scholarly journals Antiplasmodial Activity of Lauryl-Lysine Oligomers

2007 ◽  
Vol 51 (5) ◽  
pp. 1753-1759 ◽  
Author(s):  
I. Radzishevsky ◽  
M. Krugliak ◽  
H. Ginsburg ◽  
A. Mor
Keyword(s):  
Antimicrobial Peptides ◽  
Self Assembly ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
New Drugs ◽  
Developmental Cycle ◽  
Compound A ◽  
Structure Activity ◽  
Full Effect ◽  
Further Development

ABSTRACT The ever evolving resistance of the most virulent malaria parasite, Plasmodium falciparum, to antimalarials necessitates the continuous development of new drugs. Our previous analysis of the antimalarial activities of the hemolytic antimicrobial peptides dermaseptins and their acylated derivatives implicated the importance of hydrophobicity and charge for drug action. Following these findings, an oligoacyllysine (OAK) tetramer designed to mimic the characteristics of dermaseptin was synthesized and assessed for its antimalarial activity in cultures of P. falciparum. The tetramer inhibited the growth of different plasmodial strains at low micromolar concentrations (mean 50% inhibitory concentration [IC50], 1.8 μM). A structure-activity relationship study involving eight derivatives unraveled smaller, more potent OAK analogs (IC50s, 0.08 to 0.14 μM). The most potent analogs were the most selective, with selectivity ratios of 3 orders of magnitude. Selectivity was strongly influenced by the self-assembly properties resulting from interactions between hydrophobic OAKs, as has been observed with conventional antimicrobial peptides. Further investigations performed with a representative OAK revealed that the ring and trophozoite stages of the parasite developmental cycle were equally sensitive to the compound. A shortcoming of the tested compound was the need for long incubation times in order for it to exert its full effect. Nevertheless, the encouraging results obtained in this study regarding the efficiency and selectivity of some compounds establish them as leads for further development.

Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

2020 ◽  
Vol 20 (14) ◽  
pp. 1264-1273 ◽  
Author(s):  
Bruno Casciaro ◽  
Floriana Cappiello ◽  
Walter Verrusio ◽  
Mauro Cacciafesta ◽  
Maria Luisa Mangoni
Keyword(s):  
Antimicrobial Peptides ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Lead Compounds ◽  
Bacterial Pathogenicity ◽  
Growth Inhibitory ◽  
Resistant Strains ◽  
Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

The Evaluation of Metal Co-ordinating Bis-Thiosemicarbazones as Potential Anti-malarial Agents

2019 ◽  
Vol 15 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Fady N. Akladios ◽  
Scott D. Andrew ◽  
Samantha J. Boog ◽  
Carmen de Kock ◽  
Richard K. Haynes ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
New Drugs ◽  
Preliminary Assessment ◽  
Human Lung Fibroblast ◽  
Antimalarial Agents ◽  
Fibroblast Line ◽  
Discrete Manner ◽  
Emergence Of Resistance ◽  
Further Development

Background:The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority.Objective:The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents. </P><P> Methods: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line.Results:The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 < 250 nM).Conclusion:Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.

scholarly journals Synthesis of Oxadiazole-2-Oxide Derivatives as Potential Drug Candidates for Schistosomiasis Targeted on SjTGR

2020 ◽  
Author(s):  
dequn sun ◽  
Gongming Li ◽  
Qingqing Guo ◽  
Chao Feng ◽  
Huan Chen ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Pyridine Ring ◽  
Inhibitory Concentration ◽  
New Drugs ◽  
Wild Type ◽  
Drug Candidates ◽  
Structure Activity ◽  
Docking Method ◽  
Antigen Protein ◽  
Thioredoxin Glutathione Reductase

Abstract Background: Schistosomiasis is a chronic parasitic disease that affects the health of millions people worldwide. Developing new drugs to treat schistosomiasis is crucial because of the increasing drug resistant to praziquantel (PZQ), the main drug for schistosomiasis. Oxadiazole-2-oxides have been identified as a potential anti-schistosomiasis reagent targeted to thioredoxin glutathione reductase (TGR).Methods: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicumi TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild type Schistosoma japonicumi TGR (wtSjTGR) in order to develop new leading compound for schistosomasis. Thirty nine novel derivatives were prepared to test their activity to both rSjTGR-Sec and SWAP containing wtSjTGR. The docking method was used to detect the bind sites between active molecule and SjTGR; The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed.Results: It was founded that several new derivatives such as compounds 6a-6d, 9ab, 9bd, 9be have better activity to rSjTGR-Sec or SWAP containing wtSjTGR than furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity to both rSjTGR-Sec and SWAP containing wtSjTGR especially, compound 6d with trifluoromethyl on pyridine ring was found to have much higher inhibition to both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan (4µM to SWAP containing wtSjTGR and 5.87µM to rSjTGR-Sec). Additionally, the docking method revealed the matching sites between 6d and Schistosoma japonicumi TGR (SjTGR), which theoretically lends support to inhibitory activity of 6d. Conclusion: The data obtained herein showed preliminarily that 6d with trifluoromethyl on pyridine ring could be a valuable leading compound for further study.

scholarly journals In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates of Plasmodium falciparum in Cameroon

2003 ◽  
Vol 47 (4) ◽  
pp. 1391-1394 ◽  
Author(s):  
Leonardo K. Basco ◽  
Pascal Ringwald
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Central Africa ◽  
New Drugs ◽  
Clinical Isolates ◽  
Highly Active ◽  
Synthetic Drug ◽  
Further Development

ABSTRACT The spread of chloroquine-resistant Plasmodium falciparum calls for a constant search for new drugs. The in vitro activity of piperaquine, a new Chinese synthetic drug belonging to the bisquinolines, was evaluated in 103 fresh clinical isolates of P. falciparum in Cameroon, Central Africa, and compared with that of other 4-aminoquinoline and Mannich base derivatives and dihydroartemisinin. Piperaquine was highly active (geometric mean 50% inhibitory concentration, 38.9 nmol/liter; range, 7.76 to 78.3 nmol/liter) and equally active (P > 0.05) against the chloroquine-sensitive and the chloroquine-resistant isolates. There was a significant but low correlation of response between chloroquine and piperaquine (r = 0.257, P < 0.05). These results suggest that further development of piperaquine, in combination with dihydroartemisinin, holds promise for use in chloroquine-resistant regions of endemicity.

Clathrin-Inspired Coating and Stabilization of Liposomes by DNA Self-Assembly

2019 ◽  
Author(s):  
Kevin N. Baumann ◽  
Luca Piantanida ◽  
Javier García-Nafría ◽  
Diana Sobota ◽  
Kislon Voïtchovsky ◽  
...  
Keyword(s):  
Self Assembly ◽  
Mechanical Stability ◽  
Lipid Vesicles ◽  
The Self ◽  
Force Microscopy ◽  
Atomic Force ◽  
Cryo Electron Microscopy ◽  
Further Development ◽  
Liposome Surface ◽  
Dna Coating

The self-assembly of the protein clathrin on biological membranes facilitates essential processes of endocytosis in biological systems and has provided a source of inspiration for materials design by the highly ordered structural appearance. By mimicking the architecture of clathrin self-assemblies to coat liposomes with biomaterials, new classes of hybrid carriers can be derived. Here we present a method for fabricating DNA-coated liposomes by hydrophobically anchoring and subsequently growing a DNA network on the liposome surface which structurally mimics clathrin assemblies. Dynamic light scattering (DLS), ζ-potential and cryo-electron microscopy (cryo-EM) measurements independently demonstrate successful DNA coating. Nanomechanical measurements conducted with atomic force microscopy (AFM) show that the DNA coating enhances the mechanical stability of the liposomes relative to uncoated ones. Furthermore, we provide the possibility to reverse the coating process by triggering the disassembly of the DNA coating through a toehold-mediated displacement reaction. Our results describe a straightforward, versatile, and reversible approach for coating and stabilizing lipid vesicles by an interlaced DNA network. This method has potential for further development towards the ordered arrangement of tailored functionalities on the surfaces of liposomes and for applications as hybrid nanocarrier.

Biological Activity of Trans-Membrane Anion Carriers

2018 ◽  
Vol 25 (30) ◽  
pp. 3560-3576 ◽  
Author(s):  
Massimo Tosolini ◽  
Paolo Pengo ◽  
Paolo Tecilla
Keyword(s):  
Biological Activity ◽  
Membrane Transport ◽  
Anticancer Agents ◽  
Biological Effects ◽  
Structure Activity Relationship ◽  
New Drugs ◽  
Activity Relationship ◽  
Anion Channels ◽  
Cellular Homeostasis ◽  
Structure Activity

Natural and synthetic anionophores promote the trans-membrane transport of anions such as chloride and bicarbonate. This process may alter cellular homeostasis with possible effects on internal ions concentration and pH levels triggering several and diverse biological effects. In this article, an overview of the recent results on the study of aniontransporters, mainly acting with a carrier-type mechanism, is given with emphasis on the structure/activity relationship and on their biological activity as antibiotic and anticancer agents and in the development of new drugs for treating conditions derived from dysregulation of natural anion channels.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

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