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1.
Future Med Chem ; 12(17): 1533-1546, 2020 09.
Article in English | MEDLINE | ID: mdl-32820960

ABSTRACT

Aim: Eight coumarin derivatives (1a-h) obtained from natural (-)-mammea A/BB (1) and 13 synthetic coumarins (2-14) had their cytotoxicity and biological activity evaluated against Mycobacterium tuberculosis H37Rv reference strain and multidrug-resistant clinical isolates. Materials & methods: Anti-M. tuberculosis activity was evaluated by resazurin microtiter assay plate, and the cytotoxicity of natural and synthetic products using J774A.1 macrophages by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Results: Compounds 1g, 5, 6, 12 and 14 were more active against M. tuberculosis H37Rv and multidrug-resistant clinical isolates with MIC values ranging from 15.6 to 62.5 µg/ml. Conclusion: These results demonstrate that the coumarin derivatives were active against multidrug-resistant clinical isolates, becoming potential candidates to be used in the treatment of resistant tuberculosis.


Subject(s)
Antitubercular Agents/pharmacology , Biological Products/pharmacology , Coumarins/pharmacology , Mycobacterium tuberculosis/drug effects , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Calophyllum/chemistry , Cells, Cultured , Coumarins/chemical synthesis , Coumarins/chemistry , Macrophages/drug effects , Mice , Microbial Sensitivity Tests , Molecular Structure , Plant Extracts
2.
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
3.
ChemSusChem ; 11(1): 25-47, 2018 01 10.
Article in English | MEDLINE | ID: mdl-28834397

ABSTRACT

The upgrading of biomass-derived compounds has arisen in recent years as a very promising research field in both academia and industry. In this sense, a lot of new processes and products have been developed, often involving levulinic acid as a starting material or intermediate. In the last few years, though, other scaffolds have been receiving growing attention, especially, angelica lactones. Considering these facts and the emergent applications of said molecules, in this review we will discuss their preparation and applications; the use of these frameworks as starting materials in organic synthesis to produce potential bioactive compounds will be covered, as will their use as a foundation to highly regarded compounds such as liquid alkanes with prospective use as fuels and polymers.


Subject(s)
Angelica/chemistry , Biomass , Lactones/chemistry , Biological Products/chemistry , Polymers/chemistry
4.
Chemistry ; 23(1): 176-186, 2017 01 01.
Article in English | MEDLINE | ID: mdl-27775849

ABSTRACT

We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2 O2 ) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeII catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including . CF3 , . C4 F9 , . CH2 CN, and . CH2 CO2 Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3 I and C4 F9 I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.

5.
Angew Chem Int Ed Engl ; 54(26): 7621-5, 2015 Jun 22.
Article in English | MEDLINE | ID: mdl-25967546

ABSTRACT

In an endeavor to provide an efficient route to natural product hybrids, described herein is an efficient, highly stereoselective, one-pot process comprising an organocatalytic conjugate addition of 1,3-dicarbonyls to α,ß-unsaturated aldehydes followed by an intramolecular isocyanide-based multicomponent reaction. This approach enables the rapid assembly of complex natural product hybrids including up to four different molecular fragments, such as hydroquinolinone, chromene, piperidine, peptide, lipid, and glycoside moieties. The strategy combines the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions, thus leading to structurally unique peptidomimetics integrating heterocyclic, lipidic, and sugar moieties.


Subject(s)
Biological Products/chemistry , Biological Products/chemical synthesis , Carbohydrates , Catalysis , Molecular Structure , Stereoisomerism
6.
Rev. bras. farmacogn ; 23(3): 447-454, May-June 2013. ilus, tab
Article in English | LILACS | ID: lil-676274

ABSTRACT

Two natural amides isolated from the chloroform extract of Piper amalago L., Piperaceae, leaves, a hydrogenated derivative and seven synthetic analogs were tested against the promastigote and intracellular amastigote forms of Leishmania amazonensis. The antileishmanial activity was evaluated in terms of growth inhibitory concentration for 50% of protozoa (IC50). The cytotoxicity toward the J774A1 macrophages was evaluated in terms of the cytotoxic concentrations for 50% of macrophages (CC50). The ability to induce nitric oxide production was also investigated for all compounds. The saturated amide 7-(1,3-benzodioxol-5-yl)-1-(1-pyrrolidinyl)-1-heptanone was obtained by hydrogenation of the natural compound N-[7-(3',4'-methylenedioxyphenyl)-2(Z),4(Z)-heptadienoyl]pyrrolidine. Synthetic amides were prepared by addition of the appropriate amine to the corresponding acyl chloride. The natural compound, N-[7-(3',4'-methylenedioxyphenyl)-2(E),4(E)-heptadienoyl]pyrrolidine, was the most active of all tested compounds against the promastigote and intracellular amastigote forms with IC50 values of 15 µM and 14.5 µM, respectively. None of the compounds modulated the production of nitric oxide.

7.
J Agric Food Chem ; 59(9): 4822-7, 2011 May 11.
Article in English | MEDLINE | ID: mdl-21443174

ABSTRACT

The fall armyworm Spodoptera frugiperda is a polyphagous pest that causes important damage in different regions of America and mainly affects corn crops in both tropical and subtropical areas. Currently, control relies on both transgenic plants and/or chemical pesticides. In this work we describe the preparation of an indexed combinatorial library of amides and its toxic effect by contact against S. frugiperda . (E)-1-(1-Piperidinyl)-3-[4-(trifluoromethoxy)phenyl]-2-propen-1-one was the most active compound with an LD(50) = 0.793 µg mg(-1) of larva. This amide was also evaluated by ingestion and at the lowest concentration (1 mg kg(-1)) achieved 83.3% mortality.


Subject(s)
Amides/chemical synthesis , Insecticides/chemical synthesis , Spodoptera/drug effects , Amides/pharmacology , Animals , Insecticides/pharmacology
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