DEFAR - Artigos publicados em periódicos
URI permanente para esta coleçãohttp://www.hml.repositorio.ufop.br/handle/123456789/531
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Item Structure-activity relationship study of antitrypanosomal analogues of gibbilimbol B using multivariate analysis and computation-aided drug design.(2023) Leão, Luiz Paulo Melchior de Oliveira; Vieira, Nátalie de Barros; Oliveira, Paula P. S.; Paula, Daniela Aparecida Chagas de; Soares, Marisi Gomes; Souza, Thiago Belarmino de; Zanin, João Luiz Baldim; Silva, Thais Alves da Costa; Cardoso, André Gustavo Tempone; Dias, Danielle Ferreira; Lago, João Henrique GhilardiGibbilimbol B and analogues were isolated from the Brazilian plant Piper malacophyllum and displayed activity against trypomastigote forms of Trypanosoma cruzi as well as reduced toxicity against NCTC cells. These results stimulated the preparation of a series of 24 chemically related analogues to study the potential of these com- pounds against T. cruzi trypomastigotes and explore structure–activity relationships. Initially, 12 compounds were planned, maintaining the same extension of the linear side chain of gibbilimbol B and unsaturation on the C-4 position but changing the functional groups – ester and amide – and variating the substituent at the p-po- sition in the aromatic ring. Other 12 compounds were prepared using a branched side chain containing an ethyl group at the C-2 position. Overall, these structurally-related analogues demonstrated promising activity against trypomastigote forms (EC50 < 20 μM) and no mammalian cytotoxicity to fibroblasts (CC50 > 200 μM). Using multivariate statistics and machine learning analysis, aspects associated with structure/activity were related to their three-dimensional structure and, mainly, to the substituents on the aromatic ring. Obtained results sug- gested that the presence of t-butyl or nitro groups at p-position with appropriate side chains causes an alteration in the electron topological state, Van der Waals volumes, surface areas, and polarizabilities of tested compounds which seem to be essential for biological activity against T. cruzi parasites.Item Synthesis and antimicrobial activity of molecular hybrids based on eugenol and chloramphenicol pharmacophores.(2023) Oliveira, Lucas Martins; Siqueira, Fallon dos Santos; Silva, Michelle T.; Machado, José Vaz Cardoso; Cordeiro, Cleydson Finotti; Diniz, Lívia de Figueiredo; Campos, Marli Matiko Anraku de; Franco, Lucas Lopardi; Souza, Thiago Belarmino de; Hawkes, Jamie Anthony; Carvalho, Diogo TeixeiraIn the constant search for new pharmacological compounds, molecular hybridisation is a well-known technique whereby two or more known pharmacophoric subunits are combined to create a new “hybrid” compound. This hybrid is expected to maintain the characteristics of the original compounds whilst demonstrating improvements to their pharmacological action. Accordingly, we report here a series of molecular hybrid compounds based upon eugenol and chloramphenicol pharmacophores. The hybrid compounds were screened for their in vitro antimicrobial potential against Gram-negative and Gram-positive bacteria and also rapidly growing mycobacteria (RGM). The results highlight that the antimicrobial profiles of the hybrid compounds improve in a very clear fashion when moving through the series. The most prominent results were found when comparing the activity of the hybrid compounds against some of the multidrug-resistant clinical isolates of Pseudomonas aeruginosa, methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA) and clinical isolates of rapidly growing mycobacteria.Item In vitro and in silico evaluation of the schistosomicidal activity of eugenol derivatives using biochemical, molecular, and morphological tools.(2022) Souza, Isabella Maria Monteiro de; Novaes, Rômulo Dias; Gonçalves, Reggiani Vilela; Fialho, Felipe Leonardo Bley; Carvalho, Diogo Teixeira; Souza, Thiago Belarmino de; Dias, Danielle Ferreira; Lavorato, Stefânia Neiva; Souza, Raquel Lopes Martins; Marques, Marcos José; Castro, Aline PereiraBackground: Eugenol shows both antibacterial and antiparasitic activities, suggesting that it might be evaluated as an option for the treatment of praziquantel-resistant schistosome. Methods: The in vitro activities of three eugenol derivatives (FB1, FB4 and FB9) on adult worms from Schistosoma mansoni were examined by fluorescence and scanning electron microscopy to analyze effects on the excretory system and integument damage, respectively. Biochemical tests with verapamil (a calcium channel antagonist) and ouabain (a Na+ /K+-ATPase pump inhibitor) were used to characterize eugenol derivative interactions with calcium channels and the Na+/K+-ATPase, while in silico analysis identified potential Na+/K+-ATPase binding sites. Results: The compounds showed effective doses (ED50) of 0.324 mM (FB1), 0.167 mM (FB4), and 0.340 mM (FB9). In addition, FB4 (0.322 mM), which showed the lowest ED50, ED90 and ED100 (p < 0.05), caused the most damage to the excretory system and integument, according to both fluorescence and scanning electron microscopy analysis. The death of adult worms was delayed by ouabain treatment plus FB1 (192 versus 72 hours) and FB9 (192 versus 168 hours), but the response to FB4 was the same in the presence or absence of ouabain. Besides, no changes were noted when all of the eugenol derivatives were combined with verapamil. Moreover, FB1 and FB9 inhibited Na+/K+-ATPase activity according to in silico analysis but FB4 did not show a time- dependent relationship and may act on targets other than the parasite Na+/K+-ATPase. Conclusion: Eugenol derivatives, mainly FB4 when compared to FB1 and FB9, seem to act more effectively on the integument of adult S. mansoni worms.Item New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis.(2023) Péret, Vinícius Augusto Campos; Reis, Rúbia Castro Fernandes Melo; Braga, Saulo Fehelberg Pinto; Benedetti, Monique Dias; Caldas, Ivo Santana; Carvalho, Diogo Teixeira; Santana, Luiz Felipe de Andrade; Johann, Susana; Souza, Thiago Belarmino deThis work describes the design, synthesis and antifungal activity of new imidazoles and 1,2,4-triazoles derived from eugenol and dihydroeugenol. These new compounds were fully characterized by spectroscopy/spectro- metric analyses and the imidazoles 9, 10, 13 e 14 showed relevant antifungal activity against Candida sp. and Cryptococcus gattii in the range of 4.6–75.3 μM. Although no compound has shown a broad spectrum of antifungal activity against all evaluated strains, some azoles were more active than either reference drugs employed against specific strains. Eugenol-imidazole 13 was the most promising azole (MIC: 4.6 μM) against Candida albicans being 32 times more potent than miconazole (MIC: 150.2 μM) with no relevant cytotoxicity (selectivity index >28). Notably, dihydroeugenol-imidazole 14 was twice as potent (MIC: 36.4 μM) as miconazole (MIC: 74.9 μM) and more than 5 times more active than fluconazole (MIC: 209.0 μM) against alarming multi-resistant Candida auris. Furthermore, in vitro assays showed that most active compounds 10 and 13 altered the fungal ergosterol biosynthesis, reducing its content as fluconazole does, suggesting the enzyme lanosterol 14α-demethylase (CYP51) as a possible target for these new compounds. Docking studies with CYP51 revealed an interaction between the imidazole ring of the active substances with the heme group, as well as insertion of the chlorinated ring into a hydrophobic cavity at the binding site, consistent with the behavior observed with control drugs miconazole and fluconazole. The increase of azoles-resistant isolates of Candida species and the impact that C. auris has had on hospitals around the world reinforces the importance of discovery of azoles 9, 10, 13 e 14 as new bioactive compounds for further chemical optimization to afford new clinically antifungal agents.Item Synthesis, trypanocidal and cytotoxic activities of α,β-unsaturated ketones derived from eugenol and analogues.(2022) Reis, Rúbia Castro Fernandes Melo; Reis, Adriana Cotta Cardoso; Torchelsen, Fernanda Karoline Vieira da Silva; Lana, Marta de; Sales Júnior, Policarpo Ademar; Brandão, Geraldo Célio; Braga, Saulo Fehelberg Pinto; Souza, Thiago Belarmino deThis work describes the synthesis, structural characterization, trypanocide and cytotoxic evaluation of α,β-unsaturated ketones derived from eugenol and analogues. Among the synthesized compounds, the cyclopentanonic/dihydroeugenol derivative 12 was active against amastigote forms of Trypanosoma cruzi at 5.2 nM (700 times more potent than benznidazole) and represents a potential hit for future structural optimizations to reduce its toxicity. All the compounds were also evaluated against a healthy human and four cancer cell lines and the derivative 10 was more active than doxorubicin against three cancer cells (IC50 values between 2.03–23.51 μM) and showed the higher selectivity index considering the human cells. Derivative 14 was also more potent and selective than doxorubicin against two cancer cells (IC50 values between 4.71–8.86 μM).Item Benzophenone derivatives showed dual anti-inflammatory and antiproliferative activities by inhibiting cox enzymes and promote cyclin e downregulation.(2022) Folquitto, Laís Regina dos Santos; Souza, Thiago Belarmino de; Januário, Jaqueline Pereira; Nascimento, Isadora M.; Brandão, Brenda Tavares de Vasconcelos; Moreira, Maria E. C.; Horvath, Renato de Oliveira; Santos, Marcelo Henrique dos; Coelho, Luiz Felipe Leomil; Veloso, Marcia Paranho; Soares, Marisi Gomes; Carvalho, Diogo Teixeira; Ionta, Marisa; Paula, Daniela Aparecida Chagas de; Dias, Danielle FerreiraConsidering the promising antitumor effects of compounds with dual anti-inflammatory and antiproliferative activities, thus benzophenones analogs (2-7) were evaluated on in vivo anti- inflammatory assay and molecular docking analysis. Those with the best molecular docking results were in vitro evaluated on cyclooxygenase (COX) enzymes and tested regarding antiproliferative activity. All derivatives displayed in vivo anti-inflammatory activity. Among them, the substances 2’-hydroxy-4’-benzoylphenyl-β-D-glucopyranoside (4), 4-hydroxy-4’-methoxybenzophenone (5) and 4’-(4’’-methoxybenzoyl)phenyl-β-D-glucopyranoside (7)showed the best values of Glide Score in COX-2 docking evaluation and 4 and 5 selectively inhibited COX-2 and COX-1 in vitro enzymatic assay, respectively. Thus, 4 and 5 were tested against breast cancer (MCF-7, MDA-MB-231, Hs578T) and non-small-cell-lung cancer (A549) cell lines. The estrogen-positive MCF-7 cell line was more responsive compared to other tested cell lines. They induced cell cycle arrest at G1/S transition in MCF-7 cell line once there was an increase in G0/G1 population with concomitant reduction of S population. The antiproliferative activity of these substances on MCF-7 was associated with their ability to inhibit cyclin E expression, a critical regulator of G1/S transition. Taken together, the data indicate that 4 and 5 have dual anti-inflammatory and antiproliferative activities and support further studies to evaluate their antitumor potential.Item Glucosyl-1,2,3-triazoles derived from eugenol and analogues : synthesis, anti-Candida activity, and molecular modeling studies in CYP-51.(2021) Magalhães, Lorena Severiano de; Reis, Adriana Cotta Cardoso; Nakao, Izadora Amaral; Péret, Vinícius Augusto Campos; Reis, Rúbia Castro Fernandes Melo; Silva, Naiara Chaves; Dias, Amanda Latercia Tranches; Carvalho, Diogo Teixeira; Dias, Danielle Ferreira; Brandão, Geraldo Célio; Braga, Saulo Fehelberg Pinto; Souza, Thiago Belarmino deThis work describes the synthesis, anti-Candida, and molecular modeling stud- ies of eighteen new glucosyl-1,2,3-triazoles derived from eugenol and corre- lated phenols. The new compounds were characterized by combined Fourier Transform Infrared, 1 H and 13C nuclear magnetic resonance and spectroscopy of high-resolution mass spectrometry. The synthesized compounds did not show significant cytotoxicity against healthy fibroblast human cells (MCR-5) providing interesting selectivity indexes (SI) to active compounds. Considering the antifun- gal activity, nine compounds showed anti-Candida potential and the peracety- lated triazoles 17 and 18 were the most promising ones. Eugenol derivative 17 was active against three species of Candida at 26.1–52.1 μM. This compound was four times more potent than fluconazole against Candida krusei and less toxic (SI > 6.6) against the MCR-5 cells than fluconazole (SI > 3.3) considering this strain. Dihydroeugenol derivative 18 showed similar activity to 17 and was four times more potent and less toxic than fluconazole against C. krusei. The deacety- lated glucosides and non-glucosylated corresponding derivatives did not show considerable antifungal action, suggesting that the acetyl groups are essential for their anti-Candida activity. Molecular docking coupled with molecular dynam- ics showed that 14α-lanosterol demethylase is a feasible molecular target, since 17 and 18 could bind to this enzyme once deacetylated in vivo, thereby acting as prodrugs. Also, these studies demonstrated the importance of hydrophobic sub- stituents at the phenyl ring.Item A mixture of trehalose derivatives mitigates the adverse effects of water deficits in maize : an analysis of photosynthetic efficiency.(2020) Ambrósio, Alexandra dos Santos; Portugal, J. A. N.; Souza, K. R. D.; Silva, L. C.; Dias, Danielle Ferreira; Mantovani, J. R.; Magalhães, P. C.; Souza, Thiago Belarmino de; Souza, T. C.This study tested a tosylated and azide trehalose derivative mixture for its ability to mitigate water deficit-induced stress in maize via photosynthetic efficiency analyses. The experiment was conducted in greenhouse pots, using a maize hybrid that is sensitive to drought. The mixture of derivatives (28 mM) was applied with a hand sprayer. Plants containing five/six fully expanded leaves were subjected to water deficit stress for 12 d, followed by rehydration. The derivative mixture increased the photosynthetic rate, electron transport rate, and photochemical quenching, and mitigated damage to photosystem II. Moreover, it led to anatomical modifications in the leaf that increased the photosynthetic rate. These results suggest that the trehalose derivative mixture mitigates stress-induced damage in the maize hybrid and may represent a new stimulant for water-deficit tolerance.Item Synthesis of novel papulacandin D analogs and evaluation of their antifungal potential.(2020) Bretas, Ana Carolina Oliveira; Souza, Thiago Belarmino de; Borelli, Beatriz; Johan, Suzana; Alves, Ricardo JoséSystemic fungal infections are a growing problem in contemporary medicine and few drugs are licensed for therapy of invasive fungal infections. Differences between fungi and humans, like the presence of a cell wall in fungal cells, can be explored for designing new drugs. (1,3)-β-D-glucan synthase, an enzyme that catalyzes the synthesis of (1,3)-β-D-glucan, a structural and essential component of the fungal cell wall, is absent in mammals and this makes it an excellent target for the development of new antifungal agents. Papulacandins are a family of natural antifungal agents targeting (1,3)-β-D-glucan synthase. In this study we describe the synthesis and biological evaluation of two new Papulacandin analogs as potential (1,3)-β-D-glucan synthase inhibitors.Item Synthesis of eugenol-derived glucosides and evaluation of their ability in inhibiting the angiotensin converting enzyme.(2020) Alvarenga, Dalila Junqueira; Matias, Laira Maria Faria; Cordeiro, Cleydson Finotti; Souza, Thiago Belarmino de; Lavorato, Stefânia Neiva; Pereira, Marília Gabriella Alves Goulart; Dias, Danielle Ferreira; Carvalho, Diogo TeixeiraWe report here a series of glucosides which are active as inhibi tors of the angiotensin converting enzyme (ACE). They are struc turally related to the natural compound eugenol and exhibited significant inhibition values. Their syntheses were expeditious and we could obtain informative docking plots of them complexed to this enzyme. A glucoside derived from eugenol, carrying a carbox ylic group in the aglycone, was the most active of them (with an IC50 of 0.4 mM) and showed good binding energies in docking studies with ACE. Moreover, computational prediction of toxicity risks, physicochemical properties and drug score show that the glucoside derivative of eugenol is a suitable compound for opti misation studies aimed at finding new drug candidates.