1,2,3-Triazole derivatives: synthesis, docking, cytotoxicity analysis and in vivo antimalarial activity.

Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy.

In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway.

Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthetic pathway (IBP), produces the isoprenoid (geranylgeranyl pyrophosphate, GGPP) used in protein geranylgeranylation reactions. Our prior studies utilizing triazole bisphosphonate-based GGDPS inhibitors (GGSIs) have revealed that these agents represent a novel strategy by which to induce cancer cell death, including multiple myeloma and pancreatic cancer. Statins inhibit the rate-limiting enzyme in the IBP and potentiate the effects of GGSIs in vitro. The in vivo effects of combination therapy with statins and GGSIs have not been determined. Here we evaluated the effects of combining VSW1198, a novel GGSI, with a statin (lovastatin or pravastatin) in CD-1 mice. Twice-weekly dosing with VSW1198 at the previously established maximally tolerated dose in combination with a statin led to hepatotoxicity, while once-weekly VSW1198-based combinations were feasible. No abnormalities in kidney, spleen, brain or skeletal muscle were observed with combination therapy. Combination therapy disrupted protein geranylgeranylation in vivo. Evaluation of hepatic isoprenoid levels revealed decreased GGPP levels in the single drug groups and undetectable GGPP levels in the combination groups. Additional studies with combinations using 50% dose-reductions of either VSW1198 or lovastatin revealed minimal hepatotoxicity with expected on-target effects of diminished GGPP levels and disruption of protein geranylgeranylation. Combination statin/GGSI therapy significantly slowed tumor growth in a myeloma xenograft model. Collectively, these studies are the first to demonstrate that combination IBP inhibitor therapy alters isoprenoid levels and disrupts protein geranylgeranylation in vivo as well as slows tumor growth in a myeloma xenograft model, thus providing the framework for future clinical exploration.

Social disruption: Sublethal pesticides in pollen lead to Apis mellifera queen events and brood loss.

Eusocial Apis mellifera colonies depend on queen longevity and brood viability to survive, as the queen is the sole reproductive individual and the maturing brood replenishes the shorter-lived worker bees. Production of many crops rely on both pesticides and bee pollination to improve crop quantity and quality, yet sublethal impacts of this pesticide exposure is often poorly understood. We investigated the resiliency of queens and their brood after one month of sublethal exposure to field relevant doses of pesticides that mimic exposure during commercial pollination contracts. We exposed full size colonies to pollen contaminated with field-relevant doses of the fungicides (chlorothalonil and propicanizole), insecticides (chlorypyrifos and fenpropathrin) or both, noting a significant reduction in pollen consumption in colonies exposed to fungicides compared to control. While we found no difference in the total amount of pollen collected per colony, a higher proportion of pollen to non-pollen foragers was detected in all pesticide exposed colonies. After ceasing treatments, we measured brood development, discovering a significant increase in brood loss and/or cannibalism across all pesticide exposed groups. Sublethal pesticide exposure in general was linked to reduced production of replacement workers and a change in protein acquisition (pollen vs. non-pollen foraging). Fungicide exposure also resulted in increased loss of the reproductive queen.

Tebuconazole-induced toxicity and the protective effect of Ficus carica extract in Neotropical fruit-eating bats.

Tebuconazole (TEB) is a triazole fungicide widely used in agriculture known to cause metabolic and endocrine disorders in mammals. Several plant extracts have shown to be beneficial against pesticide effects due to their hepatoprotective, antioxidant and anti-inflammatory properties. As fruit bats play a critical role in rainforest regeneration and are constantly exposed to pesticides, we aimed at evaluating TEB-induced toxicity and the possible protective effect of the Ficus carica plant extract in Neotropical fruit-eating bats (Artibeus lituratus). Bats were captured and assigned to 4 experimental groups, offered: 1) CTL (n = 6): papaya; 2) DMSO (n = 6): papaya treated with 1.25% dimethyl sulfoxide (DMSO); 3) TEB (n = 6): papaya treated with tebuconazole (commercial formulation) 0.1%; and 4) TEBFC (n = 6): papaya treated with tebuconazole 0.1% and Ficus carica extract (20%) in DMSO (1.25%). After seven days of exposure, TEB bats showed increased lipid peroxidation, increased superoxide dismutase (SOD) and catalase (CAT) activities, vascular congestion and inflammatory infiltrate in the liver, and increased serum transaminase enzyme activities. We found the same alterations in oxidative stress parameters in the breast muscles of TEB-exposed bats. In the testes, all oxidative stress markers were increased in TEB bats and corroborate findings of histopathological and increased serum testosterone levels observed following TEB exposure. The co-administration of the fungicide with the F. carica plant extract attenuated most oxidative stress markers in exposed bats' liver and testes and decreased liver damage, but failed to revert the steroid imbalance caused by the fungicide exposure.

Screening of Some Novel 4, 5 Disubstituted 1, 2, 4-Triazole-3-thiones for Anticonvulsant Activity.

OBJECTIVE: In the present study, we synthesized fifteen 4, 5-disubstituted 1, 2, 4-triazol- 3-thione derivatives and evaluated for anticonvulsant activity with neurotoxicity determination. METHODS: The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The molecular docking study was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. The anticonvulsant activity was assessed by maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) tests. The neurotoxicity was assessed by rotarod ataxia test. RESULTS: In MES test, compounds 5a, 8a and 9a were found active at 100 mg/kg and five compounds were found active at 300 mg/kg dose after 1 hr of administration. After 4 hr of drug administration, only two compounds 8a and 9a exhibited protection at 100 mg/kg. In scPTZ test, three compounds 2a, 6a and 8a were found active at 100 mg/kg and 7a was active at 300 mg/kg after 1 hr of test drug administration. Most of the compounds were found active in MES test with 8a and 9a being the most active among all. In docking study, 2a was found to be best compound based on the binding energy of -6.5 kcal/mol and estimated inhibition constant of 17.2 µM. CONCLUSION: Majority of synthesized compounds were found active in MES test, whereas only few were found to possess anti scPTZ activity. Among all compounds, only 14a caused motor coordination impairment in rotarod ataxia test at 300 mg/kg 1 hr duration.

Environmental behavior of paclobutrazol in soil and its toxicity on potato and taro plants.

The environmental behavior of paclobutrazol in soil and its toxicity were studied by field investigation and an outdoor pot experiment, and the residue of paclobutrazol was detected by gas chromatography-mass spectrometry. Field investigation has found that the residual paclobutrazol in the former succession crop could severely inhibit the growth of succeeding crops of potato; with migration and transformation of residual paclobutrazol in the soil, the stems of potato were thickened with residual amount of 1.23 mg kg-1, the growth was slow, and the height of potato in soil with residual amount of 1.34 mg kg-1 and the control was significantly different. The degradation dynamics of paclobutrazol fits with the first-order degradation kinetics, although T1/2 of paclobutrazol of the taro planting soil was 30.14-46.21 days and the residual paclobutrazol remained detectable even on day 120 after application. Taro leaves were sensitive to the stress of paclobutrazol pollution; the taro leaf thickness increased, the leaf area decreased, the chlorophyll content per area unit of taro leaf showed an obvious increased trend, and SOD and CAT activities and MDA and proline content increased significantly. Paclobutrazol promoted the tillering of taro, and the taro seedlings were dwarfed by 58.01, 63.27, and 75.88% at different concentrations. It indicated that taro had strong stress response ability under paclobutrazol pollution.

The biological activities of prothioconazole enantiomers and their toxicity assessment on aquatic organisms.

Chiral fungicide prothioconazole has a wide range of antifungal spectrum; however, little research has been conducted to evaluate prothioconazole on an enantiomeric level. Five target pathogens and three common aquatic organisms were tested for the enantioselective bioactivity and toxicity of prothioconazole in this work. The antifungal activity of the enantiomers against wheat phytoalexin, rice blast fungus, exserohilum turcicum, Alternaria triticina, and Fusarium avenaceum was determined, and it was found that (-)-prothioconazole were 85 to 2768 times more active than (+)-prothioconazole toward these target organisms. In order to reflect the risk to aquatic ecosystem, the acute toxicity of the enantiomers to Daphnia magna, Chlorella pyrenoidosa, and Lemna minor L. was assessed. It was observed that the toxicity of (-)-prothioconazole to D. magna was 2.2 times higher than (+)-prothioconazole, but it was lower to C. pyrenoidosa and L. minor L. The toxicities of (+)-enantiomer and (-)-enantiomer to D. magna and C. pyrenoidosa were synergy, indicating that the racemate had higher threat to the organisms. It could be concluded that the effects of prothioconazole on target organisms and the acute toxicity to nontarget species were enantioselective with (-)-enantiomer possessing higher efficiency and lower toxicity. Such enantiomeric differences should be taken into consideration when assessing the performance of prothioconazole.

The effects of hexaconazole and epoxiconazole enantiomers on metabolic profile following exposure to zebrafish (Danio rerio) as well as the histopathological changes.

Hexaconazole and epoxiconazole are the worldwidely used fungicides. However, limited information is known about the toxicological effects of their enantiomers on aquatic organisms. In this study, zebrafish were separately exposed to 100 and 1000 µgL-1 hexaconazole and epoxiconazole enantiomers for 21 d 1H NMR-based metabolomics analysis showed that the exposure of low and high dose of hexaconazole enantiomers altered energy metabolism, lipid metabolism and amino acid metabolism of zebrafish, with the different metabolic profiles resulted from the same dose of (+)-hexaconazole and (-)-hexaconazole. Similar to hexaconazole enantiomers, the metabolic profiles, including the changes related to energy metabolism, lipid metabolism and amino acid metabolism, were demonstrated in low and high dose epoxiconazole enantiomers treatment groups. There are differences in the metabolic profiles of zebrafish between exposed to (+)-epoxiconazole and (-)-epoxiconazole of the same dose. The results of histological examination revealed that the exposure of both enantiomers for hexaconazole and epoxiconazole resulted in the similar histopathological changes. The exposure of hexaconazole and epoxiconazole enantiomers at low and high dose resulted the vacuolization and swell in the liver of the female and male zebrafish. Compared to female zebrafish, more liver damage was found in male zebrafish in the hexaconazole enantiomers exposure groups. The reduction of spermatids was observed in hexaconazole and epoxiconazole enantiomers treatment groups of both doses. Hexaconazole enantiomers exposure of low and high dose resulted the increase in the number of mature eggs, while such effect was not observed in epoxiconazole enantiomers exposure groups. Hexaconazole and epoxiconazole enantiomers exposure resulted in no changes in brains of female and male zebrafish. As a result, both triazole-based chiral bactericides, hexaconazole and epoxiconazole, have similar toxicological effects but their mechanisms of action are not exactly the same. The above results will play an important part in making the differences in toxic effects of hexaconazole and epoxiconazole enantiomers clear. What's more, it is an indispensable part for an integrated environmental risk assessment.

Epoxiconazole exposure affects terpenoid profiles of oilseed rape plantlets based on a targeted metabolomic approach.

Epoxiconazole is a broad-spectrum fungicide described as highly persistent in soil and as such can be considered as an abiotic agent like other problematic agrochemicals. Furthermore, the plant phenotyping tool involving non-invasive monitoring of plant-emitted volatile organic compounds (VOCs) may be useful in the identification of metabolic markers for abiotic stress. We therefore decided to profile the VOCs from secondary metabolism of oilseed rape through a dose-response experiment under several epoxiconazole concentrations (0, 0.01, 0.1 and 1 mg L-1). VOC collections of 35-day-old whole plantlets were performed through a dynamic headspace sampling technique under defined and controlled conditions. The plantlets grew freely within a home-made, laboratory and high-throughput glass chamber without any disturbance. Putative metabolic markers were analysed using a targeted metabolomic approach based on TD-GC-MS method coupled with data acquisition in SIM mode in order to focus on terpenes and sulphur-containing volatiles. Chromatograms of emitted terpenes were achieved accurately for the 35-day-old oilseed rape plantlets. We also analysed the presence of sulphur-containing volatiles in samples of shoot and root tissues using an innovative DHS-TD-GC-MS method, but no difference was found between qualitative profiles. Nevertheless, we demonstrated through this experiment that sesquiterpenes such as ß-elemene and (E,E)-α-farnesene are involved in epoxiconazole dose-response. In particular, (E,E)-α-farnesene could serve as a metabolic marker of fungicide exposure for oilseed rape plantlets.

Carvacrol ameliorates behavioral disturbances and DNA damage in the brain of rats exposed to propiconazole.

Propiconazole (PCZ) is an ergosterol biosynthesis inhibiting fungicide. Carvacrol (CAR) is a monoterpenoid phenol that has various beneficial health effects. The current research was designed to study the impact of PCZ on the behavior of rats and its ability to induce DNA damage in neurons as well as to clarify the ameliorative effect of CAR against these toxic impacts. Sixty Sprague-Dawley rats were randomly and equally divided into 4 experimental groups and treated daily by oral gavage for 2 months as follows: Group 1 (control); group 2 treated with PCZ (75 mg/kg); group 3 treated with CAR (50 mg/kg) and group 4 treated with both PCZ and CAR. Behavioral tests demonstrated that exposure to PCZ had a deleterious effect on psychological, motor and cognitive neural functions. Additionally, antioxidant enzyme activities, SOD and GSH-Px, were declined in brain tissue following exposure to PCZ. Moreover, comet assay revealed a high percent of DNA damage in the brain of rats exposed to PCZ. On the other hand, CAR administration ameliorated the harmful effects induced by PCZ through a protective mechanism that involved the improvement of neural functions and attenuation of oxidative stress and DNA damage.

Efficacy of Allium sativum oil to alleviate tebuconazol-induced oxidative stress in the liver of adult rats.

The present study focused on the protective efficacy of Allium sativum oil (ASO) against tebuconazol (TEB)-induced oxidative stress in the liver of adult rats. Thirty-two rats were randomly divided into four groups of eight each: group I served as control rats, group II was treated with TEB (100 mg/kg bw), group III received ASO (5ml/kg bw). The animals of group IV were treated with TEB and ASO, during 4 weeks. The obtained results showed that TEB induced a significant change of some hematological parameters, including red blood cells (RBC), haemoglobin content (Hb), haematocrit (Ht), white blood cells (WBC) and platelet (Plt) compared to the control group. Moreover, while the total cholesterol levels and the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and γ-Glutamyltranspeptidase (γGT) significantly increased due to TEB administration, the concentrations of plasma total protein, albumin and triglyceride considerably decreased. Furthermore, the exposure to TEB significantly increased the malondialdehyde (MDA), protein carbonyl (PCO) and advanced oxidation protein products (AOPP) levels and decreased glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities in the hepatic tissues. The results were confirmed by the histological impairments. Besides, the co-administration of ASO improved the status of all studied parameters. Therefore, our investigation revealed that ASO had protective effects against TEB-induced liver injury, which could be attributed to its phenolic compounds.

The evaluation of acute toxicity, antimicrobial activity of 1-phenyl-5-p-tolyl-1H-1, 2, 3-triazole, and binding to human serum albumin.

1-Phenyl-5-p-tolyl-1H-1, 2, 3-triazole (PPTA) was a synthesized compound. The result of acute toxicities to mice of PPTA by intragastric administration indicated that PPTA did not produce any significant acute toxic effect on Kunming strain mice. It exhibited the various potent inhibitory activities against two kinds of bananas pathogenic bacteria, black sigatoka and freckle, when compared with that of control drugs and the inhibitory rates were up to 64.14% and 43.46%, respectively, with the same concentration of 7.06 mM. The interaction of PPTA with human serum albumin (HSA) was studied using fluorescence polarization, absorption spectra, 3D fluorescence, and synchronous spectra in combination with quantum chemistry and molecular modeling. Multiple modes of interaction between PPTA and HSA were suggested to stabilize the PPTA-HSA complex, based on thermodynamic data and molecular modeling. Binding of PPTA to HSA induced perturbation in the microenvironment around HSA as well as secondary structural changes in the protein.

Disruption of quercetin metabolism by fungicide affects energy production in honey bees (Apis mellifera).

Cytochrome P450 monooxygenases (P450) in the honey bee, Apis mellifera, detoxify phytochemicals in honey and pollen. The flavonol quercetin is found ubiquitously and abundantly in pollen and frequently at lower concentrations in honey. Worker jelly consumed during the first 3 d of larval development typically contains flavonols at very low levels, however. RNA-Seq analysis of gene expression in neonates reared for three days on diets with and without quercetin revealed that, in addition to up-regulating multiple detoxifying P450 genes, quercetin is a negative transcriptional regulator of mitochondrion-related nuclear genes and genes encoding subunits of complexes I, III, IV, and V in the oxidative phosphorylation pathway. Thus, a consequence of inefficient metabolism of this phytochemical may be compromised energy production. Several P450s metabolize quercetin in adult workers. Docking in silico of 121 pesticide contaminants of American hives into the active pocket of CYP9Q1, a broadly substrate-specific P450 with high quercetin-metabolizing activity, identified six triazole fungicides, all fungal P450 inhibitors, that dock in the catalytic site. In adults fed combinations of quercetin and the triazole myclobutanil, the expression of five of six mitochondrion-related nuclear genes was down-regulated. Midgut metabolism assays verified that adult bees consuming quercetin with myclobutanil metabolized less quercetin and produced less thoracic ATP, the energy source for flight muscles. Although fungicides lack acute toxicity, they may influence bee health by interfering with quercetin detoxification, thereby compromising mitochondrial regeneration and ATP production. Thus, agricultural use of triazole fungicides may put bees at risk of being unable to extract sufficient energy from their natural food.

Nitraria retusa fruit prevents penconazole-induced kidney injury in adult rats through modulation of oxidative stress and histopathological changes.

CONTEXT: Nitraria retusa (Forssk.) Asch. (Nitrariaceae) is a medicinal plant which produces edible fruits whose antioxidant activity has been demonstrated. OBJECTIVE: The current study elucidates the potential protective effect of N. retusa fruit aqueous extract against nephrotoxicity induced by penconazole, a triazole fungicide, in the kidney of adult rats. MATERIALS AND METHODS: Adult Wistar rats were exposed either to penconazole (67 mg/kg body weight), or to N. retusa extract (300 mg/kg body weight) or to their combination. Penconazole was administered by intra-peritoneal injection every 2 days from day 7 until day 15, the sacrifice day, while N. retusa extract was administered daily by gavage during 15 days. Oxidative stress parameters, kidney biomarkers and histopathological examination were determined. RESULTS: Nitraria retusa extract administration to penconazole treated rats decreased kidney levels of malondialdehyde (-10%), hydrogen peroxide (-12%), protein carbonyls (PCOs, -11%) and advanced oxidation protein products (AOPP, -16%); antioxidant enzyme activities: catalase (-13%), superoxide dismutase (-8%) and glutathione peroxidase (GPx, -14%), and the levels of non-enzymatic antioxidants: non-protein thiols (-9%), glutathione (-7%) and metallothionein (-12%). Furthermore, this plant extract prevented kidney biomarker changes by reducing plasma levels of creatinine, urea, uric acid and LDH and increasing those of ALP and GGT. Histopathological alterations induced by penconazole (glomeruli fragmentation, Bowman's space enlargement, tubular epithelial cells necrosis and infiltration of inflammatory leucocytes) were attenuated following N. retusa administration. DISCUSSION AND CONCLUSION: Our results indicated that N. retusa fruit extract had protective effects against penconazole-induced kidney injury, which could be attributed to its phenolic compounds.

Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights.

Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 µM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells. Mechanistic role for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) was also elucidated. These compounds could provide promising new lead derivatives for more potent anticancer drug development and delivery, and represent one of the most active classes of lapachones reported.

Synthesis, Anticlotting and Antiplatelet Effects of 1,2,3-Triazoles Derivatives.

Cardiovascular diseases, such as thrombosis and stroke, represent the major cause of disability and death worldwide; and dysfunctions in platelet aggregation and blood coagulation processes are involved. The regular antithrombotic drugs have unsatisfactory results and may produce side effects. Therefore, alternative therapies have been extensively investigated. OBJECTIVE: The anticoagulant and antiplatelet aggregation potential of a series of six synthetic 1,2,3-triazole derivatives were investigated through in vitro models. METHODS: Coagulation tests included the prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) assays, and were performed on a multichannel coagulometer, using human plasma. The platelet aggregation assays were carried out using human platelet-rich-plasma (PRP). Aggregation was initiated by adding ADP or collagen and monitored turbidimetrically on a Whole Blood Aggregometer. Toxicity of derivatives was evaluated on platelets and red blood cells, by measuring the release of lactate dehydrogenase and hemoglobin, respectively. Moreover, theoretical toxicity of derivatives was calculated using the software Osiris® Property Explorer. RESULTS: All the six derivatives tested inhibited, but with different potencies, the plasma coagulation assessed by the PT and TT assays, and also inhibited platelet aggregation of PRP induced by collagen or ADP. The derivatives did not interfere in the aPTT assay and did not affect the viability of platelets or red blood cells. Theoretical studies also revealed that all derivatives will likely to have low toxicity, great pharmacological and oral bioavailability profiles, and a Druglikeness and Drug score similar to some commercial anticoagulant and antiplatelet drugs. CONCLUSION: 1,2,3-triazoles are potential candidates for molecular modeling of new antithrombotic drugs.

Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator.

Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present study investigates the new role of deferasirox as an anticancer agent due to its ability to chelate with iron. Because of aminoacids antioxidant effect, deferasirox and its two novel amino acid derivatives have been synthesized through the treatment of deferasirox with DCC as well as glycine or phenylalanine methyl ester. All new compounds have been characterized by elemental analysis, FT-IR NMR and mass spectrometry. Therefore, the cytotoxicity of these compounds was screened for antitumor activity against some cell lines using cisplatin as a comparative standard by MTT assay and Flow cytometry. The impact of iron in the intracellular generation of reactive oxygen species was assessed on HT29 and MDA-MB-231 cells. The potential of the synthesized iron chelators for their efficacy to protect cells against model oxidative injury induced was compared. The reactive oxygen species intracellular fluorescence intensity were measured and the result showed that the reactive oxygen species intensity after iron incubation increased while after chelators incubation the reactive oxygen species intensity were decreased significantly. Besides, the effect of the synthesized compounds on mouse fibroblast cell line (L929) was simultaneously evaluated as control. The pharmacological results showed that deferasirox and its two novel aminoacid derivatives were potent anticancer agents.

Preliminary Pharmacological Screening of Some Thiosemicarbazide, s-triazole, and Thiadiazole Derivatives.

Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.

Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes.

The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD90) and 50% (APD50) repolarization, reduced the maximum upstroke velocity (dV/dtmax) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including IKr, IKs, INa, and ICa. Among them, IKr and INa showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K(+) channels.

Improvement of Heart Redox States Contributes to the Beneficial Effects of Selenium Against Penconazole-Induced Cardiotoxicity in Adult Rats.

The present study was performed to evaluate the protective effect of selenium (Se) against penconazole (PEN)-induced oxidative stress in the cardiac tissue of adult rats. Male Wistar rats were divided into four groups of six each. The first group represented the controls. For the second group (PEN), no treatment was performed during the first 6 days, and then, the rats received intraperitoneally 67 mg/kg body weight (bw) of PEN every 2 days from day 7 until day 15, the sacrifice day. For the third group (Se + PEN), Se was administered daily through the diet at a dose of 0.5 mg/kg of diet for 15 days. Rats of this group received also every 2 days PEN (67 mg/kg bw) from day 7 until day 15. The fourth group (Se) received daily, through the diet, Se (0.5 mg/Kg of diet) during 15 days. Our results showed that Se reduced significantly the elevated cardiac levels of malondialdehyde and protein carbonyl following PEN treatment, and attenuated DNA fragmentation induced by this fungicide. In addition, Se modulated the alterations of antioxidant status: enzymatic (superoxide dismutase, glutathione peroxidase, and catalase) and nonenzymatic (glutathione and vitamin C) antioxidants in the heart of PEN-treated rats. This trace element was also able to alleviate perturbations of lipid profile. The protective effect of selenium was further evident through the histopathological changes produced by PEN in the heart tissue. Taken together, our results indicated that Se might be beneficial against PEN-induced cardiac oxidative damage in rats.