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1.
Chem Commun (Camb) ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38957144

RESUMO

Pyridyloxy-directed Ir(III)-catalyzed diacylmethylation of protected tyrosines was achieved with alkyl and (hetero)aryl sulfoxonium ylides, furnishing tyrosine-based unnatural amino acids in good yields. Furthermore, the late stage exemplification of the strategy was successfully accomplished in tyrosine-containing dipeptides, tripeptides and tetrapeptides in moderate yields. This methodology is distinguished by its site-selectivity, tolerance of sensitive functional groups, scalability, and retention of the chiral configuration for tyrosine motifs.

2.
Org Lett ; 25(42): 7673-7677, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37853547

RESUMO

Pyridyloxy-directed Rh(III)-catalyzed regioselective C3Ar-H alkenylation of protected tyrosines was achieved with N-aryl and N-alkyl maleimides, furnishing a series of maleimide-appended tyrosine-based unnatural amino acids in good yields. Further, the late-stage exemplification of the strategy was successfully accomplished on tyrosine-containing dipeptides, tripeptides, and tetrapeptides in moderate reactivity. Also, the chemical applications of the strategy were successfully executed toward nailing tyrosine with other amino acids via a maleimide linker and intramolecular hydroarylation to produce tyrosine-centered stapled products and succinimide-glued macrocyclized products, respectively.


Assuntos
Ródio , Estrutura Molecular , Ródio/química , Tirosina , Aminoácidos , Maleimidas/química , Peptídeos , Catálise
3.
Org Biomol Chem ; 21(33): 6719-6729, 2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37555287

RESUMO

A Pd(II)-catalyzed strategy for the diastereo- and regioselective (hetero)arylation of unactivated C(sp3)-H bonds in bile acids is accomplished with aryl and heteroaryl iodides under solvent-free conditions using the 8-aminoquinoline auxiliary as a directing group. This methodology demonstrated excellent functional group tolerance with respect to aryl/heteroaryl iodides on O-protected N-(quinolin-8-yl)cholyl/deoxycholyl amides to afford ß-C(sp3)-H (hetero)arylated products in good-to-excellent yields. Moreover, the 8-aminoquinoline (AQ) auxiliary can easily be removed to obtain modified bile acids.

4.
Steroids ; 197: 109258, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37330161

RESUMO

Steroids are biomolecules that play pivotal roles in various physiological and drug discovery processes. Abundant research has been fuelled towards steroid-heterocycles conjugates over the last few decades as potential therapeutic agents against various diseases especially as anticancer agents. In this context various steroid-triazole conjugates have been synthesized and studied for their anticancer potential against various cancer cell lines. A thorough search of the literatures revealed that a concise review pertaining the present topic is not compiled. Therefore, in thus review we summarize the synthesis, anticancer activity against various cancer cell lines and structure activity relationship (SAR) of various steroid-triazole conjugates. This review can lay down the path towards the development of various steroid-heterocycles conjugates with lesser side effects and profound efficacy.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Triazóis/química , Antineoplásicos/química , Relação Estrutura-Atividade , Esteroides/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células , Linhagem Celular Tumoral
5.
J Control Release ; 359: 161-174, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37182806

RESUMO

Glioblastoma multiforme (GBM) is the deadliest brain tumor with a poor prognosis and limited therapeutic options. Temozolomide (TMZ) is the first-line chemotherapeutic agent used for the treatment of GBM; however, it suffers from several limitations, including short half-life, rapid metabolism, <1% brain bioavailability, methyl guanine methyl transferase (MGMT) based chemoresistance, and hematological toxicities. Several approaches have been adopted to overcome these limitations, particularly by using nanotechnology-based systems, but its physicochemical properties make TMZ challenging to load into these nanocarriers. In the current research, we conjugated TMZ with different fatty acids, i.e., linoleic acid (LA), oleic acid (OA), and palmitic acid (PA), to obtain TMZ-fatty acid conjugates, which are comparatively hydrophobic, less prone to degradation and potent. These conjugates were thoroughly characterized using 1H NMR spectroscopy, high-resolution mass spectrometry (HR-MS), and reverse phase-high performance liquid chromatography (RP-HPLC). The synthesized conjugates, namely Temozolomide-oleic acid (TOA,6R1), Temozolomide-linoleic acid (TLA, 6R2), and Temozolomide-palmitic acid (TPA, 6R3), showed an IC50 of 101.4, 67.97, and 672.04 µM, respectively in C6 cells and 428.257, 366.43 and 413.69 µM, respectively in U87-MG cells. On the other hand, the free TMZ showed an IC50 of >1000 µM and 564.23 µM in C6 and U87-MG, respectively. Further, the in vivo efficacy of the TMZ-fatty acid conjugates was evaluated in the C6-induced orthotropic rat glioblastoma model, wherein the TMZ-fatty acid conjugate showed improved survival rate (1.6 folds) and overall health of the animals. Collectively, the conjugation of fatty acids with TMZ improves its anticancer potential against glioblastoma multiforme (GBM).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Ratos , Animais , Temozolomida/uso terapêutico , Glioblastoma/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Ácidos Graxos , Linhagem Celular Tumoral , Neoplasias Encefálicas/metabolismo , Ácidos Linoleicos/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Ácidos Oleicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Org Chem ; 88(3): 1457-1468, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36631396

RESUMO

Serendipitous and expedite transformation of 1-aryl- and 2-aryl-1,2-dihydro-3H-indazol-3-ones to 1,2-di(hetero)aryl- and 2,3-di(hetero)aryl-2,3-dihydroquinazolin-4(1H)-ones, respectively, was achieved in high efficiency by reacting them with aldehydic N-tosylhydrazones. The protocol proceeded through a cascade process involving base-mediated Pd-carbenoid generation by the decomposition of N-tosylhydrazones, nucleophilic attack of indazolone on the Pd-carbenoid complex, and intramolecular ring expansion via N-N bond cleavage. The utility of the strategy is demonstrated toward the synthesis of bioactive NPS 53574, a calcium receptor antagonist.

7.
Org Lett ; 24(37): 6857-6862, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36074726

RESUMO

A Rh(III)-catalyzed [5+2] annulation of vinyl tyrosines with symmetrical and unsymmetrical internal alkynes was achieved, furnishing a series of oxepine-mounted tyrosine-based unnatural amino acids. In addition, the chemical applicability of the developed strategy was exemplified by stapling amino acid/peptide-appended alkynes with vinyl tyrosines and late stage functionalization of tyrosine-containing dipeptides and tripeptide with internal alkynes.


Assuntos
Ródio , Alcinos/química , Catálise , Dipeptídeos , Oxepinas , Peptídeos , Ródio/química , Tirosina
8.
ChemMedChem ; 17(13): e202200164, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35511203

RESUMO

Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43 mm to 2 mm in comparison to 5.7 mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.


Assuntos
Antineoplásicos , Isatina , Fluoruracila/farmacologia , Humanos , Relação Quantitativa Estrutura-Atividade , Bases de Schiff/farmacologia , Sunitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Org Biomol Chem ; 20(23): 4753-4764, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35616276

RESUMO

Ru(II)-catalyzed strategies were developed for the [4 + 1] and [4 + 2] oxidative coupling between N-aryl-2,3-dihydrophthalazine-1,4-diones and 1,4-benzoquinones, achieving spiro-indazolones and fused-cinnolines, respectively. Mild, aerobic and external oxidant-free conditions, as well as the use of a ruthenium catalyst for such (spiro)annulative strategies with quinones over reported Rh/Ir-catalyts, underline the rewards of the disclosed protocols.


Assuntos
Rutênio , Compostos de Espiro , Catálise , Compostos Heterocíclicos com 2 Anéis , Estrutura Molecular , Quinonas
10.
Pharmaceuticals (Basel) ; 15(2)2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-35215303

RESUMO

The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential drug candidates using the known scaffolds. We synthesized a total of 31 diverse linezolid conjugates 3, 5, 7, 9, 11, 13, and 15 using our established benzotriazole chemistry with good yield and purity. Some of the synthesized conjugates exhibited promising antibacterial properties against different strains of bacteria. Among all the synthesized compounds, 5d is the most promising antibacterial agent with MIC 4.5 µM against S. aureus and 2.25 µM against B. subtilis. Using our experimental data pool, we developed a robust QSAR (R2 = 0.926, 0.935; R2cvOO = 0.898, 0.915; R2cvMO = 0.903, 0.916 for the S. aureus and B. subtilis models, respectively) and 3D-pharmacophore models. We have also determined the drug-like properties of the synthesized conjugates using computational tools. Our findings provide valuable insight into the possible linezolid-based antibiotic drug candidates.

11.
J Org Chem ; 87(5): 3701-3706, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35077162

RESUMO

A tender-hearted Pd(II)-catalyzed C-H activation of 1-arylindazolones followed by an oxidative [4 + 2] annulation reaction has been accomplished, engaging allenoates as annulating partners. Using this strategy, two different regioisomeric forms of cinnoline-fused indazolones possessing internal and exocyclic double bonds were synthesized in acetic acid and dioxane, respectively. Mild and aerobic conditions, avoiding the use of any metal-oxidant, highlights the rewards of this oxidative annulation protocol.


Assuntos
Compostos Heterocíclicos com 2 Anéis , Paládio , Catálise , Paládio/química
12.
Molecules ; 26(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34641285

RESUMO

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Ácidos e Sais Biliares/química , Cetonas/administração & dosagem , Cetonas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Cetonas/química , Cetonas/farmacocinética , Células MCF-7 , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
13.
Org Biomol Chem ; 19(35): 7695-7700, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524312

RESUMO

Fluorescent probes have become valuable tools in chemical biology, providing interesting inferences for unfolding the complexities of natural biochemical processes. In this study, we report the synthesis and characterization of fluorescent labelled glutamine (Gln) and asparagine (Asn) derivatives via traceless Staudinger ligation, which exhibited high fluorescence quantum yields, excellent photostabilities and emission of blue fluorescence in the visible region. The successful permeation of these fluorescent amino acids into cellular components proved their potential as fluorescent probes for chemical biology.


Assuntos
Asparagina
14.
Bioorg Chem ; 114: 105117, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34214752

RESUMO

At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs.


Assuntos
Antivirais/síntese química , Tratamento Farmacológico da COVID-19 , Quinolinas/síntese química , Triazóis/síntese química , Antivirais/química , Química Click , Humanos , Simulação de Acoplamento Molecular , Quinolinas/química , SARS-CoV-2 , Triazóis/química
15.
J Org Chem ; 86(3): 2734-2747, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33476149

RESUMO

A mild Rh-catalyzed method was developed for the synthesis of hydroxyimino functionalized indazolo[1,2-a]cinnolines and phthalazino[2,3-a]cinnolines by reductive [4 + 2] annulation between 1-arylindazolones and 2-aryl-2,3-dihydrophthalazine-1,4-diones with varied nitroolefins. The targeted oxime decorated tetracyclic fused cinnolines were synthesized via sequential C-H activation/olefin insertion/reduction under reducing-agent-free conditions.


Assuntos
Compostos Heterocíclicos com 2 Anéis , Ródio , Catálise , Substâncias Redutoras
16.
Med Chem ; 17(1): 71-84, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-31483233

RESUMO

BACKGROUND: Bacterial infections are considered as one of the major global health threats, so it is very essential to design and develop new antibacterial agents to overcome the drawbacks of existing antibacterial agents. METHODS: The aim of this work is to synthesize a series of new fluoroquinolone-3-carboxamide amino acid conjugates by molecular hybridization. We utilized benzotriazole chemistry to synthesize the desired hybrid conjugates. RESULTS: All the conjugates were synthesized in good yields, characterized, evaluated for their antibacterial activity. The compounds were screened for their antibacterial activity using methods adapted from the Clinical and Laboratory Standards Institute. Synthesized conjugates were tested for activity against medically relevant pathogens; Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27856) Staphylococcus aureus (ATCC 25923) and Enterococcus faecalis (ATCC 19433). CONCLUSION: The observed antibacterial experimental data indicates the selectivity of our synthesized conjugates against E.Coli. The protecting group on amino acids decreases the antibacterial activity. The synthesized conjugates are non-toxic to the normal cell lines. The experimental data were supported by computational studies.


Assuntos
Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Modelos Moleculares , Antibacterianos/química , Linhagem Celular , Técnicas de Química Sintética , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Relação Estrutura-Atividade
17.
AAPS PharmSciTech ; 21(7): 280, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037506

RESUMO

Docetaxel (DTX), an FDA approved chemotherapeutic agent, is used as a first-line treatment for triple-negative breast cancer (TNBC). Its poor aqueous solubility, rapid metabolism, short half-life, and effective targeting to the cancer cells limits its optimal therapeutic use. Herein, we report folate targeted amphiphilic lipopolymer grafted with cholesterol conjugated carbonate and DL-lactide prepared by microwave assisted ring opening polymerization, for the efficient actively targeted delivery of DTX. The DTX-loaded folate-targeted lipopolymeric nanoparticles (F-DTX-LPNs) prepared by the emulsion solvent evaporation method exhibited a smaller size of ∼115.17 nm with a PDI of 0.205 and encapsulation efficiency of >80%. Further, these lipopolymeric nanoparticles (F-DTX-LPNs) showed a good on-bench stability and sustained DTX release for 7 days. Cell-based assays in MDA-MB-231 cells revealed a significant enhancement in the intracellular uptake of folate-targeted lipopolymeric nanoparticles compared to non-targeted nanoparticles. Further, methyl beta-cyclodextrin (Mß-CD) completely inhibited the uptake of these nanoparticles in the cells, indicating a lipid raft-mediated uptake mechanism. The developed F-DTX-LPNs showed improved cytotoxicity, apoptosis, and significant fold-change in expression levels of Bcl-2, BAX and Ki-67 as compared to non-targeted DTX-LPNs and free DTX. Further, F-DTX-LPNs showed an improved in vivo pharmacokinetic profile in Sprague Dawley rats as compared to the free DTX. The bio-imaging of ex vivo tissues demonstrated that the DiR loaded folate targeted LPNs exhibited intense signals after 24 h because of slow release of DiR dye from the nanoparticles.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Colesterol/química , Docetaxel/administração & dosagem , Portadores de Fármacos , Ácido Fólico/química , Polímeros/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Docetaxel/química , Docetaxel/farmacologia , Feminino , Humanos , Camundongos , Nanopartículas , Ratos , Ratos Sprague-Dawley
18.
J Org Chem ; 85(19): 12147-12159, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32885657

RESUMO

A smooth traceless ligation strategy using an air-stable phosphane probe (2-(diphenylphosphanyl)phenyl)methanol as a C-terminus activator has been demonstrated at simple and sterically hindered amino acid junctions (Gly, Ala, Trp, Glu). This Staudinger peptide ligation proceeds via formation of a seven-membered transition state to afford di-, tetra-, and pentapeptides in 78-95% yields. The experimental results of ligation at Gly junction and regioselective ligation at Glu junction were theoretically studied by computational calculations. These findings established the versatile behavior of our synthesized phosphane probe for Staudinger peptide ligation toward synthesizing peptides and proteins of choice.

19.
Steroids ; 160: 108659, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439407

RESUMO

Four novel deoxycholic acid tethered α-cyanostilbenes were designed, synthesized and characterized using detailed spectroscopic analysis. The synthesized deoxycholic acid tethered α-cyanostilbene derivatives formed stable gels with a variety of solvents, such as xylene, toluene, mesitylene, decane, dodecane etc. The stable gels showed lamellar sheet type structures stacked over each other, consisting of entangled fibres as evident from SEM, TEM and Fluorescence Microscopy images; The synthesized compounds exhibited AIEE behaviour in H2O/THF mixture, with the maximum emission observed in 70% H2O/THF fraction along with a bathochromic shift. A solvent thickening experiment was perform to establish the mechanism of AIEE and the AIEE property was explored for bacterial bio-imaging. The synthesized derivatized steroids proved their potential as multifunctional organic materials.


Assuntos
Acrilonitrila/análogos & derivados , Ácido Desoxicólico/química , Corantes Fluorescentes/química , Imagem Molecular , Serratia marcescens/isolamento & purificação , Staphylococcus aureus/isolamento & purificação , Acrilonitrila/química , Corantes Fluorescentes/síntese química , Géis/síntese química , Géis/química , Microscopia de Fluorescência , Conformação Molecular , Peso Molecular
20.
Chem Biol Drug Des ; 95(2): 248-259, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31623026

RESUMO

A series of new fluoroquinolone conjugates 8a-g and 9a-f were synthesized via benzotriazole-mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR-QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Ácido Dicloroacético/farmacologia , Fluoroquinolonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Ácido Dicloroacético/química , Escherichia coli/efeitos dos fármacos , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
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