scholarly journals Acute toxicity of the iron clathrochelate complexes

2019 ◽  
Vol 10 (3) ◽  
pp. 276-279
Author(s):  
V. Dukhnitsky ◽  
I. Derkach ◽  
M. Plutenko ◽  
I. Fritsky ◽  
S. Derkach
Keyword(s):  
Aqueous Media ◽  
Lethal Dose ◽  
New Drugs ◽  
Reaction Conditions ◽  
New Class ◽  
White Rats ◽  
Low Toxicity ◽  
Source Materials ◽  
Clathrochelate Complexes

A new class of highly valent iron compounds is formed by atmospheric oxidation in aqueous media and it is extremely stable both in solid and soluble conditions and may exist indefinitely in a medium without signs of degradation. The first clathrochelate complexes of iron (IV) are infinitely stable in water and readily available from simple, commercially available, inexpensive source materials with surprisingly mild reaction conditions. To create new drugs on their bases, research on their toxicity is required. In this study, the results of preclinical studies of a new iron clathrochelates drug are presented. Experiments were carried out on white rats and quails, which in the previous experiment were divided into five experimental and two control groups. The solution of iron clathrochelate complexes was administered intragastrically in doses 50, 500, 1000, 2000 and 5000 mg/kg, respectively. Our results have shown that there were no grounds for using rats in the advanced experiment because the conducted research has established that iron clathrochelate is non toxic to rats. Thus, the minimum dose of iron clathrochelate complexes did not cause death of quails, and the largest dose caused 100% mortality. The basic experiment was conducted on 6 groups of birds, each consisting of 7 quails. The drug was administered in the following doses: 500, 600, 700, 800, 900, 1000 mg/kg. The monitoring observation of the laboratory birds lasted for 14 days. It has been established that the average lethal dose of clathrochelate of the investigated drug for internal administration in quails is 764 ± 33 mg/kg. According to the classification of chemicals by the degree of danger (State ST 12.1.007-76), iron (IV) clathrochelate complexes correspond to the third class of hazard, and according to the classification of substances for toxicity they are classified as category 4 (low toxicity substances). The prospect of further research is to investigate the pharmacological and toxicological properties of iron (IV) clathrochelate for chronic toxicity.

scholarly journals Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

2018 ◽  
Vol 115 (41) ◽  
pp. E9649-E9658 ◽  
Author(s):  
Mario D. Garcia ◽  
Sheena M. H. Chua ◽  
Yu-Shang Low ◽  
Yu-Ting Lee ◽  
Kylie Agnew-Francis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Drug ◽  
New Drugs ◽  
Acetohydroxyacid Synthase ◽  
Drug Candidates ◽  
New Class ◽  
Branched Chain Amino Acid ◽  
Low Toxicity ◽  
Chlorimuron Ethyl ◽  
Branched Chain

The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.

Biocatalytic synthesis of novel electronic and photovoltaic materials

2005 ◽  
Vol 77 (1) ◽  
pp. 263-272 ◽  
Author(s):  
Ravi Mosurkal ◽  
Rajesh Kumar ◽  
Ferdinando F. Bruno ◽  
Ramaswamy Nagarajan ◽  
Lynne Samuelson ◽  
...  
Keyword(s):  
Ruthenium Complex ◽  
Aqueous Media ◽  
Dinuclear Complex ◽  
Environmentally Benign ◽  
Polystyrene Sulfonate ◽  
Polymeric Complex ◽  
Reaction Conditions ◽  
New Class ◽  
Photovoltaic Materials ◽  
Biomimetic Method

A new class of ruthenium complex-based macrodye and a dinuclear complex were synthesized via a biocatalytic route employing hematin as an efficient biocatalyst. The photovoltaic overall efficiency of the dinuclear complex was found to be 2.1 % and higher than the polymeric complex (0.33 %). Furthermore, we have developed an environmentally benign methodology for the synthesis of novel pegylated polyphenolics. The reaction conditions used do not require any organic solvents, and all the reactions were performed in aqueous media. The synthesized polymers were soluble in both organic and aqueous media, and provide further opportunity to tailor the properties. Finally, a novel biomimetic method for the synthesis of a conducting molecular complex of polypyrrole and of thiophene substitute in the presence of a polyelectrolyte, such as polystyrene sulfonate (SPS), is presented. A synthetic enzyme based on hematin was used to catalyze the polymerization of pyrrole (PYR) and 3,4-ethylenedioxythiophene (EDOT) in the presence of SPS. Copolymers of EDOT and PYR have also been synthesized, and these novel materials have been shown to exhibit high electrical conductivity.

Acute toxicity of an insecticidal little containing ivermectin and fipronil for white mice

2020 ◽  
pp. 31-32
Author(s):  
Mikhail A. Levchenko ◽  
◽  
Natalia A. Sennikova ◽  
Keyword(s):  
Acute Toxicity ◽  
Lethal Dose ◽  
Live Weight ◽  
Acute Oral Toxicity ◽  
Oral Toxicity ◽  
Toxicological Assessment ◽  
Russian Research Institute ◽  
Veterinary Entomology ◽  
Russian Research

Toxicological assessment is a mandatory research step in the development of new insecticidal drugs. At the All-Russian Research Institute of Veterinary Entomology and Arachnology, a prototype of the insecticidal bait Mukhnet IF was obtained with an active ingredient content of 0.06% ivermectin and 0.015% fipronil, which showed a highly effective effect against houseflies. This work presents the results of the study of acute oral toxicity of the above agent. For this, male white mice with a live weight of 16-26 g were selected. They were kept on a starvation diet for one day in individual houses with water. The drug was given in mg/kg body weight the next day. A total of 33 doses have been tested, ranging from 100 mg/kg to 40,000 mg/kg. The animals were observed for 14 days. According to the research results, it was revealed that at doses up to 20,000 mg/kg there were no signs of intoxication, but when tested at 25,000 mg/kg in some mice, these signs were noted, and at 30,000, 35,000 and 40,000 mg/kg deaths were recorded 20±10, 45±30 and 60±20%, respectively. It was not possible to test the drug over the last above dose due to incomplete eaten by mice. According to the degree of danger for warm-blooded animals, the drug belongs to the 4th class of low-hazard drugs (average lethal dose of 5000 mg/kg or more) in accordance with the classification of GOST 12.1.007-76. When analyzing the literature data on the toxicological characteristics of preparations containing ivermectin and chlorfenapyr, it was revealed that the insecticidal agent in its acute toxicity for warm-blooded animals is comparable to known analogues.

Anti-adhesion Molecules in IBD: Does Gut Selectivity Really Make the Difference?

2019 ◽  
Vol 25 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Ferdinando D'Amico ◽  
Giulia Roda ◽  
Laurent Peyrin-Biroulet ◽  
Silvio Danese
Keyword(s):  
Adhesion Molecules ◽  
Biological Treatment ◽  
Current Data ◽  
New Drugs ◽  
Inflammatory Infiltration ◽  
New Class ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
The Difference ◽  
Necrosis Factor

Inflammatory Bowel Disease is lifetime chronic progressive inflammatory disease. A considerable portion of patients, do not respond or lose response or experience side effect to “traditional” biological treatment such as anti-tumor necrosis factor (TNF)-α agents. The concept that the blockade of T cell traffic to the gut controls inflammation has stimulated the development of new drugs which selectively targets molecules involved in controlling cell homing to the intestine. The result is the reduction of the chronic inflammatory infiltration in the gut. In this regard, anti-adhesion molecules represent a new class of drugs for patients who don’t respond or lose response to traditional therapy. Moreover, some of these molecules such as vedolizumab, offer the advantage to target the delivery of a drug to the gut (gut selectivity) which could increase clinical efficacy and limit potential adverse events. In this article, we will give an overview of the current data on anti-adhesion molecules in Inflammatory Bowel Diseases.

Chemometric Analysis for the Classification of some Groups of Drugs with Divergent Pharmacological Activity on the Basis of some Chromatographic and Molecular Modeling Parameters

2018 ◽  
Vol 21 (2) ◽  
pp. 125-137
Author(s):  
Jolanta Stasiak ◽  
Marcin Koba ◽  
Marcin Gackowski ◽  
Tomasz Baczek
Keyword(s):  
Correlation Analysis ◽  
Pharmacological Activity ◽  
Correlation Coefficients ◽  
Principal Component ◽  
Cardiovascular Drugs ◽  
New Drugs ◽  
Analgesic Drugs ◽  
Starting Point ◽  
Chromatographic Parameters

Aim and Objective: In this study, chemometric methods as correlation analysis, cluster analysis (CA), principal component analysis (PCA), and factor analysis (FA) have been used to reduce the number of chromatographic parameters (logk/logkw) and various (e.g., 0D, 1D, 2D, 3D) structural descriptors for three different groups of drugs, such as 12 analgesic drugs, 11 cardiovascular drugs and 36 “other” compounds and especially to choose the most important data of them. Material and Methods: All chemometric analyses have been carried out, graphically presented and also discussed for each group of drugs. At first, compounds’ structural and chromatographic parameters were correlated. The best results of correlation analysis were as follows: correlation coefficients like R = 0.93, R = 0.88, R = 0.91 for cardiac medications, analgesic drugs, and 36 “other” compounds, respectively. Next, part of molecular and HPLC experimental data from each group of drugs were submitted to FA/PCA and CA techniques. Results: Almost all results obtained by FA or PCA, and total data variance, from all analyzed parameters (experimental and calculated) were explained by first two/three factors: 84.28%, 76.38 %, 69.71% for cardiovascular drugs, for analgesic drugs and for 36 “other” compounds, respectively. Compounds clustering by CA method had similar characteristic as those obtained by FA/PCA. In our paper, statistical classification of mentioned drugs performed has been widely characterized and discussed in case of their molecular structure and pharmacological activity. Conclusion: Proposed QSAR strategy of reduced number of parameters could be useful starting point for further statistical analysis as well as support for designing new drugs and predicting their possible activity.

Anti-Mycobacterial Peroxides: A New Class of Agents for Development Against Tuberculosis

2020 ◽  
Vol 16 (3) ◽  
pp. 392-402
Author(s):  
Christiaan W. van der Westhuyzen ◽  
Richard K. Haynes ◽  
Jenny-Lee Panayides ◽  
Ian Wiid ◽  
Christopher J. Parkinson
Keyword(s):  
Subsequent Development ◽  
Antitubercular Activity ◽  
Organic Peroxide ◽  
New Drugs ◽  
Skeletal Myoblast ◽  
Artemisinin Derivatives ◽  
Malaria Therapy ◽  
New Class ◽  
Alternative Approach

Background: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. Objective: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. Methods: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. Results: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. Conclusion: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.

scholarly journals Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

2021 ◽  
Vol 22 (13) ◽  
pp. 7236
Author(s):  
Endah Dwi Hartuti ◽  
Takaya Sakura ◽  
Mohammed S. O. Tagod ◽  
Eri Yoshida ◽  
Xinying Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Chemical Library ◽  
New Class ◽  
De Novo Biosynthesis ◽  
Starting Point ◽  
Novel Drugs ◽  
Low Toxicity ◽  
Fourth Step

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

The Effect of Sodium Nitrite on Experimental Animals

1942 ◽  
Vol 6a (1) ◽  
pp. 63-73 ◽  
Author(s):  
H. L. A. Tarr ◽  
N. M. Carter
Keyword(s):  
Sodium Nitrite ◽  
Lethal Dose ◽  
Oral Route ◽  
Female Rats ◽  
Male Rats ◽  
Subcutaneous Route ◽  
Healthy Male ◽  
Experimental Animals ◽  
White Rats ◽  
Healthy Female

Incorporation of sodium nitrite in the diet of cats and white rats on the basis of an average sized man consuming 1 lb. (454 g.) of fish containing 0.2 per cent (908 mg.) of this salt daily for six days each week does not appear to affect their growth rate nor the development (weight) of their thyroid, heart, lungs, spleen, liver, kidneys or adrenals. The fecundity of white rats as judged by their ability to breed and raise normal litters is apparently not affected thereby. The lethal dose of sodium nitrite by oral route is about 1.1 to 2.0 g./kg. for healthy male rats, 0.46 to 1.2 g./kg. for healthy female rats and 0.073 g./kg. for cats (one animal). The lethal dose by subcutaneous route is about 0.19 to 0.20 g./kg. for healthy male rats and 0.057 to 0.13 g./kg. for healthy female rats.

scholarly journals Synthesis of new Cα-tetrasubstituted α-amino acids

2009 ◽  
Vol 5 ◽  
Author(s):  
Andreas A Grauer ◽  
Burkhard König
Keyword(s):  
Amino Acids ◽  
Secondary Structure ◽  
Aromatic Aldehydes ◽  
Building Blocks ◽  
Reaction Conditions ◽  
Peptide Backbone ◽  
Aliphatic Aldehydes ◽  
New Class ◽  
Cyclic Amino Acids

Cα-Tetrasubstituted α-amino acids are important building blocks for the synthesis of peptidemimetics with stabilized secondary structure, because of their ability to rigidify the peptide backbone. Recently our group reported a new class of cyclic Cα-tetrasubstituted tetrahydrofuran α-amino acids prepared from methionine and aromatic aldehydes. We now report the extension of this methodology to aliphatic aldehydes. Although such aldehydes are prone to give aldol products under the reaction conditions used, we were able to obtain the target cyclic amino acids in low to moderate yields and in some cases with good diastereoselectivity.

Allee’s Effect Bifurcation in Generalized Logistic Maps

2019 ◽  
Vol 29 (03) ◽  
pp. 1950039
Author(s):  
J. Leonel Rocha ◽  
Abdel-Kaddous Taha
Keyword(s):  
Allee Effect ◽  
Dynamical Behavior ◽  
Complete Classification ◽  
Unimodal Maps ◽  
New Class ◽  
New Type ◽  
Local And Global Bifurcations ◽  
One Dimensional Maps ◽  
Necessary And Sufficient

This paper concerns the study of the Allee effect on the dynamical behavior of a new class of generalized logistic maps. The fundamentals of the dynamics of this 4-parameter family of one-dimensional maps are presented. A complete classification of the nature and stability of its fixed points is provided. The main results relate to the Allee effect bifurcation: a new type of bifurcation introduced for this class of unimodal maps. A necessary and sufficient condition so that the Allee fixed point is a snap-back repeller is established. In addition, in the parameters space is defined an Allee’s effect region, which determines the existence of an essential extinction for the generalized logistic maps. Local and global bifurcations of generalized logistic maps are investigated.

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