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1.
Nat Prod Res ; 38(6): 978-985, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37154616

ABSTRACT

Investigation of the endophytic fungi Nigrospora sphaerica, Nigrospora oryzae, and Pseudofusicoccum stromaticum MeOH fractions isolated from the leaves of Vochysia divergens, a medicinal species from the Brazilian Pantanal, led to the identification of five compounds, namely a new compound (1E,8Z)-10,11-dihydroxy-5,5,8-trimethyl-4-oxocycloundeca-1,8-diene-1-carbaldehyde (1) and four known compounds: 5-methylmellein (2), sclerone (3), daldinone A (4), and lasiodiplodin (5). All compounds were identified using spectroscopic methods, and 1 was corroborated with mass spectrometry, while the known compounds were compared with data in the literature. The relative configuration of compound 1 was determined based on theoretical conformational studies as well as the J experimental values between the hydroxymethyne hydrogens. The antimicrobial activity of the compounds was evaluated. Promising results were obtained for compounds 2, 4, and 5 since they inhibited the bacterium Pseudomonas aeruginosa, an opportunistic pathogen, suggesting the potential of these microorganisms as a source of new antibacterial agents.


Subject(s)
Anti-Infective Agents , Anti-Infective Agents/chemistry , Fungi/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Plant Leaves/microbiology , Brazil , Endophytes/metabolism
2.
Chem Biodivers ; 19(12): e202200586, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36383100

ABSTRACT

In the current work, we describe the synthesis of 1,4-dihydropyridine (1,4-DHP) derivatives via Hantzsch multicomponent reaction and their evaluation as photosystem II (PSII) inhibitors through chlorophyll a fluorescence bioassay. Among all the compounds tested, 1,1'-(2,4,6-trimethyl-1,4-dihydropyridine-3,5-diyl)bis(ethan-1-one) (4b) showed best results, reducing the parameters performance index on absorption basis (PIabs ) and electron transport per reaction center by 61 % and 49 %, respectively, as compared to the control. These results indicate the inhibitory activity of PSII over the electron transport chain. Additionally, a molecular docking approach using the protein D1 (PDB code 4V82) was performed in order to assess the structure-activity relationship among the 1,4-DHP derivatives over the PSII, which revealed that both, size of the group at position 4 and the carbonyl groups at the dihydropyridine ring are important for the ligand's interaction, particularly for the hydrogen-bonding interaction with the residues His215, Ser264, and Phe265. Thus, the optimization of these molecular features is the aim of our research group to extend the knowledge of PSII electron chain inhibitors and the establishment of new potent bioactive molecular scaffolds.


Subject(s)
Herbicides , Herbicides/pharmacology , Herbicides/chemistry , Molecular Docking Simulation , Chlorophyll A , Photosynthesis , Photosystem II Protein Complex , Chlorophyll/chemistry
3.
Chem Biodivers ; 18(10): e2100350, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34399029

ABSTRACT

Endophytic fungi are an important class of microorganisms, able to interact with a host plant via a mutualistic mechanism without visible symptoms of the fungal colonization. The synergy between endophytic fungi and their host plant can promote morphological, physiological and biochemical changes through the expression of bioactive metabolites. This work aims to correlate metabolic changes in the Combretum lanceolatum plant metabolome with its endophytic fungi Diaporthe phaseolorum (Dp) and Trichoderma spirale (Ts), and to discover corresponding metabolite-biomarkers, with the principal focus being on its primary metabolism. The 1 H-NMR metabolomic analysis of qualitative and quantitative changes was performed through multivariate statistical analysis and the identification of primary metabolites was achieved on the Madison Metabolomics Consortium Database. The presence of Dp significantly impacted the plant's metabolic pathways, improving the biosynthesis of primary metabolites such as threonine, malic acid and N-acetyl-mannosamine, which are precursors of special metabolites involved in plant self-defence. This work represents a valuable contribution to advanced studies on the metabolic profiles of the interaction of plants with endophytes.


Subject(s)
Ascomycota/metabolism , Combretum/metabolism , Metabolomics , Trichoderma/metabolism , Ascomycota/chemistry , Combretum/chemistry , Proton Magnetic Resonance Spectroscopy , Trichoderma/chemistry
4.
J Environ Sci Health B ; 55(5): 470-476, 2020.
Article in English | MEDLINE | ID: mdl-32009547

ABSTRACT

A central pillar of modern weed control is the discovery of new herbicides which are nontoxic to humans and the environment and which have low application dosage. The natural products found in plants and microorganisms are well suited in this context because they are generally nontoxic and have a wide variety of biological activities. In this work, Diaporthe phaseolorum (Dp), Penicillium simplicissimum (Ps) and Trichoderma spirale (Ts) (methanolic extracts) were evaluated as photosynthesis and plant growth inhibitors in Senna occidentalis and Ipomoea grandifolia. The most significant results were observed for Ts and Dp in S. occidentalis and I. grandifolia, respectively. Ts reduced PI(abs), ET0/CS0, PHI(E0) and PSI0 parameters by 64, 28, 40 and 38%, respectively, indicating a reduction on electron transport efficiency. Additionally, Ts decreased shoot length by 9%, affecting the plant growth. Dp reduced PI(abs), ET0/CS0 and PHI(E0) parameters by 50, 20, 26 and 22%, respectively, revealing the inhibition competency on PSII acceptor site. Furthermore, Dp decreased by 50% the shoot length on germination assay. Thus, the phytotoxic behaviors based on endophytic fungal extracts may serve as a valuable tool in the further development of a bioherbicide since natural products represent an interesting alternative to replace commercial herbicides.


Subject(s)
Endophytes/chemistry , Herbicides/pharmacology , Ipomoea/drug effects , Photosynthesis/drug effects , Senna Plant/drug effects , Ascomycota/chemistry , Germination/drug effects , Methanol , Penicillium/chemistry , Plant Growth Regulators/pharmacology , Plant Roots/drug effects , Plant Roots/growth & development , Plant Stems/drug effects , Plant Stems/growth & development , Trichoderma/chemistry , Weed Control/methods
5.
J Mol Model ; 24(8): 207, 2018 Jul 14.
Article in English | MEDLINE | ID: mdl-30008113

ABSTRACT

Alzheimer's disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (KD) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with KD = 30 µM ,even greater than tacrine (KD = 140 µM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future.


Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Coumarins/chemistry , Nootropic Agents/chemistry , Tacrine/chemistry , Acetylcholinesterase/metabolism , Animals , Binding Sites , Cholinesterase Inhibitors/chemical synthesis , Coumarins/chemical synthesis , Crystallography, X-Ray , Electrophorus/metabolism , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/chemistry , GPI-Linked Proteins/metabolism , Humans , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Nootropic Agents/chemical synthesis , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Tacrine/chemical synthesis , Thermodynamics
6.
Org Biomol Chem ; 15(29): 6098-6103, 2017 Jul 26.
Article in English | MEDLINE | ID: mdl-28702593

ABSTRACT

γ-Butenolides have been recognized as an important structural framework in a number of natural products and medicinally important agents. In this work we describe a new metal-free sequential strategy for the asymmetric synthesis of substituted γ-butenolides having epoxychalcones as the advanced intermediate. Using the optimized reaction conditions, we were able to carry out the three-step sequence, epoxidation, olefination and hydrolysis, with only one single chromatographic purification of the final product, furnishing new enantiomerically enriched γ-butenolides in moderate overall yield and good enantiomeric excess.

7.
Angew Chem Int Ed Engl ; 54(21): 6217-21, 2015 May 18.
Article in English | MEDLINE | ID: mdl-25864491

ABSTRACT

The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.


Subject(s)
Chromosomal Proteins, Non-Histone/antagonists & inhibitors , Drug Discovery , Lactams/chemistry , Lactams/pharmacology , Transcription Factors/antagonists & inhibitors , Chromosomal Proteins, Non-Histone/chemistry , Chromosomal Proteins, Non-Histone/metabolism , Humans , Models, Molecular , Transcription Factors/chemistry , Transcription Factors/metabolism
8.
Angew Chem Weinheim Bergstr Ger ; 127(21): 6315-6319, 2015 May 18.
Article in English | MEDLINE | ID: mdl-27346896

ABSTRACT

The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

9.
J Med Chem ; 56(5): 2038-44, 2013 Mar 14.
Article in English | MEDLINE | ID: mdl-23330848

ABSTRACT

The use of immobilized capillary enzyme reactors (ICERs) for online ligand screening has been adopted as a new technique for high-throughput screening (HTS). In this work, the selected target was the enzyme acetylcholinesterase (AChE), and the AChE-ICERs produced were used in a liquid chromatograph-tandem ion-trap mass spectrometer. The activity and kinetic parameters were evaluated by monitoring the choline's precursor ion (M + H)(+)m/z 104.0 and its ion fragment (C2H3OH) - (M + H)(+)m/z 60.0. The assay method was validated using the reference AChE inhibitors tacrine and galanthamine. Two new ligands, out of a library of 17 coumarin derivatives, were identified, and the half-maximal inhibitory concentration (IC50), inhibition constant (K(i)), and the inhibition mechanism were determined. A coumarin derivative with IC50 similar to tacrine was highlighted.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/isolation & purification , Enzymes, Immobilized/metabolism , Cholinesterase Inhibitors/pharmacology , Chromatography, Liquid , Coumarins/isolation & purification , Coumarins/pharmacology , Galantamine/pharmacology , High-Throughput Screening Assays/methods , Inhibitory Concentration 50 , Kinetics , Ligands , Tacrine/pharmacology , Tandem Mass Spectrometry
10.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 3): m251, 2010 Feb 03.
Article in English | MEDLINE | ID: mdl-21580206

ABSTRACT

In the title salt, (C(24)H(20)P)(2)[Pt(C(7)H(3)Cl(2)NO(2)S(3))(2)], the Pt(II) ion (site symmetry ) is coordinated by two S,S'-bidentate N-(2,5-dichloro-phenyl-sulfon-yl)dithio-carbimate ligands, resulting in a slightly distorted PtS(4) square-planar geometry. In the crystal, a C-H⋯O inter-action is observed, as well as electrostatic attraction between the oppositely charged ions.

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