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1.
Photochem Photobiol Sci ; 23(7): 1353-1360, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38888704

RESUMO

A variety of 3-hydroxy-isoindolin-1-one derivatives were synthesized using the photodecarboxylative addition of carboxylates to phthalimide derivatives in aqueous media. Subsequent acid-catalyzed dehydration furnished 3-(alkyl and aryl)methyleneisoindolin-1-ones with variable E-diastereoselectivity in good to excellent overall yields. Noteworthy, the parent 3-phenylmethyleneisoindolin-1-one underwent isomerization and oxidative decomposition when exposed to light and air. Selected 3-hydroxy-isoindolin-1-one and 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives showed moderate antibacterial activity that justifies future elaboration and study of these important bioactive scaffolds.


Assuntos
Antibacterianos , Ácidos Carboxílicos , Isoindóis , Testes de Sensibilidade Microbiana , Ftalimidas , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Ftalimidas/química , Ftalimidas/síntese química , Ftalimidas/farmacologia , Isoindóis/química , Isoindóis/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Processos Fotoquímicos , Luz , Estrutura Molecular , Relação Estrutura-Atividade , Catálise
2.
Org Biomol Chem ; 22(20): 4057-4061, 2024 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-38716633

RESUMO

An efficient and practical one-pot synthesis of isoindolines from readily available starting materials was achieved under mild conditions by implementing an isoindole umpolung strategy. A variety of isoindolines were prepared with good to excellent yields. Biological screens of these identified compounds demonstrated that they are potent potentiators of colistin for multi-drug resistant Acinetobacter baumannii.


Assuntos
Acinetobacter baumannii , Antibacterianos , Colistina , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana , Acinetobacter baumannii/efeitos dos fármacos , Colistina/farmacologia , Colistina/síntese química , Colistina/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Isoindóis/síntese química , Isoindóis/farmacologia , Isoindóis/química , Estrutura Molecular , Relação Estrutura-Atividade
3.
J Inorg Biochem ; 257: 112581, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38718499

RESUMO

Type 2 diabetes (T2DM) is a progressive metabolic disease associated with high blood sugar levels that affects 537 million people worldwide. This study aim is to investigate the potential for use in the treatment of T2DM by examining the in vitro glucosidase inhibitory effects of novel synthesized metallophthalocyanines. For this reason, we have synthesized cobalt(II), copper(II) phthalocyanines (3PY-ON-CoQ, 3PY-ON-CuQ) that are both water-soluble and do not aggregate in water. These compounds were characterized by using various spectroscopic methods. The α-glucosidase inhibitory properties of 3PY-ON-CoQ and 3PY-ON-CuQ were carried out using the spectrophotometric method. Then, Lineweaver-Burk and Dixon plots were examined to determine the inhibitory type and constant (Ki). The IC50 values of 3PY-ON-CoQ and 3PY-ON-CuQ were 6.85 ± 1.25 µM and 55.09 ± 2.64 µM, respectively. Both compounds displayed mixed inhibitory effects on α-glucosidase according to Lineweaver-Burk plots. The Ki values of 3PY-ON-CoQ and 3PY-ON-CuQ were calculated as 6.30 ± 1.55 µM and 54.25 ± 1.20 µM, respectively. The results of this work may lead to the discovery of new compounds for the treatment of T2DM.


Assuntos
Cobalto , Cobre , Inibidores de Glicosídeo Hidrolases , Indóis , Isoindóis , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Cobre/química , Indóis/química , Indóis/farmacologia , Isoindóis/química , Isoindóis/farmacologia , alfa-Glucosidases/metabolismo , Cobalto/química , Solubilidade , Água/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química
4.
Eur J Med Chem ; 272: 116467, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38735150

RESUMO

The World Health Organization (WHO) identifies several bunyaviruses as significant threats to global public health security. Developing effective therapies against these viruses is crucial to combat future outbreaks and mitigate their impact on patient outcomes. Here, we report the synthesis of some isoindol-1-one derivatives and explore their inhibitory properties over an indispensable metal-dependent cap-snatching endonuclease (Cap-ENDO) shared among evolutionary divergent bunyaviruses. The compounds suppressed RNA hydrolysis by Cap-ENDOs, with IC50 values predominantly in the lower µM range. Molecular docking studies revealed the interactions with metal ions to be essential for the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold activity. Calorimetric analysis uncovered Mn2+ ions to have the highest affinity for sites within the targets, irrespective of aminoacidic variations influencing metal cofactor preferences. Interestingly, spectrophotometric findings unveiled sole dinuclear species formation between the scaffold and Mn2+. Moreover, the complexation of two Mn2+ ions within the viral enzymes appears to be favourable, as indicated by the binding of compound 11 to TOSV Cap-ENDO (Kd = 28 ± 3 µM). Additionally, the tendency of compound 11 to stabilize His+ more than His- Cap-ENDOs suggests exploitable differences in their catalytic pockets relevant to improving specificity. Collectively, our results underscore the isoindolinone scaffold's potential as a strategic starting point for the design of pan-antibunyavirus drugs.


Assuntos
Desenho de Fármacos , Endonucleases , Simulação de Acoplamento Molecular , Endonucleases/metabolismo , Endonucleases/antagonistas & inibidores , Isoindóis/síntese química , Isoindóis/farmacologia , Isoindóis/química , Relação Estrutura-Atividade , Estrutura Molecular , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Bunyaviridae/efeitos dos fármacos , Bunyaviridae/metabolismo , Relação Dose-Resposta a Droga , Humanos
5.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732115

RESUMO

Favipiravir (FP) and ebselen (EB) belong to a diverse class of antiviral drugs known for their significant efficacy in treating various viral infections. Utilizing molecular dynamics (MD) simulations, machine learning, and van der Waals density functional theory, we accurately elucidate the binding properties of these antiviral drugs on a phosphorene single-layer. To further investigate these characteristics, this study employs four distinct machine learning models-Random Forest, Gradient Boosting, XGBoost, and CatBoost. The Hamiltonian of antiviral molecules within a monolayer of phosphorene is appropriately trained. The key aspect of utilizing machine learning (ML) in drug design revolves around training models that are efficient and precise in approximating density functional theory (DFT). Furthermore, the study employs SHAP (SHapley Additive exPlanations) to elucidate model predictions, providing insights into the contribution of each feature. To explore the interaction characteristics and thermodynamic properties of the hybrid drug, we employ molecular dynamics and DFT calculations in a vacuum interface. Our findings suggest that this functionalized 2D complex exhibits robust thermostability, indicating its potential as an effective and enabled entity. The observed variations in free energy at different surface charges and temperatures suggest the adsorption potential of FP and EB molecules from the surrounding environment.


Assuntos
Antivirais , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Antivirais/química , Antivirais/farmacologia , Teoria da Densidade Funcional , Termodinâmica , Isoindóis/química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Azóis/química , Azóis/farmacologia
6.
ChemMedChem ; 19(11): e202400093, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38482564

RESUMO

Inhibition of poly (ADP-ribose) polymerase-1 (PARP1), a DNA repair enzyme, has proven to be a successful strategy for the treatment of various cancers. With the appropriate selection conditions and protein design, DNA-encoded library (DEL) technology provides a powerful avenue to identify small molecules with the desired mechanism of action towards a target of interest. However, DNA-binding proteins, such as PARP1, can be challenging targets for DEL screening due to non-specific protein-DNA interactions. To overcome this, we designed and screened a PARP1 catalytic domain construct without the autoinhibitory helical domain. This allowed us to interrogate an active, functionally-relevant form of the protein resulting in the discovery of novel isoindolinone PARP1 inhibitors with single-digit nanomolar potency. These inhibitors also demonstrated little to no PARP1-DNA trapping, a property that could be advantageous in the clinic.


Assuntos
DNA , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , DNA/química , DNA/metabolismo , Relação Estrutura-Atividade , Descoberta de Drogas , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Relação Dose-Resposta a Droga , Isoindóis/química , Isoindóis/farmacologia , Isoindóis/síntese química , Domínio Catalítico
7.
Chem Biol Drug Des ; 102(6): 1448-1457, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37712451

RESUMO

In this study, synthesis of novel isoindole-1,3-dione analogues bearig halo, hydroxy, and acetoxy groups at the position 4,5,6 of the bicyclic imide ring was performed to examine their potential anticancer effects against some cell lines. A multistep chemical pathway was used to synthesize the derivatives. The cytotoxic effect of trisubstituted isoindole derivatives were evaluated by determining cellular viability using the MTT assay against A549, PC-3, HeLa, Caco-2, and MCF-7 cell lines. The C-2 selective ring-opening products were obtained from the ring-opening reaction of 5-alkyl/aryl-2-hydroxyhexahydro-4H-oxireno[2,3-e]isoindole-4,6(5H)-diones with nucleophiles such as chloride (Cl- ) and bromide (Br- ) ions. In addition, the ring-opening products halodiols were converted to their related acetates. The anticancer activity of synthesized isoindole-1,3-dione derivatives was investigated against HeLa, A549, MCF-7, PC3, and Caco-2 cells in vitro and resulted in varies cytotoxic effect depend on the group attached to the isoindole molecule. Furthermore, the evaluation of the antimicrobial action of trisubstituted isoindole derivatives against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was assessed and found out selective inhibition of the both bacterial growth via different trisubstituted isoindole derivatives. The results of this work encourage further research on the potential utilization of trisubstituted isoindole derivatives as cytotoxic and antimicrobial agents.


Assuntos
Anti-Infecciosos , Antineoplásicos , Humanos , Células CACO-2 , Isoindóis/química , Isoindóis/farmacologia , Antibacterianos/química , Antineoplásicos/química , Anti-Infecciosos/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular
8.
RFO UPF ; 27(1): 14-29, 08 ago. 2023. ilus, tab, graf
Artigo em Português | LILACS, BBO | ID: biblio-1509381

RESUMO

Introdução: O efeito branqueador dos dentifrícios contendo Blue covarine é fundamentado no seu mecanismo de ação, caracterizado pela sua deposição na superfície dentária, alterando a percepção da cor. Objetivo: Revisar a literatura e buscar evidência científica sobre o efeito branqueador do Blue Covarine em tecidos mineralizados e materiais restauradores estéticos. Materiais e métodos: Para a revisão da literatura foram feitas buscas nas bases de dados PubMed, LILACS, BBO, SciELO e MEDLINE para identificar estudos clínicos e laboratoriais que avaliassem a ação branqueadora do agente óptico Blue covarine. Como estratégia de busca foram utilizados os descritores "Blue covarine", "Blue covarine e pasta de dentes", "Blue covarine and toothpaste", "Blue covarine e dentifrícios", "Blue covarine and dentifrices", "Blue covarine e dentifrícios branqueadores", "Blue covarine and whitening dentifrices", "Blue covarine e dentifrícios clareadores", "Blue covarine and bleaching dentifrices", "Blue covarine e pasta de dentes branqueadoras", "Blue covarine and whitening toothpaste", "Blue covarine e pasta de dentes clareadoras", "Blue covarine and bleaching toothpaste". Resultados: Dois pesquisadores selecionaram e analisaram criticamente 31 artigos, sendo 2 revisões da literatura, 4 estudos clínicos e 25 estudos laboratoriais. Divergências quanto ao desenho de estudo, métodos, amostra, critérios clínicos e parâmetros laboratoriais foram observados, além de conflitos de interesse. Conclusão: O Blue Covarine presente nos dentifrícios branqueadores parece ser efetivo na promoção do branqueamento dentário apenas quando associado aos agentes abrasivos presentes nas formulações, evidenciando que ensaios clínicos e laboratoriais, com metodologias semelhantes, são necessários para se obter evidência científica conclusiva sobre o efeito deste agente branqueador.(AU)


Introduction: The whitening effect of dentifrices containing Blue Covarine is based on its mechanism of action, characterized by its deposition on the tooth surface, altering the perception of color. Objective: To review the literature and seek scientific evidence on the whitening effect of Blue Covarine on mineralized tissues and aesthetic restorative materials. Materials and methods: For the literature review, searches were carried out in the PubMed, LILACS, BBO, SciELO and MEDLINE databases, in order to identify clinical and laboratory studies that evaluated the whitening action of the optical agent Blue Covarine. As a search strategy, the descriptors "Blue Covarine", "Blue Covarine and toothpaste", "Blue Covarine and dentifrices", "Blue Covarine and whitening dentifrices", "Blue Covarine and bleaching dentifrices", "Blue Covarine and whitening toothpaste", "Blue Covarine and bleaching toothpaste". Results: Two researchers selected and critically analyzed 31 articles, including 2 literature reviews, 4 clinical studies and 25 laboratory studies. Differences in study design, methods, sample, clinical criteria and laboratory parameters were observed, in addition to conflicts of interest. Conclusion: Blue Covarine present in whitening dentifrices seems to be effective in promoting dental whitening only when associated with abrasive agents present in the formulations, showing that clinical and laboratory tests, with similar methodologies, are necessary to obtain conclusive scientific evidence on the effect of this bleaching agent.(AU)


Assuntos
Humanos , Clareamento Dental/métodos , Dentifrícios/química , Isoindóis/química , Clareadores Dentários/química , Metaloporfirinas/química , Colorimetria , Esmalte Dentário/química
9.
Molecules ; 28(12)2023 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-37375194

RESUMO

Photodynamic therapy (PDT) is recognized as a powerful method to inactivate cells. However, the photosensitizer (PS), a key component of PDT, has suffered from undesired photobleaching. Photobleaching reduces reactive oxygen species (ROS) yields, leading to the compromise of and even the loss of the photodynamic effect of the PS. Therefore, much effort has been devoted to minimizing photobleaching in order to ensure that there is no loss of photodynamic efficacy. Here, we report that a type of PS aggregate showed neither photobleaching nor photodynamic action. Upon direct contact with bacteria, the PS aggregate was found to fall apart into PS monomers and thus possessed photodynamic inactivation against bacteria. Interestingly, the disassembly of the bound PS aggregate in the presence of bacteria was intensified by illumination, generating more PS monomers and leading to an enhanced antibacterial photodynamic effect. This demonstrated that on a bacterial surface, the PS aggregate photo-inactivated bacteria via PS monomer during irradiation, where the photodynamic efficiency was retained without photobleaching. Further mechanistic studies showed that PS monomers disrupted bacterial membranes and affected the expression of genes related to cell wall synthesis, bacterial membrane integrity, and oxidative stress. The results obtained here are applicable to other types of PSs in PDT.


Assuntos
Isoindóis , Compostos Organometálicos , Fotodegradação , Fotoquimioterapia , Fármacos Fotossensibilizantes , Compostos de Zinco , Compostos de Zinco/química , Fármacos Fotossensibilizantes/química , Isoindóis/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/efeitos da radiação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/efeitos da radiação
10.
Eur J Med Chem ; 245(Pt 1): 114865, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335743

RESUMO

The development of novel therapeutics promoting selective tumor elimination is the mainstay of clinical oncology. Emerging insights into tumor targeting reveal caspases activation, especially caspase-3, as a personalized anticancer strategy. Our on-going cancer research has exploited Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers. Herein, we adopted scaffold hopping design to introduce new series of isoindole-based Passerini adducts as caspase-3/7 activators inspired by natural alkaloids from Lion's Mane mushroom promoting caspase-3-mediated apoptosis. Additional pharmacophoric motifs of lead caspase activators were merged into the tailored Passerini skeleton. The rationally designed adducts were synthesized utilizing one-pot reaction of the novel 4-(2'-phthalimido)phenylisonitrile 5, cyclohexanone and miscellaneous carboxylic acids under Passerini conditions. All derivatives were screened for their antiproliferative activities against lung A549, colorectal Caco-2 and breast MDA-MB 231 cancer cells compared to normal fibroblasts utilizing MTT assay. Most of the evaluated derivatives were superior to 5-fluorouracil. The 2-(1H-indol-3-yl)acetate derivative (8a) recorded the highest anticancer potency (IC50 = 0.04-0.11 µM) and selectivity (SI = 42.59-125.53), followed by the 3-(4-(trifluoromethyl)phenyl)acrylate (8m), the 2-(phenylsulfonyl)glycinate (8q), and the 2-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetate (8c) derivatives, respectively. The four hits induced cancer cells apoptosis (up to 57.99%) via caspase-3/7 activation (up to 5.47 folds). Apoptosis-inducing factor1 (AIF1) quantification assay excluded their caspase-independent apoptosis induction potential via AIF1 signaling pathway. Docking simulations clarified the possible binding modes of the hit compounds with XIAP BIR2 domain; the specific receptor of caspase-3/7 activators, and aided identifying their structural determinants of activity. Finally, their practical LogP, efficiency metrics, in silico ADMET profiling were drug-like.


Assuntos
Antineoplásicos , Apoptose , Caspase 3 , Caspase 7 , Isoindóis , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Células CACO-2 , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Isoindóis/química , Isoindóis/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Células A549
11.
Molecules ; 27(23)2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36500412

RESUMO

New hydroxy- and anilinoindanone derivatives 3 and 4 were synthesized starting from 3-hydroxybenzo[e]isoindolinone 1 via the addition of alkyllithium (s-BuLi, n-BuLi, MeLi or i-PrLi) to the carbonyl group, followed by lactam ring opening and, finally, an intramolecular cyclization leading to target compounds. The same starting material was used for the preparation of the new benzo[f]phthalazinone derivatives 12-16 through multi-step reactions. The target derivative 16 was obtained from the corresponding bromolactam 15 by the Buchwald-Hartwig amination. Structures of the obtained compounds were confirmed by the NMR spectra.


Assuntos
Indanos , Isoindóis , Isoindóis/química , Ciclização
12.
Molecules ; 27(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36080411

RESUMO

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.


Assuntos
Isoindóis , Ftalimidas , Isoindóis/química , Naftiridinas , Compostos de Espiro , Estereoisomerismo
13.
Dalton Trans ; 51(19): 7539-7550, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35506569

RESUMO

This study reports the synthesis of three novel axially disubstituted silicon phthalocyanines (1-3-Si) and their quaternized phthalocyanines (1-3-QSi). The resulting compounds were characterized by applying spectroscopic techniques including 1H NMR, FT-IR, UV-vis, and mass spectroscopy. The biological properties of compounds 1-3-QSi, including DNA cleavage activities, DNA binding modes, and topoisomerase enzyme inhibition activities, were investigated using agarose gel electrophoresis. pBR322 plasmid DNA, CT-DNA, and AL-DNA (isolated from apricot leaf) were used for DNA studies. All the quaternized compounds exhibited acceptable DNA cleavage activities. Human topoisomerase I and E. coli topoisomerase enzymes were used for the topoisomerase I inhibition studies. All the quaternized complexes inhibited topoisomerase I activity. Moreover, these compounds were screened for cytotoxic and apoptotic effects against a human colon cancer cell line (DLD-1) by performing MTT and Annexin V assays. They exhibited toxicity and apoptotic effect on the DLD-1 cell line. The findings reveal that the compounds can be utilized for cancer therapy after further investigations.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo I , Isoindóis/química , Compostos de Silício/química , Antineoplásicos/química , DNA/química , DNA Topoisomerases Tipo I/metabolismo , Escherichia coli , Humanos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
14.
Sci Rep ; 12(1): 3316, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35228662

RESUMO

The new coronavirus, SARS-CoV-2, caused the COVID-19 pandemic, characterized by its high rate of contamination, propagation capacity, and lethality rate. In this work, we approach the use of phthalocyanines as an inhibitor of SARS-CoV-2, as they present several interactive properties of the phthalocyanines (Pc) of Cobalt (CoPc), Copper (CuPc) and without a metal group (NoPc) can interact with SARS-CoV-2, showing potential be used as filtering by adsorption on paints on walls, masks, clothes, and air conditioning filters. Molecular modeling techniques through Molecular Docking and Molecular Dynamics were used, where the target was the external structures of the virus, but specifically the envelope protein, main protease, and Spike glycoprotein proteases. Using the g_MM-GBSA module and with it, the molecular docking studies show that the ligands have interaction characteristics capable of adsorbing the structures. Molecular dynamics provided information on the root-mean-square deviation of the atomic positions provided values between 1 and 2.5. The generalized Born implicit solvation model, Gibbs free energy, and solvent accessible surface area approach were used. Among the results obtained through molecular dynamics, it was noticed that interactions occur since Pc could bind to residues of the active site of macromolecules, demonstrating good interactions; in particular with CoPc. Molecular couplings and free energy showed that S-gly active site residues interacted strongly with phthalocyanines with values ​​of - 182.443 kJ/mol (CoPc), 158.954 kJ/mol (CuPc), and - 129.963 kJ/mol (NoPc). The interactions of Pc's with SARS-CoV-2 may predict some promising candidates for antagonists to the virus, which if confirmed through experimental approaches, may contribute to resolving the global crisis of the COVID-19 pandemic.


Assuntos
COVID-19 , Cobalto/química , Complexos de Coordenação/química , Cobre/química , Isoindóis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , SARS-CoV-2/química , Proteínas Virais/química , Humanos
15.
Dalton Trans ; 51(11): 4466-4476, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35229854

RESUMO

The emergence of nanoscience and its effect on the development of diverse scientific fields, particularly materials chemistry, are well known today. In this study, a new di-substituted phthalonitrile derivative, namely 4,5-bis((4-(dimethylamino)phenyl)ethynyl)phthalonitrile (1), and its octa-substituted metal phthalocyanines {M = Co (2), Zn (3)} were prepared. All the newly synthesized compounds were characterized using a number of spectroscopic approaches, including FT-IR, mass, NMR, and UV-vis spectroscopy. The resultant compounds modified the surface of the gold nanoparticles (NG-1-3). Characterization of the newly synthesized conjugates was carried out by transmission electron microscopy. The antioxidant activity of compounds 1-3, NG-1-3, and NG was evaluated using the DPPH scavenging process and the highest radical scavenging activity was obtained with compounds 1, NG-1, 2, and NG-2 (100%). The antimicrobial activity of compounds 1-3, NG-1-3, and NG was studied using a microdilution assay and the most effective antimicrobial activity was obtained for NG-3 against all the tested microorganisms. The newly synthesized compounds demonstrated high DNA cleavage activity. Compounds 1-3, NG-1-3, and NG significantly inhibited the microbial cell viability of E. coli and exhibited perfect antimicrobial photodynamic therapeutic activity with 100% inhibition after 20 min LED irradiation. Besides, the biofilm inhibition activity of compounds 1-3, NG-1-3, and NG on the growth of S. aureus and P. aeruginosa were examined and compounds 1-3 and NG-1-3, especially NG-1-3, displayed high biofilm inhibition activities.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Complexos de Coordenação/farmacologia , Escherichia coli/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Isoindóis/química , Isoindóis/farmacologia , Nanopartículas Metálicas , Metais Pesados/química , Metais Pesados/farmacologia , Testes de Sensibilidade Microbiana , Picratos/antagonistas & inibidores
16.
ChemMedChem ; 17(4): e202100582, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-34850566

RESUMO

The reactive organoselenium compound ebselen is being investigated for treatment of coronavirus disease 2019 (COVID-19) and other diseases. We report structure-activity studies on sulfur analogues of ebselen with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro ), employing turnover and protein-observed mass spectrometry-based assays. The results reveal scope for optimisation of ebselen/ebselen derivative- mediated inhibition of Mpro , particularly with respect to improved selectivity.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , Isoindóis/farmacologia , Compostos Organosselênicos/farmacologia , Inibidores de Proteases/farmacologia , SARS-CoV-2/enzimologia , COVID-19/virologia , Humanos , Isoindóis/química , Compostos Organosselênicos/química , Inibidores de Proteases/química , Relação Estrutura-Atividade
17.
Dalton Trans ; 51(2): 478-490, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34755751

RESUMO

This study presents the preparation of a novel tetra-substituted phthalonitrile (1), namely, 3,6-bis(hexyloxy)-4,5-bis(4-(trifluoromethoxy)phenoxy)phthalonitrile (1) and its metal-free (2)/metal {M = Zn (3), Cu (4), Co (5), Lu(CH3COO) (6), Lu (7)} phthalocyanines. A series of various spectroscopic methods (UV-vis, FT-IR, mass, and 1H NMR spectroscopy) were performed for the characterization of the newly synthesized compounds. The potential of compounds 2, 3, and 6 as photosensitizing materials for photodynamic and sonophotodynamic therapies was evaluated by photophysical, photochemical, and sonochemical methods. The highest singlet quantum yields were obtained for the zinc phthalocyanine derivative 3 by performing photochemical and sonochemical methods. In addition, several biological activities of the new compounds 1-7 were investigated. The newly synthesized phthalocyanines exhibited excellent DPPH scavenging activity and also DNA nuclease activity. The antimicrobial activity of the new compounds was evaluated by the disc diffusion assay. Effective microbial cell viability inhibition was observed with phthalocyanine macromolecules. The photodynamic antimicrobial therapy of the phthalocyanines showed 100% bacterial inhibition when compared to the control. They also exhibited significant biofilm inhibition activity against S. aureus and P. aeruginosa. These results indicate that new phthalocyanines are promising photodynamic antimicrobial therapies for the treatment of infectious diseases.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Isoindóis/farmacologia , Metais/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Anti-Infecciosos/química , Antioxidantes/química , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Biofilmes/efeitos dos fármacos , Compostos de Bifenilo/química , Candida parapsilosis/efeitos dos fármacos , Candida parapsilosis/crescimento & desenvolvimento , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/crescimento & desenvolvimento , Desoxirribonucleases/química , Halogenação , Isoindóis/química , Metais/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Picratos/química , Oxigênio Singlete/química
18.
J Mater Chem B ; 10(2): 306-320, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34935023

RESUMO

Poor tumor selectivity, low stability and quenched fluorescence are the main challenges to be overcome for nanomedicine, and are mainly caused by the dissociation of the nanostructure and aggregation of chromophores in the biological environment. Herein, covalently connected nanoparticles RGD-graphene-phthalocyanine (RGD-GO-SiPc) were constructed based on RGD peptide, silicon phthalocyanine (SiPc) and graphene oxide (GO) via a conjugation reaction for fluorescence imaging-guided cancer-targeted combinatorial phototherapy. The prepared RGD-GO-SiPc exhibited supreme biological stability, high-contrast fluorescence imaging, significantly enhanced NIR absorption, high photothermal conversion efficiency (25.6%), greatly improved cancer-targeting capability, and synergistic photodynamic (PDT) and photothermal therapy (PTT) efficacy along with low toxicity. Both in vitro and in vivo biological studies showed that RGD-GO-SiPc is a kind of promising multifunctional nanomedicine for fluorescence imaging-guided combined photothermal and photodynamic therapy with dual active/passive tumor-targeting properties.


Assuntos
Antineoplásicos/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Nanocompostos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Grafite/química , Grafite/efeitos da radiação , Grafite/uso terapêutico , Células HEK293 , Humanos , Isoindóis/química , Isoindóis/efeitos da radiação , Isoindóis/uso terapêutico , Luz , Camundongos , Nanocompostos/química , Nanocompostos/efeitos da radiação , Nanopartículas/química , Nanopartículas/efeitos da radiação , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Oligopeptídeos/química , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Oxigênio Singlete/metabolismo
19.
Mol Pharm ; 19(1): 115-123, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34927440

RESUMO

Herein, four zinc phthalocyanines (ZnPcs) with chiral lysine modification were synthesized. We found that the chirality of lysine and the chiral structure position strongly influence the properties of ZnPcs. Among the four ZnPcs, d-lysine-modified ZnPc through -NH2 on Cε [denoted N(ε)-d-lys-ZnPc] showed superior properties, including tumor enrichment, cancer cell uptake, and tumor retention capability, compared to the other three ZnPcs. Thus, chiral molecule modification is a simple and effective strategy to regulate the abovementioned properties to achieve a satisfactory antitumor outcome of drugs.


Assuntos
Aminoácidos/química , Isoindóis/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Estereoisomerismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Células HeLa/efeitos dos fármacos , Humanos , Isoindóis/síntese química , Isoindóis/química , Lisina/química , Camundongos , Transplante de Neoplasias , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/química , Compostos de Zinco/síntese química , Compostos de Zinco/química , Compostos de Zinco/farmacologia
20.
Molecules ; 26(23)2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34885959

RESUMO

Due to the unusual properties of gold nanoparticles, these structures are widely used in medicine and biology. This paper describes for the first time the synthesis of colloidal gold nanoparticles by the cell-free filtrate obtained from the Coriolus versicolor biomass and the use of these biogenic nanostructures to increase the photosensitizing efficiency of di- (AlPcS2) and tetrasulfonated (AlPcS4) hydroxyaluminum phthalocyanines in antibacterial photodynamic therapy. The obtained monodisperse particles were extremely stable, and this remarkable stability was due to the presence of phosphoprotein as a capping agent. The studied gold nanoparticles had a spherical shape, were uniformly distributed, and were characterized by a single plasmon band at wavelength of 514-517 nm. Almost 60% of the gold particles were found to be in the range of 13 to 15 nm. In accordance with the regulations of the American Microbiological Society, indicating that any antimicrobial technique must kill at least 3 log CFU (99.9%) to be accepted as "antimicrobial", this mortality of Staphylococcus aureus was shown to be achieved in the presence of AlPcS4 + AuNPs mixture and 4.8 J cm-2 light dose compared to AlPcS4 alone, which required a light dose of 24 J cm-2. The best effect of increasing the effectiveness of combating this pathogen was observed in the case of AlPcS2 + AuNPs as a photosensitizing mixture. The light dose of 24 J cm-2 caused a lethal effect of the studied coccus in the planktonic culture.


Assuntos
Alumínio/farmacologia , Antibacterianos/farmacologia , Ouro/farmacologia , Isoindóis/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Alumínio/química , Antibacterianos/química , Ouro/química , Humanos , Isoindóis/química , Nanopartículas Metálicas/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/química , Infecções Estafilocócicas/tratamento farmacológico
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