scholarly journals Inhibitory Properties of Aldehydes and Related Compounds against Phytophthora infestans—Identification of a New Lead

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 542 ◽  
Author(s):  
John J. Mackrill ◽  
Roberta A. Kehoe ◽  
Limian Zheng ◽  
Mary L. McKee ◽  
Elaine C. O’Sullivan ◽  
...  
Keyword(s):  
Phytophthora Infestans ◽  
Aromatic Aldehydes ◽  
Global Scale ◽  
Crop Damage ◽  
Lead Compounds ◽  
Discovery Research ◽  
Research Programmes ◽  
Resistant Strains ◽  
Related Compounds ◽  
New Discovery

The pathogen Phytophthora infestans is responsible for catastrophic crop damage on a global scale which totals billions of euros annually. The discovery of new inhibitors of this organism is of paramount agricultural importance and of critical relevance to food security. Current strategies for crop treatment are inadequate with the emergence of resistant strains and problematic toxicity. Natural products such as cinnamaldehyde have been reported to have fungicidal properties and are the seed for many new discovery research programmes. We report a probe of the cinnamaldehyde framework to investigate the aldehyde subunit and its role in a subset of aromatic aldehydes in order to identify new lead compounds to act against P. infestans. An ellipticine derivative which incorporates an aldehyde (9-formyl-6-methyl ellipticine, 34) has been identified with exceptional activity versus P. infestans with limited toxicity and potential for use as a fungicide.

scholarly journals Synthesis and Evaluation of Novel Ellipticines and Derivatives as Inhibitors of Phytophthora infestans

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 558
Author(s):  
Mary L. McKee ◽  
Limian Zheng ◽  
Elaine C. O’Sullivan ◽  
Roberta A. Kehoe ◽  
Barbara M. Doyle Prestwich ◽  
...  
Keyword(s):  
Phytophthora Infestans ◽  
Natural Product ◽  
Human Cell ◽  
Inhibitory Activity ◽  
Human Cell Line ◽  
Crop Damage ◽  
Apparent Lack ◽  
Lead Compounds ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity

The pathogen Phytophthora infestans is responsible for worldwide catastrophic crop damage and discovery of new inhibitors of this organism is of paramount agricultural and industrial importance. Current strategies for crop treatment are inadequate with limitations of efficacy and market alternatives. Ellipticines have recently been reported to have fungicidal properties and have been assessed against P. infestans growth with promising results. We hereby report a probe of the ellipticine framework to investigate the alkyl subunit and screen a set ellipticines and derivatives to identify new lead compounds to act against P. infestans. A series of ellipticinium salt derivatives have been identified with exceptional growth inhibitory activity and apparent lack of toxicity towards a human cell-line surpassing the effect of known and marketed fungicides. This report identifies the potential of this natural product derivative as a novel fungicide.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4323-4354 ◽  
Author(s):  
Ana Cristina Lima Leite ◽  
José Wanderlan Pontes Espíndola ◽  
Marcos Veríssimo de Oliveira Cardoso ◽  
Gevanio Bezerra de Oliveira Filho
Keyword(s):  
Biologically Active ◽  
Neglected Diseases ◽  
Financial Return ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Current Therapies ◽  
Resistant Strains ◽  
Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

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 Antimicrobial Activities of Mefloquine and a Series of Related Compounds

2000 ◽  
Vol 44 (4) ◽  
pp. 848-852 ◽  
Author(s):  
C. M. Kunin ◽  
W. Y. Ellis
Keyword(s):  
Staphylococcus Epidermidis ◽  
Antimicrobial Activities ◽  
Walter Reed Army Institute ◽  
Gram Negative Bacteria ◽  
Antimicrobial Drugs ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Related Compounds

ABSTRACT Mefloquine was found to have bactericidal activity against methicillin- and fluoroquinolone-susceptible and -resistant strains ofStaphylococcus aureus and Staphylococcus epidermidis and gentamicin- and vancomycin-resistant strains ofEnterococcus faecalis and Enterococcus faecium. The MICs were 16 μg/ml, and the minimal bactericidal concentrations (MBCs) were 16 to 32 μg/ml. These concentrations cannot be achieved in serum. Mefloquine was active at a more achievable concentration against penicillin-susceptible and -resistant Streptococcus pneumoniae, with MICs of 0.2 to 1.5 μg/ml. Mefloquine was not active against gram-negative bacteria and yeasts. In an attempt to find more active derivatives, 400 mefloquine-related compounds were selected from the chemical inventory of The Walter Reed Army Institute of Research. We identified a series of compounds containing a piperidine methanol group attached to pyridine, quinoline, and benzylquinoline ring systems. These had activities similar to that of mefloquine against S. pneumoniae but were far more active against other gram-positive bacteria (MICs for staphylococci, 0.8 to 6.3 μg/ml). They had activities similar to that of amphotericin B againstCandida spp. and Cryptococcus neoformans. Combinations of the compounds with gentamicin and vancomycin were additive against staphylococci and pneumococci. The MIC and MBC of gentamicin were decreased by four- to eightfold when this drug was combined with limiting dilutions of the compounds. There was no antagonism with other antimicrobial drugs. The compounds were rapidly bactericidal. They appear to act by disrupting cell membranes. Combinations of the compounds with aminoglycoside antibiotics may have potential for therapeutic use.

Virtual Screening of Natural Curcumins and Related Compounds Against SARS-CoV-2

2020 ◽  
pp. 1-18
Author(s):  
Daniela Ribeiro Alves ◽  
Matheus Nunes da Rocha ◽  
Damião Sampaio de Sousa ◽  
Iris Cristina Maia Oliveira ◽  
Marcia Machado Marinho ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Viral Replication ◽  
Viral Disease ◽  
Global Scale ◽  
Strong Interactions ◽  
Significant Activity ◽  
In Silico Screening ◽  
Biological Target ◽  
Genus Capsicum ◽  
Related Compounds

The new coronavirus (COVID-19) is a viral disease that was classified as a pandemic situation on a global scale in early 2020. Severe Acute Respiratory Syndrome (SARS-CoV)-2 has the enzyme Mpro, until then, best characterized as an important biological target for intracellular viral replication. To investigate the interactions between curcumins and other compounds derived from cinnamic acid with the SARS-CoV-2 Mpro protease as well as to infer their physicochemical and drug-like properties, four natural curcumins and eight related compounds were selected for in silico screening, of molecular docking with the biological target Mpro, to suggest a therapeutic method associated with antiSARS-CoV-2 drugs, such as anakinra, azithromycin, baricitinib, hydroxychloroquine and remdesivir. All curcumins and related compounds can act as synergistic inhibitors of the main viral protein in SARS-CoV-2. The curcumins and other compound ligands showed similar interactions with the enzyme comparable to the control ligands. The ligands capsaicin, dehydrozingerol, dibenzoylmethane and isoeugenol stand out, due to their strong interactions. Among the compounds tested in this study, capsaicin, an alkaloid that is obtained from the fruits of plants of the genus Capsicum, showed significant activity in terms of its potential to inhibit SARS-CoV-2 viral replication.

scholarly journals Mefloquine and New Related Compounds Target the F0 Complex of the F0F1 H+-ATPase of Streptococcus pneumoniae

2002 ◽  
Vol 46 (6) ◽  
pp. 1680-1687 ◽  
Author(s):  
Antonio Javier Martín-Galiano ◽  
Begoña Gorgojo ◽  
Calvin M. Kunin ◽  
Adela G. de la Campa
Keyword(s):  
Streptococcus Pneumoniae ◽  
Amino Acid ◽  
Proton Translocation ◽  
Point Mutations ◽  
Amino Acid Residues ◽  
Transmembrane Helices ◽  
Inhibition Of Growth ◽  
Pneumococcal Strain ◽  
Resistant Strains ◽  
Related Compounds

ABSTRACT The activities of mefloquine (MFL) and related compounds against previously characterized Streptococcus pneumoniae strains carrying defined amino acid substitutions in the c subunit of the F0F1 H+-ATPase were studied. In addition, a series of MFL-resistant (Mflr) strains were isolated and characterized. A good correlation was observed between inhibition of growth and inhibition of the membrane-associated F0F1 H+-ATPase activity. MFL was about 10-fold more active than optochin and about 200-fold more active than quinine in inhibiting both the growth and the ATPase activities of laboratory pneumococcal strain R6. Mutant strains were inhibited by the different compounds to different degrees, depending on their specific mutations in the c subunit. The resistant strains studied had point mutations that changed amino acid residues in either the c subunit or the a subunit of the F0 complex. Changes in the c subunit were located in one of the two transmembrane α helices: residues M13, G14, G20, M23, and N24 of helix 1 and residues M44, G47, V48, A49, and V57 of helix 2. Changes in the a subunit were also found in either of the transmembrane α helices, helix 5 or 6: residue L186 of helix 5 and residues W206, F209, and S214 of helix 6. These results suggest that the transmembrane helices of the c and a subunits interact and that the mutated residues are important for the structure of the F0 complex and proton translocation.

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