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1.
Bioorg Chem ; 153: 107896, 2024 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-39454497

RESUMO

This study presents the synthesis and characterization of a series of 13 novel acetamides. These were subjected to Ellman's assay to determine the efficacy of the AChE and BChE inhibitors. Finally, we report their antioxidant activity as an alternative approach for the search for drugs to treat AD. These studies revealed that compounds 1a-1k and 2l-2m were obtained in moderate yield. Four amides (1h, 1j, 1k, and 2l) were selective for one of the enzymes (BChE); thus, those that inhibited BChE were more active than the positive control (galantamine) and showed better IC50 values (3.30-5.03 µM). The theoretical free binding energies calculated by MM-GBSA indicated that all inhibitors were more stable than rivastigmine, and the inhibition mechanisms involved the entire active site: peripheral anionic site, oxyanion hole, acyl-binding pockets, and catalytic site. We examined the cytotoxicity of compounds 1h, 1j, 1k, and 2l in human dermal cells and found that they did not exhibit any toxic effects under the tested conditions. Additionally, these compounds, which also inhibited BChE, displayed mixed inhibition and did not exhibit hemolytic effects on human erythrocytes. Furthermore, the ABTS and DPPH assays indicated that, although none of the compounds showed activity in the DPPH assay, the EC50 values for radical trapping by the ABTS method showed that compounds 1a, 1d, 1e, and 1g had EC50 values lower than 10 µg/mL, indicating their strong radical scavenging capacity. We also report the crystal structures of compounds 1c, 1d, 1f, and 1g, which are found in monoclinic crystal systems.

2.
Bioorg Chem ; 90: 103034, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31280015

RESUMO

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20-89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.


Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/química , Chalconas/química , Inibidores da Colinesterase/química , Acetilcolinesterase/química , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Domínio Catalítico , Chalconas/síntese química , Chalconas/metabolismo , Chalconas/farmacocinética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Ensaios Enzimáticos , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Ondas Ultrassônicas
3.
Int J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426491

RESUMO

TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 ± 3.9 µM. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 µM. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.


Assuntos
Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Desenho de Fármacos , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Bloqueadores dos Canais de Potássio/farmacocinética
4.
Molecules ; 24(1)2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30621344

RESUMO

Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities.


Assuntos
Inibidores da Colinesterase/síntese química , Fenilalanina/síntese química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Butirilcolinesterase/metabolismo , Cianetos/química , Desenho de Fármacos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
5.
RSC Adv ; 14(8): 5222-5233, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38344003

RESUMO

The increase in and concern about neurodegenerative diseases continue to grow in an increasingly long-lived world population. Therefore, the search for new drugs continues to be a priority for medicinal chemistry. We present here the synthesis of a series of compounds with acetamide nuclei. Their structures were established using UV-Visible, NMR, HRMS and IR techniques. Furthermore, we report the crystal structures that were obtained from compounds 5a-5d by X-ray diffraction. The compounds were evaluated as potential inhibitors of the monoxidase enzymes; A (MAO-A) and B (MAO-B), and cholinesterases; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) through in silico studies using the induced fit docking (IFD) method and binding free energy (ΔGbind) calculations by the MMGBSA method. Interestingly, compounds 5b, 5c and 5d showed much better ΔGbind than the reference drug Zonisamide. Compound 5c is the best in the series, which indicates a potential selective affinity of our compounds against MAO-B, which could be a promising finding in the search for new drugs for Parkinson's disease treatment. The acetamide crystal exhibits moderate NLO properties suggesting that it could be considered a potential candidate for application in nonlinear optical devices.

6.
Front Chem ; 11: 1245941, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37663141

RESUMO

Multicomponent reactions were performed to develop novel α,ß-unsaturated carbonyl depsipeptides and peptoids incorporating various chromophores such as cinnamic, coumarin, and quinolines. Thus, through the Passerini and Ugi multicomponent reactions (P-3CR and U-4CR), we obtained thirteen depsipeptides and peptoids in moderate to high yield following the established protocol and fundamentally varying the electron-rich carboxylic acid as reactants. UV/Vis spectroscopy was utilized to study the photophysical properties of the newly synthesized compounds. Differences between the carbonyl-substituted chromophores cause differences in electron delocalization that can be captured in the spectra. The near UV regions of all the compounds exhibited strong absorption bands. Compounds P2, P5, U2, U5, and U7 displayed absorption bands in the range of 250-350 nm, absorbing radiation in this broad region of the electromagnetic spectrum. A photostability study for U5 showed that its molecular structure does not change after exposure to UV radiation. Fluorescence analysis showed an incipient emission of U5, while U6 showed blue fluorescence under UV radiation. The photophysical properties and electronic structure were also determined by TD-DFT theoretical study.

7.
Antioxidants (Basel) ; 8(10)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600955

RESUMO

In this work, we present results about the synthesis and the antioxidant properties of seven adenosine derivatives. Four of these compounds were synthesized by substituting the N6-position of adenosine with aliphatic amines, and three were obtained by modification of the ribose ring. All compounds were obtained in pure form using column chromatography, and their structures were elucidated by infrared spectroscopy (IR) and Nuclear Magnetic Resonance (NMR). All adenosine derivatives were further evaluated in vitro as free radical scavengers. Our results show that compounds 1c, 3, and 5 display a potent antioxidant effect compared with the reference compound ascorbic acid. In addition, the absorption, distribution, metabolism and excretion (ADME) calculations show favorable pharmacokinetic parameters for the set of compounds analyzed, which guarantees their suitability as potential antioxidant drugs. Furthermore, theoretical analyses using Molecular Quantum Similarity and reactivity indices were performed in order to discriminate the different reactive sites involved in oxidative processes.

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