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    A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells
    (2019) Oliveira, Maiara de Souza; Souza, Thiago Belarmino de; Moreira, Diogo Rodrigo de Magalhães; Martins, Felipe Terra; Villarreal Peña, Wilmer José; Machado, Rafael Pereira; Doriguetto, Antonio Carlos; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira
    Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.
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    Winged-cone conformation in hexa-p-tert-butylcalix[6]arene driven by the unusually strong guest encapsulation
    (2017-08-31) Martins, Felipe Terra; Oliveira, Breno Germano de Freitas; Sarotti, Ariel Marcelo; Fátima, Ângelo de
    Hexa-p-tert-butylcalix[6]arene (1) is believed to adopt a winged conformation in a solution, featured by four phenyl rings perpendicular to the calix basis and two others at 1,4-positions lying down. However, there is some controversy on the occurrence of this conformation because it has never been found in the solid state of calix[6]arenes, regardless of the substitution pattern at lower and upper rims. Here, we have observed the winged-cone conformation for the first time in a solvate form of 1 with dimethyl sulfoxide (DMSO), dimethylformamide, and pyridine. The DMSO molecule is strongly encapsulated into 1 through two OH···O hydrogen bonds with both flattened phenolic moieties, one lp(S)···π and four CH···π interactions with the four perpendicular phenyl rings. This host–guest complex has energy lower by 23.4 kcal mol–1 than the isolated species. In addition, another DMSO solvate form with 1,2,3-alternate conformation was also obtained in this study, and its structure is compared with that of the precedent one. A detailed density functional theory study has also been carried out to understand the energetic relationships among cone conformers, intramolecular hydrogen-bonding patterns, and DMSO encapsulation.
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    Preparation of a solid self-microemulsifying drug delivery system by hot-melt extrusion
    (2018) Silva, Luís Antônio Dantas; Almeida, Susana Leão; Pineze, Ellen Cristine; Gonçalves, Priscila Bianca Rodrigues da Rocha; Martins, Felipe Terra; Freitas, Luis Alexandre Pedro de; Taveira, Stephânia Fleury; Cunha Filho, Marcilio Sérgio Soares da; Marreto, Ricardo Neves
    Hot-melt extrusion (HME) has gained increasing attention in the pharmaceutical industry; however, its potential in the preparation of solid self-emulsifying drug delivery systems (S-SMEDDS) is still unexplored. This study sought to prepare enteric S-SMEDDS by HME and evaluate the effects of the process and formulation variables on S-SMEDDS properties via Box-Behnken design. Liquid SMEDDS were developed, and carvedilol was used as a class II model drug. Mean size, polydispersity index (PdI) and zeta potential of the resulting microemulsions were determined. The extrudates were then obtained by blending the lipid mixture and HPMCAS using a twin-screw hot-melt extruder. SEM, optical microscopy and PXRD were used to characterize the extrudates. In vitro microemulsion reconstitution and drug release were also studied. L-SMEDDS gave rise to microemulsions with low mean size, PdI and zeta potential (140.04 ± 7.22 nm, 0.219 ± 0.011 and −9.77 ± 0.86 mV). S-SMEDDS were successfully prepared by HME, and an HMPCAS matrix was able to avoid microemulsion reconstitution and retain drug release in pH 1.2 (12.97%–25.54%). Conversely, microemulsion reconstitution and drug release were gradual in pH 6.8 and complete for some formulations. Extrudates prepared at the lowest drug concentration and highest temperature and recirculation time promoted a complete and rapid drug release in pH 6.8 giving rise to small and uniform microemulsion droplets.
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    [Ru(pipe)(dppb)(bipy)]PF6: a novel ruthenium complex that effectively inhibits ERK activation and cyclin D1 expression in A549 cells
    (2017-08-01) Silva, Guilherme Álvaro Ferreira da; Ortega, Marina Montingelli; Banionis, Marco Aurélio; Garavelli, Graciana Yokota; Martins, Felipe Terra; Dias, Júlia Scaff Moreira; Viegas Junior, Claudio; Oliveira, Jaqueline Carvalho de; Nascimento, Fábio Batista do; Doriguetto, Antonio Carlos; Barbosa, Marília Imaculada Frazão; Ionta, Marisa
    Lung cancer is the most frequent type of cancer worldwide. In Brazil, only 14% of the patients diagnosed with lung cancer survived 5 years in the last decades. Although improvements in the therapeutic approach, it is relevant to identify new chemotherapeutic agents. In this framework, ruthenium metal compounds emerge as a promising alternative to platinum-based compounds once they displayed lower cytotoxicity and more selectivity for tumor cells. The present study aimed to evaluate the antitumor potential of innovative ruthenium(II) complex, [Ru(pipe)(dppb)(bipy)]PF6 (PIPE) on A549 cells, which is derived from non-small cell lung cancer. Results demonstrated that PIPE effectively reduced the viability and proliferation rate of A549 cells. When PIPE was used at 9 μM there was increase in G0/G1 cell population with concomitant reduction in frequency of cells in S-phase, indicating cell cycle arrest in G1/S transition. Antiproliferative activity of PIPE was associated to its ability of reducing cyclin D1 expression and ERK phosphorylation levels. Cytotoxic activity of PIPE on A549 cells was observed when PIPE was used at 18 μM, which was associated to its ability of inducing apoptosis by intrinsic pathway. Taken together, the data demonstrated that PIPE is a promising antitumor agent and further in vivo studies should be performed.
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    Carbamoyl-N-aryl-imine-urea: a new framework to obtain a putative leishmanicidal drug-candidate
    (2020) Alves, Marina Amaral; Queiroz, Aline Cavalcanti de; Leite, Anderson Brandão; Martins, Felipe Terra; Doriguetto, Antonio Carlos; Barreiro, Eliezer Jesus de Lacerda; Moreira, Magna Suzana Alexandre; Lima, Lidia Moreira
    Leishmaniasis is a neglected parasitic disease, and current treatment includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. Therefore, new leishmanicidal drugs are still an unquestionable medical need. In this paper we described the design conception of a new framework, the carbamoyl-N-aryl-imine-urea, to obtain putative leishmanicidal drug-candidates. Compounds 9a–e and 10a–e were designed and synthesized and their leishmanicidal activity was studied in comparison to pentamidine, miltefosine and meglumine antimoniate. The conformational profile of the new carbamoyl-N-aryl-imine-urea framework was investigated by X-ray diffraction studies, using compound 9a as a model. The plasma stability of this putative peptide mimetic subunit was studied for compound 10e (LASSBio-1736). Among the congeneric series, LASSBio-1736 was identified as a new antileishmanial drug-candidate, displaying plasma stability, cytotoxicity against amastigote forms of L. amazonensis and L. braziliensis, and leishmanicidal activity in a cutaneous leishmaniasis murine model, without preliminary evidence of hepatic or renal toxicity.
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    Iminecalix[4]arenes: microwave-assisted synthesis, X-ray crystal structures, and anticandidal activity
    (2019) Silva, Cleiton Moreira da; Silva, Danielle Letícia da; Magalhães, Thais Furtado Ferreira; Alves, Rosemeire Brondi; Stoianoff, Maria Aparecida Resende; Martins, Felipe Terra; Fátima, Ângelo de
    In this study, six iminecalix[4]arenes were synthesized and the crystal structures of two of the iminecalix[4]arenes were also determined. Iminecalix[4]arene adopts a strongly pinched cone conformation with two upper rim substituents pointing toward and the other two pointing away from the aromatic cavity. This uncommon conformation is stabilized by an intramolecular π…π interaction between the phenyl rings from the upper rim substituents pointing inwards the cone. In addition, phenyl rings from the substituent groups are not coplanar with respect to the calixarene phenyl rings holding them. The compounds, as well as their respective monomeric units, were evaluated for their antifungal activities against Candida strains. All the synthesized iminecalix[4]arenes were found to cause higher inhibition of all tested Candida strains than their respective monomers. The ratio between the minimal inhibitory concentration (MIC) of a monomer and the corresponding iminecalix[4]arene ranged from 2.05 to 36.50. Furthermore, the iminecalix[4]arene bearing nitrofuran group exhibited low MIC values comparable to that of fluconazole. Thus, this compound was twice more active than fluconazole against Candida krusei.
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    Synthesis and special characterization through X-ray analysis of 1,8-dioxooctahydroxanthenes
    (2020) Silva, Milene Lopes da; Teixeira, Róbson Ricardo; Santos, Lucas de Azevedo; Martins, Felipe Terra; Ramalho, Teodorico de Castro
    Pyran moiety containing heterocyclic compounds have the capability for binding to either side to cyclohex-2-enone rings and to form xanthene derivatives (1,8-dioxooctahydroxanthenes also known as xanthenodiones). These xanthene derivatives display a wide range of biological activities and find applications in laser technologies and photodynamic therapy. This paper describes the preparation, X-ray structural analysis, and theoretical investigation of a series of 1,8-dioxooctahydroxanthenes. The compounds were synthesized via Knoevenagel condensation between different aldehydes and β-diketones. The reactions were performed free of solvents and the 1,8-dioxooctahydroxanthenes were obtained in good yields (70−92%). All the compounds were fully characterized by NMR and IR spectroscopy as well as mass spectrometry. Among the synthesized compounds, seven had their crystal structures elucidated for the first time. In all the new crystal structures, the three fused rings did form an almost completely planar xanthenodione core, except for the side rings that adopt half-chair conformation with both carbons at the flaps oriented toward to the aromatic substituent, or with one of the two carbons pointing opposite to the substituent. Another conformational difference among the new compounds investigated by X-ray diffraction resides in the rotation around the bond axis connecting the xanthenodione core to its aromatic substituent. It was found that different bent levels resulted from weak intermolecular contact patterns. In addition, theoretical calculations for single molecule and dimmers have provided insights into the balance between intramolecular and intermolecular forces driving both conformational features.
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    Synthesis, anticancer activities and experimental-theoretical DNA interaction studies of 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile
    (2022) Braga, Taniris Cafiero; Silva, Marina de Magalhães; Nascimento, Eduarda O. O.; Silva, Edjan Carlos Dantas da; Rego, Yuri de Freitas; Mandal, Mullicka; Souza, Zaqueu Alves de; Ruiz, Ana Lúcia Tasca Gois; Carvalho, João Ernesto de; Martins, Felipe Terra
    Twenty chromenes were synthesized with good to excellent yields (70–96%). From the series of chromenes herein tested, compounds 14, 12, 15, 16, 17, 18, and 20 were the most potent throughout the cancer human cell lines tested. In general, the para-position electron-withdrawing substituents on the phenyl ring are favored towards potency and selectivity for cancer cells. Biophysical studies were performed with eight chromene derivatives (13-20) and ctDNA to evaluate possible biological targets. The molecular fluorescence verified that compound 16 presented a higher binding constant (Kb) with the ctDNA, agreeing with in vitro biological results and that evaluated chromenes derivatives interact preferentially via intercalation. Finally, an inverse linear correlation (logKb vs. GI50) was observed for six human carcinogenic cell lines; hence, the mechanism of action of these compounds may be related to DNA interaction.
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    Predicting chemical shelf life of mozzarella cheese submitted to irregular refrigeration practices by Nuclear Magnetic Resonance spectroscopy and statistical analysis
    (2022) Goncalves, Flávia Carneiro; Oliveira, Vitor Mendes de; Martins, Felipe Terra; Liao, Luciano Morais; Ferri, Pedro Henrique; Queiroz Júnior, Luiz Henrique Keng
    The complex mixture found in mozzarella cheese favors microorganism proliferation that causes spoilage. Appropriate refrigeration during storage is one step in the supply chain that is critical to guarantee food quality. However, the impact of the absence of night-time refrigeration, practiced by some commercial establishments, in mozzarella chemical profile has not yet been investigated. To this end, during the evening the simulation of improper refrigeration was carried out using an uncovered Styrofoam box containing ice, allowing the system to reach the thermal balance with the environment. The key degradation compounds produced in mozzarella cheese from simulated inadequate refrigeration were identified and quantified using NMR (Nuclear Magnetic Resonance). While the composition and physicochemical analyses were unable to distinguish refrigeration practices, the NMR data revealed that the succinate contents changed significantly between different refrigeration treatments. At the labelled expiry date, inadequate refrigeration had led to an increase in the succinate content of more than 600%. The results suggested a reduction of 4 weeks of the chemical shelf life. Together, NMR and Principal Response Curve analysis are powerful tools to identify mozzarella cheese submitted to different refrigeration conditions.
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    Calix[n]arene-based immunogens: a new non-proteic strategy for anti-cocaine vaccine
    (2022) Silva Neto, Leonardo da; Maia, Angélica Faleiros da Silva; Godin, Adriana Martins; Augusto, Paulo Sérgio de Almeida; Pereira, Raíssa Lima Gonçalves; Caligiorne, Sordaini Maria; Alves, Rosemeire Brondi; Fernandes, Simone Odília Antunes; Cardoso, Valbert Nascimento; Goulart, Gisele Assis Castro; Martins, Felipe Terra
    Introduction: Cocaine use disorder is a significant public health issue without a current specific approved treatment. Among different approaches to this disorder, it is possible to highlight a promising immunologic strategy in which an immunogenic agent may reduce the reinforcing effects of the drug if they are able to yield sufficient specific antibodies capable to bind cocaine and/or its psychoactive metabolites before entering into the brain. Several carriers have been investigated in the anti-cocaine vaccine development; however, they generally present a very complex chemical structure, which potentially hampers the proper assessment of the coupling efficiency between the hapten units and the protein structure. Objectives: The present study reports the design, synthesis and preclinical evaluation of two novel calix [n]arene-based anti-cocaine immunogens (herein named as V4N2 and V8N2) by the tethering of the hydrolysis-tolerant hapten GNE (15) on calix[4]arene and calix[8]arene moieties. Methods: The preclinical assessment corresponded to the immunogenicity and dose–response evaluation of V4N2 and V8N2. The potential of the produced antibodies to reduce the passage of cocaine analogue through the blood–brain-barrier (BBB), modifying its biodistribution was also investigated. Results: Both calix[n]arene-based immunogens elicited high titers of cocaine antibodies that modified the biodistribution of a cocaine radiolabeled analogue (99mTc-TRODAT-1) and decreased cocaine-induced behavior, according to an animal model. Conclusion: The present results demonstrate the potential of V4N2 and V8N2 as immunogens for the treatment of cocaine use disorder.
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    Natural organic acid as green catalyst for xanthenones synthesis: methodology, mechanism and calcium channel blocking activity
    (2017) Diniz , Bruna Silva Terra; Blandón Osorio, Aura María; Oliveira, Aline de; Mouro, Andressa Pereira; Araújo, Natália Ferreira de; Silva, Cameron Capeletti da; Martins, Felipe Terra; Vieira , Luciene Bruno; Bonaventura, Daniella; Abreu, Heitor Avelino de; Alcântara, Antônio Flávio de Carvalho; Fátima, Ângelo de
    Xanthenones were synthesized via one-pot tricomponent reaction, under solvent-free conditions, using aldehydes, phenolic and cyclic 1,3-dicarbonyl compounds. Natural organic acids (NOAs), compounds present in many living metabolisms, were used as potential green catalysts. NOA are considered to be more eco-friendly and user-friendly alternative to traditional methodologies. Optimization studies showed that oxalic acid was the best NOA catalyst for such reaction furnishing the xanthenones with up to 93% of yield. Theoretical calculations were performed to evaluate this reaction mechanism and regioselectivity. The results showed that the regiospecificity of this three-component reaction is kinetically and thermodynamically controlled by the addition of b-naphthol C2, instead of C10, to the aldehyde. Our results also disclosed two xanthenones as novel calcium channels blockers. Eco-friendly reaction conditions, easy workup procedure, short reaction times and good yields are some of the advantages of our methodology.
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    Evaluation of anti-candida albicans activity and release of ketoconazole in PMMA-G-PEG 4000 films
    (2022-09-15) Reynaldo, Juliana Ribeiro; Novack, Kátia Monteiro; Sousa, Lucas Resende Dutra; Vieira, Paula Melo de Abreu; Amparo, Tatiane Roquete; Souza, Gustavo Henrique Bianco de; Teixeira, Luiz Fernando de Medeiros; Barboza, Ana Paula Moreira; Neves, Bernardo Ruegger Almeida; Alvarenga, Meiry Edivirges; Martins, Felipe Terra
    Modified release systems depend on the selection of an appropriate agent capable of controlling the release of the drug, sustaining the therapeutic action over time, and/or releasing the drug at the level of a particular tissue or target organ. Polyethylene glycol 4000 (PEG 4000) is commonly employed in drug release formulations while polymethyl methacrylate (PMMA) is non-toxic and has a good solubility in organic solvents. This study aimed at the incorporation of ketoconazole in PMMA-g-PEG 4000 and its derivatives, thus evaluating its release profile and anti-Candida albicans and cytotoxic activities. Ketoconazole was characterized and incorporated into the copolymers. The ketoconazole incorporated in the copolymer and its derivatives showed an immediate release profile. All copolymers with ketoconazole showed activity against Candida albicans and were non-toxic to human cells in the entire concentration tested.
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    Methoxylated cinnamic esters with antiproliferative and antimetastatic effects on human lung adenocarcinoma cells
    (2023) Sampaio, João Graciano; Pressete, Carolina Girotto; Costa, Adilson Vidal; Martins, Felipe Terra; Lima, Graziela Domingues de Almeida; Ionta, Marisa; Teixeira, Róbson Ricardo
    Lung cancer is the leading cause of cancer mortality worldwide, and malignant melanomas are highly lethal owing to their elevated metastatic potential. Despite improvements in therapeutic approaches, cancer treatments are not completely effective. Thus, new drug candidates are continuously sought. We synthesized mono- and di-methoxylated cinnamic acid esters and investigated their antitumor potential. A cell viability assay was performed to identify promising substances against A549 (non-small-cell lung cancer) and SK-MEL-147 (melanoma) cells. (E)-2,5-dimethoxybenzyl 3-(4-methoxyphenyl)acrylate (4m), a monomethoxylated cinnamic acid derivative, was identified as the lead antitumor compound, and its antitumor potential was deeply investigated. Various approaches were employed to investigate the antiproliferative (clonogenic assay and cell cycle analysis), proapoptotic (annexin V assay), and antimigratory (wound-healing and adhesion assays) activities of 4m on A549 cells. In addition, western blotting was performed to explore its mechanism of action. We demonstrated that 4m inhibits the proliferation of A549 by promoting cyclin B downregulation and cell cycle arrest at G2/M. Antimigratory and proapoptotic activities of 4m on A549 were also observed. The antitumor potential of 4m involved its ability to modulate the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway once phosphorylated-ERK expression was considerably reduced in response to treatment. Our findings demonstrate that 4m is a promising anticancer drug candidate.
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    Study of the counter cation effects on the supramolecular structure and electronic properties of a dianionic oxamate-based {NIII2} helicate
    (2023-02-23) Simosono, Cintia Almeida; Silva, Rafaela Maria Ribeiro da; Campos, Nathália Rodrigues de; Silva, Marye Agnes Renata; Doriguetto, Antonio Carlos; Flores, Leonã da Silva; Correa, Charlane Cimini; Simões, Tatiana Renata Gomes; Valdo, Ana Karoline Silva Mendanha; Martins, Felipe Terra
    Herein, we describe the synthesis, crystal structure, and electronic properties of {[K2(dmso)(H2O)5][Ni2(H2mpba)3]·dmso·2H2O}n (1) and [Ni(H2O)6][Ni2(H2mpba)3]·3CH3OH·4H2O (2) [dmso = dimethyl sulfoxide; CH3OH = methanol; and H4mpba = 1,3-phenylenebis(oxamic acid)] bearing the [Ni2(H2mpba)3]2− helicate, hereafter referred to as {NiII2}. SHAPE software calculations indicate that the coordination geometry of all the NiII atoms in 1 and 2 is a distorted octahedron (Oh) whereas the coordination environments for K1 and K2 atoms in 1 are Snub disphenoid J84 (D2d) and distorted octahedron (Oh), respectively. The {NiII2} helicate in 1 is connected by K+ counter cations yielding a 2D coordination network with sql topology. In contrast to 1, the electroneutrality of the triple-stranded [Ni2(H2mpba)3] 2− dinuclear motif in 2 is achieved by a [Ni(H2O)6]2+ complex cation, where the three neighboring {NiII2} units interact in a supramolecular fashion through four R22(10) homosynthons yielding a 2D array. Voltammetric measurements reveal that both compounds are redox active (with the NiII/NiI pair being mediated by OH– ions) but with differences in formal potentials that reflect changes in the energy levels of molecular orbitals. The NiII ions from the helicate and the counter-ion (complex cation) in 2 can be reversibly reduced, resulting in the highest faradaic current intensities. The redox reactions in 1 also occur in an alkaline medium but at higher formal potentials. The connection of the helicate with the K+ counter cation has an impact on the energy levels of the molecular orbitals; this experimental behavior was further supported by X-ray absorption near-edge spectroscopy (XANES) experiments and computational calculations.
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    2-(Pyridin-4yl)benzothiazole and Its benzimidazole-analogue: biophysical and in silico studies on their interaction with urease and in vitro anti-Helicobacter pylori activities
    (2022) Pereira, Camila de Paula; Lyra, Ana Carolina Fradique de; Oliveira, Breno Germano de Freitas; Nascimento, Igor José dos Santos; Silva Júnior, Edeildo Ferreira da; Aquino, Thiago Mendonça de; Sisto, Francesca; Figueiredo, Isis Martins; Martins, Felipe Terra; Modolo, Luzia Valentina; Santos, Josué Carinhanha Caldas; Fátima, Ângelo de
    In this study, the interaction between benzothiazole (BTA, concentration of a drug required for 50% inhibition in vitro (IC50) = 0.77 mM) and benzimidazole (BIA, IC50 = 2.14 mM) with urease was quantitatively assessed, using UV-Vis, molecular fluorescence, and circular dichroism. The results showed that both compounds interact with urease by a static fluorescence quenching mechanism with a non-fluorescent complex formation. The main forces responsible for stabilizing the supramolecular complex between BTA and urease were hydrophobic while, for BIA, van der Waals interactions and hydrogen bonds were the main ones. Urease conformation changes due to the interaction process were analyzed by circular dichroism and synchronous fluorescence. Besides, a competitive assay with substrate and inhibitors was used to evaluate the preferential urease site of interaction with BTA and BIA. Our experimental and theoretical studies supported that both, BTA and BIA, are mixed-inhibitors of ureases with a slight preference to the active site of such enzymes. Finally, both BTA and BIA showed to possess anti-Helicobacter pylori (one reference strain and six clinical isolates) activity, presenting minimal inhibitory concentration (MIC) values ranging from 38-150 and 20-164 µM, respectively. The urease inhibitors omeprazole and hydroxyurea showed MIC values in the range of 46-185 µM and 1683-> 3366 µM, respectively.
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    It takes two to tango, part II: synthesis of A-ring functionalised quinones containing two redox-active centres with antitumour activities
    (2023-02-27) Oliveira, Joyce Cristina de; Carvalho, Renato Lúcio de; Sampaio, Hugo Gustavo Silva; Araujo Neto, João Honorato de; Alcides Ellena, Javier; Martins, Felipe Terra; Pereira, João Victor de Melo; Costa, Pedro Mikael da Silva; Pessoa, Claudia do Ó; Ferreira, Rafaela Salgado
    In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango!
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    Synthesis, characterization, and structural determination of copper(II) complexes with alkyl derivatives of hydroxybenzophenones
    (2017) Gonçalves, Cristiane Batista; Marinho, Maria Vanda; Dias, Danielle Ferreira; Santos, Marcelo Henrique dos; Martins, Felipe Terra; Doriguetto, Antonio Carlos
    Four mononuclear copper(II) complexes, [Cu(LFQM-115)2] (1), [Cu(LFQM-116)2] (2), [Cu(LFQM-117)2] (3) and [Cu(octyloxy)2] (4) [LFQM-115 = 2-hydroxy-4-O-methylbenzophenone (C14H11O3), LFQM-116 = 2-hydroxy-4-O-butylbenzophenone (C17H18O3), LFQM-117 = 2-hydroxy-4-O-(33-dimethylallyl)benzophenone (C18H18O3) and octyloxy = 2-hydroxy-4-O-octylbenzophenone (C21H25O3)], have been prepared and investigated by infrared spectroscopy, thermal analysis, and powder and single crystal X-ray diffraction. Even though the synthesis and infrared analysis of 1, 2, and 4 have been reported previously, their crystal structures were elucidated for the first time here. In addition, the crystal structures of LFQM-116 and LFQM-117 were also determined by single crystal X-ray diffraction. The pseudo-translational symmetry found in LFQM-116 and the isomorphism between LFQM-115 and LFQM-117 are discussed. The complexes were prepared from a reaction of copper(II) nitrate trihydrate and the respective ligand in a (1:2) molar ratio in methanol (for 1 and 2) or THF (for 3 and 4) with addition of NaOH. Furthermore, crystallographic studies show that each copper(II) exhibits a square planar geometry, coordinated by four oxygens of two ligands. The nature and crystal packing of the intermolecular interactions are discussed. Compounds 2 and 3 are isomorphic crystals and all structures have the same supramolecular synthon.
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    Structural analysis of two tetraketones and theoretical investigation of the reactions involved in their preparation
    (2018) Silva, Milene Lopes da; Teixeira, Róbson Ricardo; Santos, Lucas de Azevedo; Martins, Felipe Terra; Ramalho, Teodorico de Castro
    The 2,2'-((5-(4-bromophenyl)furan-2-yl)methylene) bis (5,5-dimethylcyclohexane-1,3-dione) (3) and 2,2'-((5-(4-chlorophenyl)furan-2-yl)methylene) bis (5,5-dimethylcyclohexane-1,3-dione) (4) were prepared in, respectively, 63% and 59% yield, via ZrOCl2⋅8H2O catalyzed condensation reactions between dimedone and appropriate aldehydes. Their structures were investigated by IR, NMR, and X-ray spectroscopy techniques. The asymmetric unit of tetraketone 3 is composed of just one molecule, while two almost identical crystallographically independent molecules of compound 4 are present there. Compound 3 is conformationally similar to both molecules of 4. The diketone rings assume a half-chair conformation with the flaps oriented toward the same side of the substituent at C1. Each diketone ring is featured by an electronic delocalization path encompassed through the keto-enol moiety. All bond lengths inside this conjugated system are intermediate between those of pure double and single bonds. Furthermore, the furan plane of the substituent at C1 is almost parallel to the bond axes bridging the diketone rings as a consequence of steric hindrance effects between the heterocycle moiety and two hydrogen bonded oxygens. The enol forms of compounds 3 and 4 were noticed via IR and NMR spectroscopies. Furthermore, thermodynamics parameters were calculated in order to interpret the experimental results. In this line, theoretical findings reveal that electronic and solvent effects play an important role in the chemical reactions involved in the preparation of tetraketones.
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    Guest-driven unusual conformations in two calix[6]arene solvates and a new calix[8]arene
    (2018) Martins, Felipe Terra; Maia, Angélica Faleiros da Silva; Santos, Fernando Machado dos; Alvarenga, Meiry Edivirges; Ribeiro, Leandro; Silva Neto, Leonardo da; Fátima, Ângelo de
    Unusual conformations have been found in a new calix[8]arene and in new solvates of two known calix[6]arenes. The chair-like conformation with 2/m point group symmetry was found for the first time in the dimethylformamide (DMF) disolvate of the basic calix[6]arene (1) without substituents in the lower and upper rims. Such symmetry is driven by the guest geometry allowing for two equivalent hydrogen bonding patterns in the chair seat. This avoids cone distortion found in the other chair-like conformers, although they have energies lower than that of new symmetrical conformer. The molecular conformation of hexa(carboxymethoxy)calix[6]arene (2) is also described as a dimethylsulfoxide (DMSO) pentasolvate. Its conformation can be described as a 1,3,5-closed cone with three alternate phenyl rings inclined inwards to the cone, thereby closing the cone entrance. Such a conformation also suggests five acid groups are pointed towards the same side of the calyx base and are able to bind metal ions or basic compounds in the lower rim, while inclusion of guests into the cone cavity is hindered. Both inclusion and cooperative acid binding/coordination abilities are still more hindered in the lowest energy 1,2,3-alternate cone conformer of 2. The role of the solvent in avoiding cone distortion was highlighted by inspecting the conformations of 5,11,17,23,29,35,41,47-octanitro-49,50,51,52,53,54,55,56-octa-n-butoxycalix[8]arene (3) and the known nitro analogues having methyl instead of n-butyl groups. Cone distortion is found in the non-solvated crystal form of 3, while non-classical hydrogen bonds with tetrahydrofuran preclude this in the literature analogue.
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    Calix[n]arene-catalysed three-component Povarov reaction: microwave-assisted synthesis of julolidines and mechanistic insights
    (2018) Abranches, Paula Aline da Silva; Paiva, Walysson Ferreira de; Fátima, Ângelo de; Martins, Felipe Terra; Fernandes, Sergio Antonio
    A new one-pot cascade reaction-based application of Povarov reactions with a p-sulfonic acid calix[4]arene catalyst for the synthesis of a series of 34 julolidine derivatives with substituents at C8 or C9 in good to excellent yields is reported. These microwave-assisted reactions proceeded efficiently, had short reaction times, were metal-free, were low cost, and used an inexpensive, easily available and nontoxic catalyst. These advantages, along with a simple workup procedure, make this protocol a very efficient and green alternative to the traditional methods for constructing these types of N-heterocyclic skeletons. In addition, this protocol allows the formation of julolidine structures, which requires the construction of four new C–C bonds and two C–N bonds. A mechanism for the Povarov reaction involving a stepwise sequence via ionic intermediates was proposed and validated.