 48 hours of treatment and was not cytotoxic to rat red blood cells after induced hemolysis. In vitro results indicated low antioxidant capacity against DPPH• and ABTS•+ radicals. Therefore, DIZE induces several adverse effects with influence on the central nervous system, changes in hematological and biochemical parameters and even mortality at the highest dose. However, absence of toxicity was observed in A. salina and rats red blood cells.

Anticonvulsant, Anxiolytic and Antidepressant Properties of the ß-caryophyllene in Swiss Mice: Involvement of Benzodiazepine-GABAAergic, Serotonergic and Nitrergic Systems.

BACKGROUND: Central nervous system disorders such as anxiety, depression and epilepsy are characterized by sharing several molecular mechanisms in common and the involvement of the L-arginine/NO pathway in neurobehavioral studies with ß-caryophyllene is still little discussed. OBJECTIVES: One of the objectives of the present study was to demonstrate the anxiolytic behavioral effect of ß-caryophyllene (ß-CBP) in female Swiss mice, as well as to investigate the molecular mechanisms underlying the results obtained. METHODS: This study evaluated the neurobehavioral effects of ß-CBP using the open field test, rota- rod test, elevated plus maze test, novelty suppressed feeding test, tail suspension test and forced swim test, as well as pilocarpine, pentylenetetrazole and isoniazid-induced epileptic seizure models. RESULTS: The results demonstrated that the neuropharmacological activities of ß-CBP may involve benzodiazepine/GABAergic receptors, since the pre-treatment of ß-CBP (200 mg/kg) associated with flumazenil (5 mg/kg, benzodiazepine receptor antagonist) and bicuculline (1 mg/kg, selective GABAA receptor antagonist) reestablished the anxiety parameters in the elevated plus-maze test, as well as the results of reduced latency to consume food in the novelty suppressed feeding test. In addition to benzodiazepine/GABAergic receptors, the neuropharmacological properties of ß-CBP may be related to inhibition of nitric oxide synthesis, since pre-treatment with L-arginine (500-750 mg/kg) reversed significantly the anxiolytic, antidepressant and anticonvulsant activities of ß-CBP. CONCLUSION: The results obtained provide additional support in understanding the neuromolecular mechanisms underlying the anxiolytic, antidepressant and anticonvulsive properties of ß-CBP in female Swiss mice.

Exercise on a vibratory platform increases blood perfusion on the stifle joint and rectal temperature in healthy dogs / Exercício em plataforma vibratória aumenta a perfusão sanguínea da articulação do joelho e a temperatura retal de cães saudáveis

The effects of two vibration platform (VP) exercise protocols on stifle and rectal temperatures were evaluated. Eleven animals participated in two exercise protocols, different in duration in each exercise. Exercise protocol 1 (EP1) took 30 seconds and EP2, 60 seconds, with different vibratory levels in both cases (L1 = acceleration ≅ 1g, L4 = acceleration ≅ 2.5g, and L7 = acceleration ≅ 5g). The animals were evaluated before and 1 minute after the exercise, using infrared thermography to obtain stifle temperatures. The rectal temperature (RT) was also checked at each moment. The dogs had higher stifle temperatures in EP1 at all vibratory levels compared to the time before the exercise; EP2 resulted in higher temperature only at maximum vibration intensity (L7). Increase in TR was observed only in EP2. The results suggested that the short duration protocol (EP1) increased the muscular and peripheral vascular activities of the joint, regardless of the vibration intensity. The long duration protocol (EP2) with maximum vibration intensity increased the RT, demonstrating activity beyond the stifle muscle group. It is concluded that exercises on the VP can be used as complementary therapy for low-impact muscle activity in dogs and may be adequate for efficient energy consumption.(AU)

Foram avaliados os efeitos de dois protocolos de exercício em plataforma vibratória (PV) sobre as temperaturas dos joelhos e retais. Onze animais participaram de dois protocolos de exercício, diferentes na duração de cada exercício. O protocolo de exercício 1 (PE1) foi de 30 segundos e o PE2 foi de 60 segundos, com diferentes níveis vibratórios em ambos (L1 = aceleração ≅ 1g; L4 = aceleração ≅ 2,5g; e L7 = aceleração ≅ 5g). Os animais foram avaliados antes e um minuto após os exercícios, por meio de termografia infravermelha para a obtenção das temperaturas dos joelhos. A temperatura retal (TR) foi aferida em cada momento. Os cães apresentaram temperaturas dos joelhos mais elevadas em PE1, em todos os níveis vibratórios, em comparação a antes do exercício; o PE2 resultou em temperatura mais alta apenas na intensidade máxima de vibração (L7). Aumento na TR foi observado apenas no PE2. Os resultados sugerem que o protocolo de curta duração (PE1) aumentou as atividades muscular e vascular periférica da articulação, independentemente da intensidade da vibração; o protocolo de longa duração (PE2) com intensidade máxima de vibração aumentou a TR demonstrando atividade além do grupo muscular do joelho. Conclui-se que os exercícios na PV podem ser utilizados como terapia complementar para atividade muscular de baixo impacto em cães e pode ser adequada para o consumo eficiente de energia.(AU)

Interação genótipo x ambiente sobre o desempenho ponderal de animais da raça Nelore na região Centro-Oeste / Genotype environment interaction on the weight gain of animals of the Nelore breed in the Midwest

Utilizaram-se registros de pesos corporais padronizados aos 120, 210, 365 e 450 dias de idade, provenientes de 30.481 animais da raça Nelore, progênies de 211 reprodutores acasalados com 19.229 matrizes, oriundos de rebanhos dos estados de Mato Grosso, Mato Grosso do Sul e Goiás, com o objetivo de avaliar a presença de interação genótipo x ambiente entre os estados. As estimativas de herdabilidade entre os estados variaram de 0,09 a 0,14; 0,11 a 0,17; 0,16 a 0,27 e 0,17 a 0,35, respectivamente, para os pesos 120, 210, 365 e 450 dias de idade. As estimativas de correlação genética aditiva entre a mesma característica para os diferentes estados apresentaram valores inferiores a 0,80. As correlações de Spearman entre os valores genéticos para os pesos corporais se reduziram à medida que se aumentou a intensidade de seleção sobre os reprodutores. A presença de interação genótipo x ambiente causa maior impacto sobre a avaliação genética dos reprodutores sob intensidade de seleção elevada, sendo interessante sua consideração no processo de avaliação genética. Estimativas de tendências genéticas para todos os pesos corporais apresentaram-se crescentes ao longo dos anos nos três estados.(AU)

Data of adjusted alive weights at 120, 210, 365 and 450 days of age of 30,481 records of animals of the Nellore beef cattle breed from herds of states of Mato Grosso, Mato Grosso do Sul, and Goiás were used to study the influence of environment genotype interaction on genetic evaluation of sires. Estimates of heritability between the states ranged from 0.09 to 0.14; 0.11 to 0.17; 0.16 to 0.27 and 0.17 to 0.35, respectively for live weights 120, 210, 365 and 450 days of age. The estimates of additive genetic correlation between the same characteristic for the different states presented values lower than 0.80. Spearman correlations between breeding values obtained from live weights of sires lowered as the intensity of selection on sires increased. The presence of environment genotype interaction has greater impact on the genetic evaluation of breeding under high intensity of selection, being an interesting consideration in the process of genetic evaluation. Estimates of genetic trends for all body weights have been increasing over the years in all three states.(AU)

Absence of toxicity in Swiss mice following treatment with 7-acetoxy-4-aryl-3,4-dihydrocoumarin: Acute and repeated-dose toxicity study.

Neoflavonoids, which are classified as 4-arylcoumarin (neoflavone), 3,4-dihydro-4-arylcoumarin and neoflavene, have been the subject of a number of studies with respect to their therapeutic potential and, despite promising in vitro, ex vivo and in vivo pharmacological activities, there is a lack of studies demonstrating their toxicological properties. Therefore, this study aims to evaluate the acute (14 days) and repeated-dose (28 days) toxicity of synthetic neoflavonoid 7-acetoxy-4-aryl-3,4-dihydrocoumarin in Swiss mice through parameters related to changes in body weight, food and water intake, hematological and biochemical parameters. Toxicity studies using acute doses (300 and 2000 mg/kg) and repeated doses (250, 500 and 1000 mg/kg) orally were carried out as per Organization for Economic Co-operation and Development (OECD) guidelines 423 and 407, respectively. Based on the results of this study, treatment with 7-acetoxy-4-aryl-3,4-dihydrocoumarin was found to not cause clinical adverse symptoms and mortality in any animal used in the acute and repeated-dose toxicity study. In addition, no significant changes were observed in body weight and internal organs, food and water intake, hematological and biochemical parameters, compared to control group. Therefore, these results provide an initial understanding regarding the toxicity profile of 7-acetoxy-4-aryl-3,4-dihydrocoumarin, which can be considered a neoflavonoid with toxicity seen at doses higher than 2000 mg/kg in Swiss mice.

Non-clinical toxicity of ß-caryophyllene, a dietary cannabinoid: Absence of adverse effects in female Swiss mice.

ß-caryophyllene is a food additive that is found in food plants and has broad pharmacological potential. However, little toxicological information has been reported and its use is based on the fact that this bicyclic sesquiterpene is daily consumed as a plant food in much larger quantities than as a food additive. Thus, this study evaluated acute (14-day) and repeated-dose (28 days) oral ß-caryophyllene toxicity in female Swiss mice analyzing changes in body weight, food intake, water intake, hematological and biochemical parameters, organ weight after necropsy, oxidative stress markers and histopathology of various tissues. Acute (300 and 2000 mg/kg) and repeated-dose (300 and 2000 mg/kg) toxicity studies were performed according to the Organization for Economic Cooperation and Development (OECD) guideline 423 and 407, respectively. There was absence of adverse clinical signs and mortality in any animal subjected to acute and repeated-dose toxicity study. In addition, no significant changes in body weight, food and water intake, oxidative stress biomarkers, hematological and biochemical parameters were observed when compared to control group from single-dose and repeated-dose toxicity study. Therefore, the results of this study provide an understanding of the toxicity profile of ß-caryophyllene which can be considered a compound with toxicity at doses higher than 2000 mg/kg body weight.

Photoperiod Differences in Sand Fly (Diptera: Psychodidae) Species Richness and Abundance in Caves in Minas Gerais State, Brazil.

Caves are unique habitats that are inhabited by a diverse and singular biota. Among these inhabitants are sand flies, which are of great epidemiological interest in the Neotropical region because they are vectors of Leishmania The period of activity of these insects is usually crepuscular and nocturnal, but there are reports of diurnal activity of sand flies in caves. Thus, the aim of this study was to evaluate the periodicity of daily activity of sand flies in cave environments in the municipality of Pains, Minas Gerais. Sand flies were collected with light traps, which were operated for 5 consecutive days in the rainy season and in the dry season. Samples were collected every 12 h and separated between photophase and scotophase periods. In total, 1,777 sand flies of 23 species were collected. The most abundant species was Lutzomyia renei (Martins, Falcão, and Silva) (44%), followed by Lutzomyia longipalpis (Lutz and Neiva) (15%), Evandromyia edwardsi (Mangabeira) (11%), and Micropygomyia quinquefer (Costa Lima) (6%). The richness and abundance of total sand flies and the abundance of male and female sand flies in the aphotic zone of the caves did not differ between the photophase and scotophase, but differed between photoperiods at the entrance and at sites surrounding the caves. From our study of the daily activity of these insects in this ecotope, it will be possible to know which period of the day is of greatest risk of exposure of vertebrates who visit or live in these environments, including the human population.

Pre-clinical toxicology of garcinielliptone FC, a tautomeric pair of polyprenylated benzophenone, isolated from Platonia insignis Mart seeds.

BACKGROUND: Garcinielliptone FC (GFC) is a tautomeric pair of polyprenylated benzophenone, which has proven to have antiepileptic, cytotoxic and antioxidant activity. PURPOSE: The aim of this study was to investigate the biochemical, hematological and pathological effects of the acute toxicity study as well as to assess the locomotor activity and motor coordination in mice treated with GFC. METHODS: Swiss mice of both sexes weighing 25-30 g divided into three separate groups of five animals matched by weight and size. GFC was aseptically suspended in 0.05% Tween 80, dissolved in 0.9% saline (vehicle) and administered orally (p.o.) and intraperitoneally (i.p.) (500, 1000 and 2000 mg/kg). The acute toxicity study was performed in compliance with the Anvisa regulations. RESULTS: Behavioral manifestations of toxicity, such as state of consciousness, coordination, muscle tone, reflexes, the activity on the central nervous system (shake, seizures, Straub tail reaction and anesthesia) and the activity of the autonomic nervous system (lacrimation, ptosis, urination, piloerection, hypothermia, breathing and hyperemia) were not seen in any of the animals treated with doses of 500, 1000 and 2000 mg/kg. Additionally, no significant difference in body weight, food and water intake, excreta production or macroscopic changes in the organs of treated animals were detected in comparison with control group. GFC did not affect the locomotor activity and motor coordination of the animals. CONCLUSION: The acute toxicity study indicated that GFC treatment, at selected doses given orally and intraperitoneally, showed relatively low risk of toxicity in all test animals, suggesting that it is safe for further investigation.

Comparison of different degrees of variability in tidal volume to prevent deterioration of respiratory system elastance in experimental acute lung inflammation.

BACKGROUND: Variable ventilation improves respiratory function, but it is not known whether the amount of variability in tidal volume (VT) can be reduced in recruited lungs without a deterioration of respiratory system elastance. METHODS: Acute lung inflammation was induced by intratracheal instillation of lipopolysaccharide in 35 Wistar rats. Twenty-eight animals were anaesthetized and ventilated in volume-controlled mode. Lungs were recruited by random variation of VT (mean 6 ml kg(-1), coefficient of variation 30%, normal distribution) for 30 min. Animals were randomly assigned to different amounts of VT variability (n=7 for 90 min per group): 30, 15, 7.5, or 0%. Lung function, diffuse alveolar damage, and gene expression of biological markers associated with cell mechanical stress, inflammation, and fibrogenesis were assessed. Seven animals were not ventilated and served as controls for post-mortem analyses. RESULTS: A VT variability of 30%, but not 15, 7.5, or 0%, prevented deterioration of respiratory system elastance [Mean (SD) -7.5 (8.7%), P<0.05; 21.1 (9.6%), P<0.05; 43.3 (25.9), P<0.05; and 41.2 (16.4), P<0.05, respectively]. Diffuse alveolar damage was lower with a VT variability of 30% than with 0% and without ventilation, because of reduced oedema and haemorrhage. A VT variability of 30, 15, or 7.5% reduced the gene expression of amphiregulin, cytokine-induced neutrophil chemoattractant-1, and tumour necrosis factor α compared with a VT variability of 0%. CONCLUSIONS: In this model of acute lung inflammation, a VT variability of 30%, compared with 15 and 7.5%, was necessary to avoid deterioration of respiratory system elastance and was not associated with lung histological damage.

Pinhal virus, a new arenavirus isolated from calomys tener in Brazil

Arenavirus Sabiá was originally isolated from a fatal human infection in Brazil, and after the occurrence of the second fatal human case in São Paulo state, epidemiologic and virologic studies were performed in the area where the patient lived, aiming at the identification of the Sabiá natural rodent reservoir. A broadly cross-reactive enzyme-linked immunosorbent assay (ELISA) was used to screen for antibody-positive samples. Antibodies to arenavirus were detected in two of the 55 samples of Calomys tener, and from these results, samples of rodents were analyzed by a broad RT-PCR assay. RT-PCR amplification detected arenavirus sequences in five of the 55 C. tener samples, and sequencing showed that this virus is a distinct form of Sabiá virus. Thus, we describe here the evidence for the circulation of a new arenavirus in Brazil (proposed name Pinhal virus) and its genetic characterization compared to other arenaviruses. This study also suggests C. tener as a probable rodent reservoir for this virus and associates this new virus with the lineage C of New World arenaviruses. Although we have defined some characteristics of this virus, so far, there is no evidence of its involvement in human disease.

Influenza virus A(H3N2) strain isolated from cerebrospinal fluid from a patient presenting myelopathy post infectious.

BACKGROUND: Neurological involvement during influenza infection has been described during epidemics and is often consistent with serious sequelae or death. OBJECTIVE: To investigate the etiologic agent involved in myelopathy post influenza-like syndrome. STUDY DESIGN: This investigation focuses on virus isolation from the cerebrospinal fluid (CSF) collected from a 19-year-old male student presenting with clinical diagnosis of myelopathy post influenza-like syndrome. To achieve this goal, different cell cultures and molecular methodologies were carried out. RESULTS: Influenza virus A(H3N2) strain was isolated in MDCK cell culture; virus particles were observed under electron microscopy. Phylogenetics analyses showed that the Brazilian influenza A(H3N2) strains were closely related to the A/Perth/16/2009-like. CONCLUSION: This study demonstrates that influenza virus A(H3N2) strain was the cause of illness of the students. According to the Brazilian influenza virus sentinel surveillance data A/Perth/16/2009-LIKE (H3N2) strain has predominated during the 2010 influenza virus season in Brasília-DF.

Ecology of phlebotomines (Diptera: Psychodidae) in a transitional area between the Amazon and the Cerrado in the State of Maranhão, Brazil.

The Amazon rainforest and the Brazilian Cerrado both possess high phlebotomine diversity. The fragmentation of these habitats has resulted in the appearance of human cases of cutaneous leishmaniasis. In one altered area of mixed primary vegetation (forest and Cerrado) and its adjacent settlement in the northeast state of Maranhão, Brazil, evidence exists for the active transmission of cutaneous leishmaniasis. Accordingly, an entomological investigation was performed in both the forest and the settlement to compare the phlebotomine vector faunain each environment. The study was conducted from September 2009 to August 2010 in the municipality of Itapecuru Mirim in the state of Maranhão, Brazil. The phlebotomine species were captured using 24 light Center for Disease Control and Prevention traps that were placed in the forest and the settlement (peridomicile and intradomicile). The similarity between the phlebotomine compositions in the forest and those in the settlement was determined using a Principal Coordinate Analysis based on a dissimilarity matrix that was calculated using the Bray-Curtis index (relative abundance) and the Jaccard index (presence and absence of species). In total, 29 Lutzomyia species and one Brumptomyia species were collected. The phlebotomines were diverse and abundant in both the forest fragment (27 species, 4,606 specimens) and the settlement (22 species, 753 specimens). The most abundant species were L. infraspinosa (25%), L. davisi (21%), L. antunesi (21%), L. longipalpis (9%), L. saulensis (6%), L. flaviscutellata (5%), and L. wellcomei (4%). Some species were found strictly in the forest, other species were exclusive to the anthropic environment, and some species colonized both of the studied environments. The phlebotomines adaptation to these modified environments explains the autochthonous outbreak of cutaneous leishmaniasis.

S1 to S2 hind- and forelimb projections in the agouti somatosensory cortex: axon fragments morphological analysis.

The integration of cutaneous, proprioceptive, and motor information in area S2 seems to be essential for manual object recognition and motor control. Part of the inputs to S2 comes from area S1. However no detailed investigations of the morphology of this projection are available. In the present study we describe and quantify the morphology of axon fragments of S1 to S2 ipsilateral projections in the agouti somatosensory cortex. Two groups of projecting axon arbors in S2 were individually reconstructed in three dimensions using Neurolucida, after a single electrophysiological guided BDA injection in either the forelimb (n=4) or the hindlimb (n=4). Electrophysiological mapping was performed 15 days after injections, allowing the localization of S2. Cluster analysis of 40 fragments after hindlimb and 40 after forelimb distinguished two clusters of terminals designated as type I and type II. On average, Type I fragments had greater surface areas and segment lengths than type II fragments, whereas type II fragments had higher number of terminal boutons, number of segments and branching points/mm than type I fragments. Type I corresponded to 58% of the axons projecting from the hindlimb representation in S1 whereas 63% of the sample originating from the forelimb representation in S1 corresponded to type II axons. The results suggest possible parallel processing by two stereotyped classes of axon terminals in the S1 to S2 projections that may represent at least part of the circuitry groundwork associated with distinct somatomotor skills of these limbs in agoutis.

Insight into Anopheles (Nyssorhynchus) (Diptera: Culicidae) species from Brazil.

Anopheles (Nyssorhynchus) benarrochi s.l., Anopheles (Nyssorhynchus) oswaldoi s.l., and Anopheles (Nyssorhynchus) konderi s.l. collected in Acrelandia, state of Acre, Brazil, were identified based on morphological characters of the male genitalia, fourth-instar larvae, and pupae. Morphological variation was observed in the male genitalia of these species in comparison with specimens from other localities in Brazil. DNA sequence from the nuclear ribosomal second internal transcribed spacer of individuals identified as An. benarrochi s.l. by using male genitalia characteristics showed that the various morphological forms are conspecific but are distinct from An. benarrochi B from Colombia. Anopheles konderi s.l. and An. oswaldoi s.l. both misidentified as An. oswaldoi s.s. (Peryassti) throughout Brazil, may actually comprise at least two undescribed species. Diagnostic morphological characteristics of the male genitalia are provided to distinguish Anopheles benarrochi s.l., Anopheles oswaldoi s.l., and Anopheles konderi s.l. from morphologically similar species. Incrimination of An. oswaldoi s.s. in malaria transmission in Brazil needs further investigation because other undescribed species from Acre may have been confounded with this taxon.

Detection of a new mumps virus genotype during parotitis epidemic of 2006-2007 in the state of São Paulo, Brazil.

Nucleotide sequence analyses of the SH gene of 18 mumps virus isolates collected in the 2006-2007 parotitis epidemic in the state of São Paulo identified a new genotype, designated genotype M. This new designation fulfills all the parameters required to define a new mumps virus genotype. The parameters were established by an expert panel in collaboration with the World Health Organization (WHO) in 2005. This information will enhance the mumps virus surveillance program both at the national and global levels.

Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats.

We evaluated the effects of cyclooxygenase-2 (COX-2) selective inhibitors, COX-1 selective inhibitor, or COX non-selective inhibitor on gastric emptying and intestinal transit of liquids, and evaluated the effect of a COX-2 selective inhibitor on gastric tonus (GT). Male Wistar rats were treated per os with saline (control), rofecoxib, celecoxib, ketorolac, rofecoxib + ketorolac, celecoxib + ketorolac, or indomethacin. After 1 h, rats were gavage-fed (1.5 mL) with the test meal (5% glucose solution with 0.05 g mL(-1) phenol red) and killed 10, 20 or 30 min later. Gastric, proximal, medial or distal small intestine dye recovery (GDR and IDR, respectively) were measured by spectrophotometry. The animals of the other group were treated with i.v. valdecoxib or saline, and GT was continuously observed for 120 min using a pletismomether system. Compared with the control group, treatment with COX-2 inhibitors, alone or with ketocolac, as well as with indomethacin increased GDR (P < 0.05) at 10-, 20- or 30-min postprandial intervals. Ketorolac alone did not change the GDR, but increased the proximal IDR (P < 0.05) at 10 min, and decreased medial IDR (P < 0.05) at 10 and 20 min. Valdecoxib increased (P < 0.01) GT 60, 80 and 100 min after administration. In conclusion, COX-2 inhibition delayed the gastric emptying of liquids and increased GT in rats.

Anticonvulsants containing the N-(3-aryl-2-propenoyl) amido pharmacophore.

A series of 1-(3-aryl-2-propenoyl)-4-oxopiperidines (1) as well as some related semicarbazones (2) and thiosemicarbazones (3) were prepared in order to determine whether the relative locations of aryl rings and amidic groups would lead to novel anticonvulsant agents. Initially the compounds were administered intraperitoneally to mice and examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. The biodata revealed that anticonvulsant properties were displayed by most of the compounds in series (1), in half of the semicarbazones (2) while protection was absent by members of series (3). Molecular modeling was utilized in order to compare the positions of a phenyl ring in relation to amidic groups in representative compounds in series (1-3) with previously reported anticonvulsant agents. Molecular simplification of 4-oxo-1-(3-phenyl-2-propenoyl)piperidine (la) led to 1-(3-phenyl-2-propenoyl)piperidine (7) and N,N-diethylcinnamamide (8) with retention of anticonvulsant properties. Both (la) and (8) afforded protection in the hippocampal kindling screen in rats. When administered orally to rats, (la) and (8) demonstrated activity in the MES screen and in the case of (8), a huge protection index was observed revealing it to be an important lead compound. The IC50 values of all of the compounds towards murine P388 cells were in excess of 50 microM while several compounds displayed cytotoxicity towards Mycobacterium tuberculosis.

Cytotoxic mannich bases of 1-arylidene-2-tetralones.

Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2-10 microM range. QSAR using the cytotoxicity data for 2a-e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a-f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate anti-neoplastic agents serving as prototypes for future development.