CAMILLA DJENNE BUARQUE MULLER
@puc-rio.br
Departament of Chemistry
Pontifícia Universidade Católica do Rio de Janeiro
RESEARCH INTERESTS
Synthetic Organic Chemistry ·
Heterocyclic Chemistry
Medicinal Chemistry
Scopus Publications
Scopus Publications
Filipa Ferreira, Camilla Buarque, and Miquéias Lopes-Pacheco
MDPI AG
The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators—small molecules acting on the basic molecular defect in CF—have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA’s) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.
Jhonny M. C. Cifuentes, Fábio J. F. S. Henrique, Carolina B. P. Ligiéro, Pierre M. Esteves, and Camilla D. Buarque
Wiley
AbstractThis work demonstrates the oxidative cross‐coupling of cinnamic acids with toluene using FeCl3 immobilized on a covalent organic framework (COF) pore wall, resulting in the synthesis of 1,3‐arylpropene derivatives. This iron‐based heterogeneous catalytic system affords the desired products in moderate yields ranging from 51 % to 65 %. Investigations using COFs with varying pore sizes indicate that larger pores facilitate the reaction, suggesting a spatial requirement for this transformation within the catalyst. The correlation between pore size and reaction efficiency provides insights into developing tailored catalysts to match the spatial requirements of the transformation. This version emphasizes the novelty of the study and the synthesis of 1,3‐arylpropene derivatives. It also clarifies that the iron‐based heterogeneous catalytic system is responsible for the reaction. Additionally, it provides a more detailed explanation of the findings regarding pore size and spatial requirements.
Vitor Won-Held Rabelo, Verônica Diniz da Silva, Maria Leonisa Sanchez Nuñez, Leonardo dos Santos Corrêa Amorim, Camilla Djenne Buarque, Richard J Kuhn, Paula Alvarez Abreu, and Izabel Christina Nunes de Palmer Paixão
Future Medicine Ltd
Aim: This work aimed to investigate the antiviral activity of two 1,4-disubstituted-1,2,3-triazole derivatives (1 and 2) against Chikungunya virus (CHIKV) replication. Materials & methods: Cytotoxicity was analyzed using colorimetric assays and the antiviral potential was evaluated using plaque assays and computational tools. Results: Compound 2 showed antiviral activity against CHIKV 181-25 in BHK-21 and Vero cells. Also, this compound presented a higher activity against CHIKV BRA/RJ/18 in Vero cells, like compound 1. Compound 2 exhibited virucidal activity and inhibited virus entry while compound 1 inhibited virus release. Molecular docking suggested that these derivatives inhibit nsP1 protein while compound 1 may also target capsid protein. Conclusion: Both compounds exhibit promising antiviral activity against CHIKV by blocking different steps of virus replication.
Henrique V. P. Hollauer, Rachel C. Vilas Novas, Guilherme P. Guedes, Camilla D. Buarque, and Lívia B. L. Escobar
International Union of Crystallography (IUCr)
Methyl 2-(2-oxo-2H-chromen-4-ylamino)benzoate, C17H13NO4 (1), was prepared by condensation between 4-hydroxycoumarin and methyl 2-aminobenzoate. It crystallizes in the orthorhombic space group Pca21 at 300 K. The molecule of compound 1 consists of the 2H-chromen-2-one part connected by an amine moiety (–NH–) to the methyl benzoate ring. The supramolecular array is formed by hydrogen bonds between the aromatic ring and the O atoms of the lactone and ester portions. The structural details match the spectroscopic data acquired from NMR and IR spectroscopy.
V.D. da Silva, K. Zalewska, Z. Petrovski, C.D. Buarque, L.C. Branco, and P.M. Esteves
Elsevier BV
Mafalda Bacalhau, Filipa C. Ferreira, Arthur Kmit, Felipe R. Souza, Verônica D. da Silva, André S. Pimentel, Margarida D. Amaral, Camilla D. Buarque, and Miquéias Lopes-Pacheco
Elsevier BV
Mafalda Bacalhau, Filipa C. Ferreira, Iris A. L. Silva, Camilla D. Buarque, Margarida D. Amaral, and Miquéias Lopes-Pacheco
MDPI AG
The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose–response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity.
C.B.P. Ligiero, T.S. Fernandes, D.L. D'Amato, F.V. Gaspar, P.S. Duarte, M.A. Strauch, J.G. Fonseca, L.G.R. Meirelles, P. Bento da Silva, R.B. Azevedo,et al.
Elsevier BV
Francisco V. Gaspar, Marcelo F.M.F. Azevedo, Leonardo S.A. Carneiro, Samuel B. Ribeiro, Pierre M. Esteves, and Camilla D. Buarque
Elsevier BV
Fernando Almeida-Souza, Verônica Diniz da Silva, Noemi Nosomi Taniwaki, Daiana de Jesus Hardoim, Ailésio Rocha Mendonça Filho, Wendel Fragoso de Freitas Moreira, Camilla Djenne Buarque, Kátia da Silva Calabrese, and Ana Lucia Abreu-Silva
American Chemical Society (ACS)
1,2,3-Triazole is one of the most flexible chemical scaffolds broadly used in various fields. Here, we report the antileishmanial activity of 1,2,3-triazole derivatives, the ultrastructural alterations induced by their treatment, and the nitric oxide (NO) modulation effect on their efficacy against Leishmania amazonensis in vitro infection. After the screening of eleven compounds, compound 4 exhibited better results against L. amazonensis promastigotes (IC50 = 15.52 ± 3.782 μM) and intracellular amastigotes (IC50 = 4.10 ± 1.136 μM), 50% cytotoxicity concentration at 84.01 ± 3.064 μM against BALB/c peritoneal macrophages, and 20.49-fold selectivity for the parasite over the cells. Compound 4 induced ultrastructural mitochondrial alterations and lipid inclusions in L. amazonensis promastigotes, upregulated tumor necrosis factor α, interleukin (IL)-1β, IL-6, IL-12, and IL-10 messenger RNA expressions, and enhanced the NO production, verified by nitrite (p = 0.0095) and inducible nitric oxide synthase expression (p = 0.0049) quantification, which played an important role in its activity against intramacrophagic L. amazonensis. In silico prediction in association with antileishmanial activity results showed compound 4 as a hit compound with promising potential for further studies of new leishmaniasis treatment options.
Leonardo S.A. Carneiro, Fernando Almeida-Souza, Yanne S.C. Lopes, Rachel C.V. Novas, Kaique B.A. Santos, Carolina B.P. Ligiero, Kátia da S. Calabrese, and Camilla D. Buarque
Elsevier BV
Daiane J Viegas, Verônica D da Silva, Camilla D Buarque, David C Bloom, and Paula A Abreu
SAGE Publications
Background Herpes simplex virus 1 (HSV-1) affects a large part of the adult population. Anti-HSV-1 drugs, such as acyclovir, target thymidine kinase and viral DNA polymerase. However, the emerging of resistance of HSV-1 alerts for the urgency in developing new antivirals with other therapeutic targets. Thus, this study evaluated a series of 1,4-disubstituted-1,2,3-triazole derivatives against HSV-1 acute infection and provided deeper insights into the possible mechanisms of action. Methods Human fibroblast cells (HFL-1) were infected with HSV-1 17 syn+ and treated with the triazole compounds at 50 μM for 24 h. The 50% effective drug concentration (EC50) was determined for the active compounds. Their cytotoxicity was also evaluated in HFL-1 with the 50% cytotoxic concentration (CC50) determined using CellTiter-Glo® solution. The most promising compounds were evaluated by virucidal activity and influence on virus egress, DNA replication and transcription, and effect on an acyclovir-resistant HSV-1 strain. Results Compounds 3 ( (E)-4-methyl-N′-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol1yl)benzylidene)benzenesulfonohydrazide) and 4 ( 2,2′-(4,4′-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1 diyl)) dibenzaldehyde) were the most promising, with an EC50 of 16 and 21 μM and CC50 of 285 and 2,593 μM, respectively. Compound 3 was able to inhibit acyclovir-resistant strain replication and to interfere with virus egress. Both compounds did not affect viral DNA replication, but inhibited significantly the expression of ICP0, ICP4 and gC. Compound 4 also affected the transcription of UL30 and ICP34.5. Conclusions Our findings demonstrated that these compounds are promising antiviral candidates with different mechanisms of action from acyclovir and further studies are merited.
Leonardo Carneiro, Leticia Real, Camilla Buarque, and Pierre Esteves
Sociedade Brasileira de Quimica (SBQ)
Arylation reactions are an important class of reactions and allow the synthesis of natural and synthetic products. Despite the efficient, but high cost and toxic methodologies involving transition metals, radical arylations have gained importance after the advent of photoredox catalysis. Arylation of enol acetates is an important tool for obtaining aryl ketones but the scope of the reaction is limited to the pattern of substitution at phenyl radical and α-carbon of the enol. Theoretical calculations ((U)BHandHLYP/6-311G**) show that the polar effect is the key factor in this reaction. A good correlation of calculated rate constants with field effect explained why phenyl radicals with electronwithdrawing groups react faster toward enol acetate. The presence of alkyl groups at α carbon at the enol showed some influence of enthalpic effect but strong influence of steric effect, evidenced by great correlations with Taft and Charton parameters. Finally, substitution at β carbon showed no significant effect at reaction rates.
Francisco Vilaça Gaspar, Joseane Alves Mendes, Paulo Roberto Ribeiro Costa, Miguel Yus, Francisco Foubelo, and Camilla Djenne Buarque
BENTHAM SCIENCE PUBLISHERS
Joseane A Mendes, Paulo R R Costa, Miguel Yus, Francisco Foubelo, and Camilla D Buarque
Beilstein Institut
The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format.
Renata Avena Maia, Leonardo Simões de Abreu Carneiro, Jhonny Mauricio Cerón Cifuentes, Camilla Djenne Buarque, Pierre Mothé Esteves, and Ana Maria Percebom
International Union of Crystallography (IUCr)
Small-angle X-ray scattering (SAXS) is an accurate nondestructive method that requires a minimum of sample preparation and is employed to study porosity, morphology and hierarchical structures. Zeolites and silica are among the porous materials that are widely investigated by SAXS. However, studies of covalent organic frameworks (COFs) are still scarce. In the present study, SAXS was employed to investigate meso- and microporous COFs, affording insightful information about their nanostructure textural properties. SAXS is especially useful when combined with other characterization techniques, such as powder X-ray diffraction and N2 adsorption isotherms, emerging as an efficient tool to further characterize COFs. For microporous COFs, SAXS was used mainly to obtain quantitative values of surface roughness as a function of fractal parameters, in all cases indicating surface fractals of the large-scale scattering object, namely the `grain'. Mesoporous COF studies allowed elucidation of their hexagonal structure on the basis of their structure peaks; however, the main result lies in the distinction between the pore and the grain, which are described as a hierarchical structure by the Beaucage model and evaluated according to their fractality. These COFs generally exhibit pores with mass fractal features and grains with surface fractal features when they are submitted to post-functionalization, which may be due to the poor diffusivity of the functionalizing agents into the pores. In addition, a proposed aggregation description of the porous scattering objects was envisioned, based on small-angle scattering premises, which was confirmed for a microporous COF by high-resolution transmission electron microscopy.
Fernando Almeida-Souza, Verônica Diniz da Silva, Gabriel Xavier Silva, Noemi Nosomi Taniwaki, Daiana de Jesus Hardoim, Camilla Djenne Buarque, Ana Lucia Abreu-Silva, and Kátia da Silva Calabrese
MDPI AG
The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.
Veronica da Silva, Rafaela Silva, João Gonçalves Neto, Beatriz López‑Corcuera, Marilia Guimarães, François Noël, and Camilla Buarque
Sociedade Brasileira de Quimica (SBQ)
Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhibitors aiming the discovery of new hits with activity in cognitive disorders. 1,4-Disubstituted α-hydroxy-1,2,3-triazoles were obtained as racemates in moderate to good yields by the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction (click chemistry) as the key step between propargyl alcohols and aryl azides, previously prepared from anilines or boronic acids. Benzo[c]chromene-triazoles were planned to be obtained by palladium-catalyzed C−H activation using [bis(trifluoroacetoxy)iodobenzene] (PhI(TFA)2) of some α-hydroxy-1,2,3-triazoles, since benzo[c]chromenes are also privileged groups with several biological activities, including to the central nervous system. Unexpectedly, 9H-fluorenes-1,2,3-triazoles, instead of benzo[c]chromenetriazoles, were obtained by Friedel-Crafts alkylation reaction. The two series of compounds were tested for inhibition of the glycine transporter (rat GlyT1 isoform) but only the α-hydroxy1,2,3-triazole 9b was active (half maximal inhibitory concentration (IC50) = 8.0 μM).
Lauana Greicy Tonon Lemos, Gabriel Mello da Cunha Longo, Bruna dos Santos Mendonça, Marcela Cristina Robaina, Mariana Concentino Menezes Brum, Caíque de Assis Cirilo, Etel Rodrigues Pereira Gimba, Paulo Roberto Ribeiro Costa, Camilla Djenne Buarque, Gabriela Nestal de Moraes,et al.
MDPI AG
Drug resistance represents a major issue in treating breast cancer, despite the identification of novel therapeutic strategies, biomarkers, and subgroups. We have previously identified the LQB-223, 11a-N-Tosyl-5-deoxi-pterocarpan, as a promising compound in sensitizing doxorubicin-resistant breast cancer cells, with little toxicity to non-neoplastic cells. Here, we investigated the mechanisms underlying LQB-223 antitumor effects in 2D and 3D models of breast cancer. MCF-7 and MDA-MB-231 cells had migration and motility profile assessed by wound-healing and phagokinetic track motility assays, respectively. Cytotoxicity in 3D conformation was evaluated by measuring spheroid size and performing acid phosphatase and gelatin migration assays. Protein expression was analyzed by immunoblotting. Our results show that LQB-223, but not doxorubicin treatment, suppressed the migratory and motility capacity of breast cancer cells. In 3D conformation, LQB-223 remarkably decreased cell viability, as well as reduced 3D culture size and migration. Mechanistically, LQB-223-mediated anticancer effects involved decreased proteins levels of XIAP, c-IAP1, and Mcl-1 chemoresistance-related proteins, but not survivin. Survivin knockdown partially potentiated LQB-223-induced cytotoxicity. Additionally, cell treatment with LQB-223 resulted in changes in the mRNA levels of epithelial-mesenchymal transition markers, suggesting that it might modulate cell plasticity. Our data demonstrate that LQB-223 impairs 3D culture growth and migration in 2D and 3D models of breast cancer exhibiting different phenotypes.
Veronica D. da Silva, Bruna M. de Faria, Eduardo Colombo, Lucas Ascari, Gabriella P.A. Freitas, Leonã S. Flores, Yraima Cordeiro, Luciana Romão, and Camilla D. Buarque
Elsevier BV
Joseane A. Mendes, Pedro Merino, Tatiana Soler, Eduardo J. Salustiano, Paulo R. R. Costa, Miguel Yus, Francisco Foubelo, and Camilla D. Buarque
American Chemical Society (ACS)
The addition of 2-bromobenzylmagnesium bromide to chiral N- tert-butanesulfinyl imines derived from tetralone-type ketones proceeds with high levels of diastereocontrol. The resulting sulfinamide derivatives were transformed into dibenzoazaspiro compounds after a palladium-catalyzed intramolecular N-arylation. DFT calculations have been performed to rationalize the stereochemical course of the reaction. Similar results have been obtained considering either diethyl ether or toluene as a solvent, in both cases in an excellent agreement with experimental findings. NCI topological calculations have also been used to evidence crucial noncovalent interactions. In addition, the azaspiro compounds reduced the viability of chronic myeloid leukemia cells in the micromolar range. Notably, both the halogen-substituted ( R)- and ( S)-8g and -8h as well as ( R)-8j were at least two times more effective on a multidrug-resistant derivative than on the parental cell line, exerting a collateral sensitivity effect.
Druval Santos de Sá, Rodrigo de Andrade Bustamante, Carlos Eduardo Rodrigues Rocha, Verônica Diniz da Silva, Elton Jorge da Rocha Rodrigues, Camilla Djenne Buarque Müller, Khosrow Ghavami, Alessandro Massi, and Omar Ginoble Pandoli
American Chemical Society (ACS)
The fabrication of a new copper-functionalized lignocellulosic microreactor (Cu-LμR) from bamboo culms is herein described together with its operation to perform a copper(I)-catalyzed 1,3-dipolar cycloaddition between azide and terminal alkyne (CuAAC). The bio-microfluidic device showed an easy prototyping and fast functionalization with copper ions. All reactions were carried out in flow regime with aqueous-methanol solvent and minimal leaching of copper, yielding a series of model 1,4-disubstitued triazole derivatives with good efficiency in a low-resource setting.
Rafaela da Costa, Francisco Farias, Luis Maqueira, Carlos Castanho Neto, Leonardo Carneiro, Joseany Almeida, Camilla Buarque, Ricardo Aucélio, and Jones Limberger
Sociedade Brasileira de Quimica (SBQ)
A series of triphenylamino (TPA)-chalcones and triphenylamino-β-arylchalcones, displaying either D-π-D or D-π-A architecture, were synthesized through aldol condensations and Heck reactions. The chalcone derivatives display intense absorption bands ranging from 389 to 432 nm and molar extinction coefficients of ca. 10 L mol cm corresponding to π-π* electronic transitions. The photoluminescence emissions are peaked between 470 and 563 nm with large Stokes shifts (80-131 nm), attributed to charge transfer in the excited state. The dyes present low fluorescence quantum yields, which is attributed to radiationless excited state deactivation related to aryl rings rotation. Spectroscopic and electrochemical methods were used to determine the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels. Both optical and electrochemical properties of the TPA-chalcone derivatives are considerably affected by the substitution pattern of the chalcones aryl rings and also by the β-arylation of the olefin moiety.
Joseane A. Mendes, Eduardo J. Salustiano, Carulini de S. Pires, Thaís Oliveira, Julio C.F. Barcellos, Jhonny M.C. Cifuentes, Paulo R.R. Costa, Magdalena N. Rennó, and Camilla D. Buarque
Elsevier BV
Jhonny M. C. Cifuentes, Bruno X. Ferreira, Pierre M. Esteves, and Camilla D. Buarque
Springer Science and Business Media LLC