Publications by authors named "Thiago Belarmino de Souza"

12 Publications

  • Page 1 of 1

Glucosyl-1,2,3-triazoles derived from eugenol and analogues: Synthesis, anti-Candida activity, and molecular modeling studies in CYP-51.

Chem Biol Drug Des 2021 Sep 4. Epub 2021 Sep 4.

School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Brazil.

This work describes the synthesis, anti-Candida, and molecular modeling studies of eighteen new glucosyl-1,2,3-triazoles derived from eugenol and correlated phenols. The new compounds were characterized by combined Fourier Transform Infrared, H and C 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 antifungal activity, nine compounds showed anti-Candida potential and the peracetylated 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 deacetylated 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 dynamics 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 substituents at the phenyl ring.
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http://dx.doi.org/10.1111/cbdd.13948DOI Listing
September 2021

Design, Synthesis, Antimicrobial Evaluation and in Silico Studies of Eugenol-Sulfonamide Hybrids.

Chem Biodivers 2021 May 7;18(5):e2100066. Epub 2021 Apr 7.

Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, Alfenas, 37130-001, MG, Brazil.

Using molecular hybridization, specific sulfonamide derivatives of eugenol were synthesized with subtle modifications in the allylic chain of the eugenol subunit (and also in the nature of the substituent group in the sulfonamide aromatic ring) which allowed us to study the influence of structural changes on the antimicrobial potential of the hybrids. Antimicrobial test results showed that most of the synthesized hybrid compounds showed good activity with better results than the parent compounds. Molecular docking studies of the hybrids with the essential bacterial enzyme DHPS showed complexes with low binding energies, suggesting that DHPS could be a possible target for the antibacterial sulfonamide-eugenol hybrids. Furthermore, most of the final compounds presented similar docking poses to that of the crystallographic ligand sulfamethoxazole. The results obtained allow us to conclude that these are promising compounds for use as new leads in the search for new antibacterial sulfonamides.
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http://dx.doi.org/10.1002/cbdv.202100066DOI Listing
May 2021

Synthesis of eugenol-derived glucosides and evaluation of their ability in inhibiting the angiotensin converting enzyme.

Nat Prod Res 2020 Oct 9:1-8. Epub 2020 Oct 9.

Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Alfenas, MG, Brazil.

We report here a series of glucosides which are active as inhibitors of the angiotensin converting enzyme (ACE). They are structurally 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 carboxylic group in the aglycone, was the most active of them (with an IC 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 optimisation studies aimed at finding new drug candidates.
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http://dx.doi.org/10.1080/14786419.2020.1827399DOI Listing
October 2020

Synthesis, activity, and molecular modeling studies of 1,2,3-triazole derivatives from natural phenylpropanoids as new trypanocidal agents.

Chem Biol Drug Des 2020 01 20;95(1):124-129. Epub 2019 Oct 20.

Instituto de Química, Universidade Federal de Alfenas, Alfenas, Brazil.

The search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3-triazoles obtained from eugenol and di-hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three-step objective route and were suitably characterized by H and C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Two compounds (9 and 10) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8-88.4 μM and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100-mg/kg oral treatment of mice infected with T. cruzi. Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds.
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http://dx.doi.org/10.1111/cbdd.13628DOI Listing
January 2020

Phenylpropanoid-based sulfonamide promotes cyclin D1 and cyclin E down-regulation and induces cell cycle arrest at G1/S transition in estrogen positive MCF-7 cell line.

Toxicol In Vitro 2019 Sep 22;59:150-160. Epub 2019 Apr 22.

LQFar - Laboratory of Research in Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Federal University of Alfenas, 37130-001 Alfenas, MG, Brazil. Electronic address:

Cancer is one of the most critical problems of public health in the world and one of the main challenges for medicine. Different biological effects have been reported for sulfonamide-based compounds including antibacterial, antifungal, and antitumor activities. Herein, a series of phenylpropanoid-based sulfonamides (4a, 4a', 4b, 4b', 5a, 5a', 5b and 5b') were synthesized and their cytotoxic activity was evaluated against four cell lines derived from human tumours (A549 - lung, MCF-7 - breast, Hep G2 - hepatocellular carcinoma, and HT-144-melanoma). Cell viability was significantly reduced in the MCF-7 cell line when compounds 4b, 4b' and 5a were used; IC values were lower than those found for their precursors (eugenol and dihydroeugenol) and sulfanilamide. We observed that 4b induced cell cycle arrest at G1/S transition. This is probably due to its ability to reduce cyclin D1 and cyclin E expression. Moreover, 4b also induced apoptosis in MCF-7 cells as demonstrated by an increase in the cell population positive for annexin V in treated cultures in comparison to the control group. Taken together, the data showed that 4b is a promising antitumor agent and it should be considered for further in vivo studies.
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http://dx.doi.org/10.1016/j.tiv.2019.04.023DOI Listing
September 2019

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.

Redox Biol 2019 01 12;20:182-194. Epub 2018 Oct 12.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador, Bahia, Brazil. Electronic address:

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)(PPh)]PF (where, PIP-OH = piplartine demethylated derivative; and PPh = 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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http://dx.doi.org/10.1016/j.redox.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198128PMC
January 2019

Synthesis, activity, and docking studies of eugenol-based glucosides as new agents against Candida sp.

Chem Biol Drug Des 2018 08 18;92(2):1514-1524. Epub 2018 May 18.

Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Alfenas, MG, Brazil.

Seventeen new synthetic derivatives of eugenol (6, 8-15 and 8'-15') were planned following literature reports on antifungal activities of nitroeugenol and eugenol glucoside. The anti-Candida activity of these compounds was investigated by in vitro assay, and the cytotoxicity evaluation was performed with the most active compounds. The peracetylated glucosides presented better biological results than their hydroxylated analogues. The glucoside 11, a 4-nitrobenzamide, showed the best potency (MIC range 11.0-151.84 μm), the wider spectrum of action, and overall the best selectivity indexes, especially against C. tropicalis (~30) and C. krusei (~15). To investigate its possible mechanism of action, glucoside 11 was subjected to molecular docking studies with Candida sp. enzymes involved in ergosterol biosynthesis. Results have shown that the peracetyl glucosyl moiety and the 4-nitrobenzamide group in 11 are effectively involved in its high affinity with the active site of squalene epoxidase.
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http://dx.doi.org/10.1111/cbdd.13318DOI Listing
August 2018

Capillary zone electrophoresis method to assay tipranavir capsules and identification of oxidation product and organic impurity by quadrupole-time of flight mass spectrometry.

Talanta 2018 May 6;181:182-189. Epub 2018 Jan 6.

Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, Santa Maria, Brazil. Electronic address:

Tipranavir (TPV) is one of the most recently developed protease inhibitors (PI) and it is specially recommended for treatment-experienced patients who are resistant to other PI drugs. In this work, a simple and friendly environmental CZE stability-indicating method to assay TPV capsules was developed and two TPV organic impurities were identified by high resolution mass spectrometry (HRMS). The optimized analytical conditions were: background electrolyte composed of sodium borate 50mM, pH 9.0 and 5% of methanol; voltage + 28kV; hydrodynamic injection of 5s (100mbar), detection wavelength 240nm, at 25°C. The separation was achieved in a fused silica capillary with 50µm × 40cm (inner diameter × effective length), using furosemide as internal standard. All the validation parameters were met and the method was specific, even in the presence of degradation products and impurities. Oxidation was indicated as the main degradation pathway among those evaluated in this study (acidic, alkaline, thermal, photolytic and oxidative) and it showed a second order degradation kinetic, under the conditions used in this study. The main oxidation product and an organic impurity detected in the standard were characterized by Q-TOF, and both of them correspond to oxidation products of TPV.
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http://dx.doi.org/10.1016/j.talanta.2018.01.012DOI Listing
May 2018

Synthesis and in vitro evaluation of peracetyl and deacetyl glycosides of eugenol, isoeugenol and dihydroeugenol acting against food-contaminating bacteria.

Food Chem 2017 Dec 8;237:1025-1029. Epub 2017 Jun 8.

Federal University of Lavras, Department of Food Science, P.O. Box 3037, 37200-000 Lavras, MG, Brazil. Electronic address:

Essential oils, as well as their separate components, have shown promise as alternatives to synthetic preservatives. Therefore, it would be interesting to optimize the effect of these compounds and to evaluate their applicability as additives in food. To this end, six peracetyl and deacetyl glycosides were synthesized from eugenol, isoeugenol and dihydroeugenol. All of the glycosides were characterized by IR and NMR. The synthesized compounds and their aglycones were evaluated to determine their minimal bactericidal concentrations (MBC) against the spoilage food bacteria Escherichia coli, Listeria monocytogenes, Staphylococcus aureus and Salmonella enteritidis. All deacetyl glycosides were about twice as active as aglycones, and the peracetyl glycosides were, in most cases, equipotent with aglycones. The deacetyl glycoside of dihydroeugenol proved to be the most active compound against the bacteria tested, with a 0.37% MBC v/v for E. coli and 0.18% v/v for the other bacteria.
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http://dx.doi.org/10.1016/j.foodchem.2017.06.056DOI Listing
December 2017

New Eugenol Glucoside-based Derivative Shows Fungistatic and Fungicidal Activity against Opportunistic Candida glabrata.

Chem Biol Drug Des 2016 Jan 31;87(1):83-90. Epub 2015 Aug 31.

Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva, 700 Alfenas, Brazil.

A new series of glucosides modified in their saccharide units were synthesized, evaluated against Candida sp., and compared to prototype 1, an eugenol tetracetyl glucoside previously synthesized and shown to be active against Candida glabrata. Among the new glucosides, benzyl derivative 5 was the most promising, showing fungistatic activity at IC50 18.1 μm against Candida glabrata (threefold higher than fluconazole) and fungicidal activity with a low IC90 value of 36.2 μm. Moreover, the cytotoxic activity of compound 5 (CC50 : 580.9 μm), tested in peripheral blood mononuclear cells, suggests its potential as an agent to treat Candida glabrata infections, with a selectivity index of 32. The new eugenol glucoside 5 may be considered as a novel structural pattern in the development of new anti-Candida drugs.
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http://dx.doi.org/10.1111/cbdd.12625DOI Listing
January 2016

Synthesis and antimicrobial activity of 6-triazolo-6-deoxy eugenol glucosides.

Carbohydr Res 2015 Jun 13;410:1-8. Epub 2015 Apr 13.

Instituto de Química, Universidade Federal de Alfenas, 37130-000, MG, Brazil. Electronic address:

A new series of 1,2,3-triazole eugenol glucosides were synthesized. The new compound structures were confirmed by MS, (1)H NMR and (13)C NMR. All of the synthesized compounds were screened for antimicrobial and cytotoxic activity. Five compounds exerted significant activity against the Gram-negative bacteria Salmonella typhimurium with low IC50 values (49.73-68.53 μΜ), and seven compounds were active against the Gram-positive bacteria Micrococcus luteus (42.89-210.94 μM). In vitro cytotoxicity on mouse spleen cells was also evaluated. One compound bearing a phenyl substituent at the triazole ring showed good activity against Salmonella typhimurium (49.73 μM) and low toxicity to normal cells (CC50=157.83 μM). Thus, the compounds herein can be considered for further modification for improving their antibacterial activity or obtaining novel antibacterial drug candidates.
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http://dx.doi.org/10.1016/j.carres.2015.04.002DOI Listing
June 2015

Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1.

Antimicrob Agents Chemother 2015 May 23;59(5):2666-77. Epub 2015 Feb 23.

Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

The pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of ≤ 10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50 = 1.2 ± 1.0 μM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series.
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http://dx.doi.org/10.1128/AAC.04601-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394791PMC
May 2015
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