scholarly journals The antiseptic and trypanocidal action of certain styryl and anil quinoline carboxylamides.*

1932 ◽  
Vol 110 (767) ◽  
pp. 249-260
Keyword(s):  
Amide Group ◽  
The Other ◽  
Amino Group ◽  
Active Compounds ◽  
Basic Group ◽  
Urethane Group ◽  
Highly Active ◽  
Quaternary Compounds ◽  
Quinoline Series

In the case of quaternary compounds of the styryl quinoline series and of the analogous benzthiazole derivatives a powerful trypanocidal effect in vivo has been shown to depend on the presence in the substance of a free basic group in one of the nuclei, and anacylamino (especially acetyl) or urethane group in the other, and also on the styryl linkage—each playing a definite part in contributing to the action (Browning, Cohen, Ellingworth and Gulbransen, 1929, 1931). This is exemplified by 2( p -aminostyryl)-6 acetylamino quinoline methochloride (No. 8), 2( p -dimethylamino styryl)-6 acetylamino quinoline methochloride (No. 25), 2( p -acetylamino)-6 dimethylamino quinoline methochloride (No. 90) and 2( p -dimethylamino styryl) quinolyl (6) urethane (Me) methochloride (No. 125). The effect of acetylation of the amino group parallels that dis­covered by Ehrlich and his co-workers in the case of p -amino phenyl arsinic acid. Gough and King (1930) have recently made the important observation that in the latter series the introduction of an amide group converts the therapeutically inactive carboxylic and sulphonic acids into active compounds. Accordingly, the effect of substituting a carboxylamide group for the acylamino in compounds of the type of No. 25 and its anil analogue (No. 62) has been investigated. In addition, the position of the carboxylamide group has been varied. These substances were further examined for antiseptic action, the results being shown in the table. Trypanocidal properties have been tested on T. brucei infections in mice as in previous work. The striking observation has been made that only those compounds with the carboxylamide group in the 6 position are therapeutically active, the anils being only slightly less effective than the styryl analogues ( cf . Nos. 410, 409 and 385, 403). This contrasts with what is found in the acetylamino derivatives, since the styryl compounds of the latter are highly active as compared with the corresponding anils. The carboxy-ethylamides (420, 419) are more toxic and less trypanocidal than the corresponding amides and methylamides.

scholarly journals In Vitro Selection and In Vivo Efficacy of Piperazine- and Alkanediamide-Linked Bisbenzamidines against Pneumocystis Pneumonia in Mice

2006 ◽  
Vol 50 (7) ◽  
pp. 2337-2343 ◽  
Author(s):  
Melanie T. Cushion ◽  
Peter D. Walzer ◽  
Alan Ashbaugh ◽  
Sandra Rebholz ◽  
Ronald Brubaker ◽  
...  
Keyword(s):  
Mouse Model ◽  
In Vitro Selection ◽  
Parent Compound ◽  
Pneumocystis Pneumonia ◽  
In Vitro Cytotoxicity ◽  
Active Compounds ◽  
Cytotoxicity Assays ◽  
Highly Active

ABSTRACT Bisbenzamidines, such as pentamidine isethionate, are aromatic dicationic compounds that are active against Pneumocystis and other microbes but are oftentimes toxic to the host. To identify potential anti-Pneumocystis agents, we synthesized bisbenzamidine derivatives in which the parent compound pentamidine was modified by a 1,4-piperazinediyl, alkanediamide, or 1,3-phenylenediamide moiety as the central linker. Several of the compounds were more active against P. carinii and less toxic than pentamidine in cytotoxicity assays. For this study, we evaluated nine bisbenzamidine derivatives representing a range of in vitro activities, from highly active to inactive, for the treatment of pneumocystosis in an immunosuppressed mouse model. Six of these in vitro-active compounds, 01, 02, 04, 06, 100, and 101, exhibited marked efficacies against infection at a dose of 10 mg/kg of body weight, and four compounds, 01, 04, 100, and 101, showed significant increases in survival versus that of untreated infected control mice. Compound 100 was highly efficacious against the infection at 20 mg/kg and 40 mg/kg, with >1,000-fold reductions in burden, and resulted in improved survival curves versus those for pentamidine-treated mice (at the same doses). All six bisbenzamidine compounds that exhibited high in vitro activity significantly decreased the infection in vivo; two compounds, 12 and 102, with marked to moderate in vitro activities had slight or no activity in vivo, while compound 31 was inactive in vitro and was also inactive in vivo. Thus, the selection of highly active compounds from in vitro cytotoxicity assays was predictive of activity in the mouse model of Pneumocystis pneumonia. We conclude that a number of these bisbenzamidine compounds, especially compound 100, may show promise as new anti-Pneumocystis drugs.

scholarly journals Anti-tuberculosis Compound Screen using a Zebrafish Infection Model identifies an Aspartyl-tRNA Synthetase Inhibitor

2021 ◽  
Author(s):  
Eva Habjan ◽  
Vien Q. T. Ho ◽  
James Gallant ◽  
Gunny Van Stempvoort ◽  
Kin Ki Jim ◽  
...  
Keyword(s):  
Zebrafish Embryo ◽  
Point Mutations ◽  
Docking Studies ◽  
Trna Synthetase ◽  
Infection Model ◽  
Active Compounds ◽  
Global Challenge ◽  
Highly Active ◽  
Zebrafish Infection

Finding new anti-tuberculosis compounds with convincing in vivo activity is an ongoing global challenge to fight the emergence of multi-drug resistant Mycobacterium tuberculosis isolates. In this work, we exploited the medium-throughput capabilities of the zebrafish embryo infection model with Mycobacterium marinum as a surrogate for M. tuberculosis. Using a representative set of clinically established drugs, we demonstrate that this model could be predictive and selective for antibiotics that can be administered orally. We further used the zebrafish-infection model to screen 240 compounds from an anti-TB hit library for their in vivo activity and identified 14 highly active compounds. One of the most active compounds was the tetracyclic compound TBA161, which was studied in more detail. Analysis of resistant mutants revealed point mutations in aspS (rv2572c), encoding an aspartyl-tRNA synthetase. The target was genetically confirmed, and molecular docking studies propose possible binding of TBA161 in a pocket adjacent to the catalytic site. This study showed that the zebrafish-infection model is suitable to rapidly identify promising scaffolds with in vivo activity.

scholarly journals Beyond K48 and K63: non-canonical protein ubiquitination

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Michal Tracz ◽  
Wojciech Bialek
Keyword(s):  
Free Amino ◽  
The Other ◽  
Critical Element ◽  
Amino Group ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
N Terminus ◽  
Lysine Residues

AbstractProtein ubiquitination has become one of the most extensively studied post-translational modifications. Originally discovered as a critical element in highly regulated proteolysis, ubiquitination is now regarded as essential for many other cellular processes. This results from the unique features of ubiquitin (Ub) and its ability to form various homo- and heterotypic linkage types involving one of the seven different lysine residues or the free amino group located at its N-terminus. While K48- and K63-linked chains are broadly covered in the literature, the other types of chains assembled through K6, K11, K27, K29, and K33 residues deserve equal attention in the light of the latest discoveries. Here, we provide a concise summary of recent advances in the field of these poorly understood Ub linkages and their possible roles in vivo.

Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

1973 ◽  
Vol 29 (02) ◽  
pp. 490-498 ◽  
Author(s):  
Hiroh Yamazaki ◽  
Itsuro Kobayashi ◽  
Tadahiro Sano ◽  
Takio Shimamoto
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Endothelial Surface ◽  
Important Interaction ◽  
Blood Coagulability ◽  
The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

Lactoferrin in Bone Tissue Regeneration

2020 ◽  
Vol 27 (6) ◽  
pp. 838-853 ◽  
Author(s):  
Madalina Icriverzi ◽  
Valentina Dinca ◽  
Magdalena Moisei ◽  
Robert W. Evans ◽  
Mihaela Trif ◽  
...  
Keyword(s):  
Bone Tissue ◽  
Tissue Regeneration ◽  
Bone Cells ◽  
Bone Diseases ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Bone Tissue Regeneration ◽  
Bone Homeostasis ◽  
Active Compounds

: Among the multiple properties exhibited by lactoferrin (Lf), its involvement in bone regeneration processes is of great interest at the present time. A series of in vitro and in vivo studies have revealed the ability of Lf to promote survival, proliferation and differentiation of osteoblast cells and to inhibit bone resorption mediated by osteoclasts. Although the mechanism underlying the action of Lf in bone cells is still not fully elucidated, it has been shown that its mode of action leading to the survival of osteoblasts is complemented by its mitogenic effect. Activation of several signalling pathways and gene expression, in an LRPdependent or independent manner, has been identified. Unlike the effects on osteoblasts, the action on osteoclasts is different, with Lf leading to a total arrest of osteoclastogenesis. : Due to the positive effect of Lf on osteoblasts, the potential use of Lf alone or in combination with different biologically active compounds in bone tissue regeneration and the treatment of bone diseases is of great interest. Since the bioavailability of Lf in vivo is poor, a nanotechnology- based strategy to improve the biological properties of Lf was developed. The investigated formulations include incorporation of Lf into collagen membranes, gelatin hydrogel, liposomes, loading onto nanofibers, porous microspheres, or coating onto silica/titan based implants. Lf has also been coupled with other biologically active compounds such as biomimetic hydroxyapatite, in order to improve the efficacy of biomaterials used in the regulation of bone homeostasis. : This review aims to provide an up-to-date review of research on the involvement of Lf in bone growth and healing and on its use as a potential therapeutic factor in bone tissue regeneration.

Aminocoumarins: A Privileged Precursor for the Synthesis of Fused Heterocycles

2019 ◽  
Vol 23 (9) ◽  
pp. 1045-1075 ◽  
Author(s):  
Saigal ◽  
Sumbulunnisan Shareef ◽  
Habibur Rahman ◽  
Md. Musawwer Khan
Keyword(s):  
Chemical Reactivity ◽  
Structural Systems ◽  
Natural Occurrence ◽  
Amino Group ◽  
Active Compounds ◽  
The Past ◽  
Fused Heterocycles

Aminocoumarins are one of the important core structural systems, present in several biologically and medicinally active compounds. Owing to its natural occurrence, potential pharmacological applications and remarkable versatility as a privileged precursor, several proficient synthetic protocols have been reported in the literature over the past years. The presence of an amino group and enamine carbon enhances its chemical reactivity and thus such functionality is repeatedly used for the construction of various fused and simple heterocycles. This review highlights the preparation of different aminocoumarins and their applications for the construction of a variety of five, six and eight membered fused heterocycles.

Design, Synthesis, Antimicrobial and Anti-biofilm Evaluation, and Molecular Docking of Newly Substituted Fluoroquinazolinones

2019 ◽  
Vol 15 (6) ◽  
pp. 659-675
Author(s):  
Mohamed F. Zayed ◽  
Sabrin R.M. Ibrahim ◽  
EL-Sayed E. Habib ◽  
Memy H. Hassan ◽  
Sahar Ahmed ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimicrobial Agents ◽  
Receptor Site ◽  
Docking Study ◽  
Diffusion Method ◽  
Molecular Docking Study ◽  
Active Compounds ◽  
Highly Active ◽  
Strong Binding ◽  
Agar Disc

Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compounds. Compounds 10b, 10c, and 10d had a good MIC and MBC against Gram-positive bacteria, whereas 10b and 10d showed significant MIC and MBC against Gram-negative bacteria. However, compounds E and F exhibited good MIC and MBC against fungi. Compound 10c and 8 exhibited significant anti-biofilm activity towards S. aureus and M. luteus. Molecular docking study revealed a strong binding of these derivatives with their receptor-site and detected their predicted mode of binding. Conclusion: The synthesized derivatives showed promising antibacterial, antifungal, and antibiofilm activities. Modeling study explained their binding mode and showed strong binding affinity with their receptor-site. The highly active compounds 5 and 10c could be subjected to future optimization and investigation to be effective antimicrobial agents.

Oxytocin analogues with non-coded amino acid residues in position 8: [8-Neopentylglycine]oxytocin and [8-cycloleucine]oxytocin

1987 ◽  
Vol 52 (9) ◽  
pp. 2317-2325 ◽  
Author(s):  
Jan Hlaváček ◽  
Jan Pospíšek ◽  
Jiřina Slaninová ◽  
Walter Y. Chan ◽  
Victor J. Hruby
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
The Other ◽  
Amino Acid Residues ◽  
Phase Synthesis ◽  
Other Hand ◽  
Fragment Condensation

[8-Neopentylglycine]oxytocin (II) and [8-cycloleucine]oxytocin (III) were prepared by a combination of solid-phase synthesis and fragment condensation. Both analogues exhibited decreased uterotonic potency in vitro, each being about 15-30% that of oxytocin. Analogue II also displayed similarly decreased uterotonic potency in vivo and galactogogic potency. On the other hand, analogue III exhibited almost the same potency as oxytocin in the uterotonic assay in vivo and in the galactogogic assay.

scholarly journals In Vitro and In Vivo Antibacterial Activities of DW-224a, a New Fluoronaphthyridone

2006 ◽  
Vol 50 (6) ◽  
pp. 2261-2264 ◽  
Author(s):  
Hee-Soo Park ◽  
Hyun-Joo Kim ◽  
Min-Jung Seol ◽  
Dong-Rack Choi ◽  
Eung-Chil Choi ◽  
...  
Keyword(s):  
Antibacterial Activities ◽  
The Other ◽  
Vitro Activity ◽  
Gram Negative Bacteria ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria

ABSTRACT DW-224a showed the most potent in vitro activity among the quinolone compounds tested against clinical isolates of gram-positive bacteria. Against gram-negative bacteria, DW-224a was slightly less active than the other fluoroquinolones. The in vivo activities of DW-224a against gram-positive bacteria were more potent than those of other quinolones.

scholarly journals Possible Future Monoclonal Antibody (mAb)-Based Therapy against Arbovirus Infections

2013 ◽  
Vol 2013 ◽  
pp. 1-21 ◽  
Author(s):  
Giuseppe Sautto ◽  
Nicasio Mancini ◽  
Giacomo Gorini ◽  
Massimo Clementi ◽  
Roberto Burioni
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Side Effects ◽  
Antiviral Activity ◽  
The Other ◽  
Viral Escape ◽  
Passive Immunotherapy ◽  
Medical Need

More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminaryin vitroandin vivomodels of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy.

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