Publications by authors named "Renata Barbosa de Oliveira"

24 Publications

  • Page 1 of 1

Quantitative structure-activity relationship and machine learning studies of 2-thiazolylhydrazone derivatives with anti- activity.

J Biomol Struct Dyn 2021 Jun 14:1-12. Epub 2021 Jun 14.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

is a fungus responsible for infections in humans with a significant number of cases in immunosuppressed patients, mainly in underdeveloped countries. In this context, the thiazolylhydrazones are a promising class of compounds with activity against . The understanding of the structure-activity relationship of these derivatives could lead to the design of robust compounds that could be promising drug candidates for fungal infections. Specifically, modern techniques such as 4D-QSAR and machine learning methods were employed in this work to generate two QSAR models (one 2D and one 4D) with high predictive power (r for the test set equals to 0.934 and 0.831, respectively), and one random forest classification model was reported with Matthews correlation coefficient equals to 1 and 0.62 for internal and external validations, respectively. The physicochemical interpretation of selected models, indicated the importance of aliphatic substituents at the hydrazone moiety to antifungal activity, corroborating experimental data.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1935321DOI Listing
June 2021

Antivirulence activity and in vivo efficacy of a thiazole derivative against candidiasis.

J Mycol Med 2021 Jun 6;31(2):101134. Epub 2021 Apr 6.

Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, PO Box 486, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Candida albicans is a pathogen equipped with a variety of commensal and virulence traits that help it colonize the microbiota and invade host tissue during infection. In this study, we investigated the potential anticandidal activity of 3-[2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazino)]butan-1-ol (MT), a thiazolylhydrazone compound synthesized by our group, and identified it as a promising antifungal agent. The activity of MT was evaluated in vitro and in vivo against C. albicans as well as its ability to inhibit virulence factors. For this, the ability of MT to inhibit the adhesion of C. albicans to human buccal epithelial cells and biofilm formation and filamentation was tested. In addition, the potential in vivo activity of MT was evaluated in murine models of oral candidiasis. Our results confirmed the antifungal activity of MT, with a minimal inhibitory concentration range of 0.5-2 µg/mL. Indeed, MT treatment in vitro decreased the expression of C. albicans genes involved in biofilm formation and morphogenesis and encoding hydrolytic enzymes, which was also confirmed through phenotypic observations. In addition, MT promoted a decrease in the colony forming units recovered from the tongues of mice with oral candidiasis. In this work, we present a potent antivirulence compound that shows potential for candidiasis therapy, especially for topical use.
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http://dx.doi.org/10.1016/j.mycmed.2021.101134DOI Listing
June 2021

Electrochemical evidence of nitrate release from the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid and its antinociceptive and anti-inflammatory activities in mice.

Biomed Pharmacother 2021 Jan 27;133:110913. Epub 2020 Nov 27.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address:

Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.
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http://dx.doi.org/10.1016/j.biopha.2020.110913DOI Listing
January 2021

Stability-indicating method for the novel antifungal compound RI76: Characterization and in vitro antifungal activity of its active degradation product.

Biomed Chromatogr 2021 Mar 13;35(3):e5014. Epub 2020 Nov 13.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

RI76 is a novel 2-thiazolylhydrazone compound with reported antifungal activity. In preclinical drug development, it is fundamental to know the impurity profile and to understand degradation mechanisms of the molecule. In our study, RI76 was subjected to forced degradation conditions, and a stability-indicating HPLC-DAD method was developed and validated. Separation was carried out on a C18 column (150 × 4.6 mm i.d., 5 μm) maintained at 40°C using a 1 mL/min flow rate of 2 mM ammonium acetate with 0.1% formic acid (pH 3.0) and acetonitrile in gradient mode. The method was linear in the range of 0.7-91 μg/mL for RI76 and 0.7-25 μg/mL for its degradation product PD76. The formation of a major degradation product was quickly observed when RI76 was in aqueous solution. The chemical structure of this product, named PD76, was proposed based on LC-UV-MS experiments, synthesized in-house, and confirmed by NMR spectroscopy and chromatographic analysis. In vitro antifungal activity assays demonstrated that this resultant product shows a promising activity against clinically important Candida and Cryptococcus strains, matching or surpassing the activity of its precursor and of well-established antifungal drugs.
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http://dx.doi.org/10.1002/bmc.5014DOI Listing
March 2021

Novel self-nanoemulsifying drug-delivery system enhances antileukemic properties of all- retinoic acid.

Nanomedicine (Lond) 2020 06 17;15(15):1471-1486. Epub 2020 Jun 17.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

All- retinoic acid (ATRA) shows erratic oral bioavailability when administered orally against leukemia, which can be solved through its incorporation in self-nanoemulsifying drug-delivery systems (SEDDS). The SEDDS developed contained a hydrophobic ion pair between benzathine (BZT) and ATRA and was enriched with tocotrienols by the input of a palm oil tocotrienol rich fraction (TRF) in its composition. SEDDS-TRF-ATRA-BZT allowed the formation of emulsions with nanometric size that retained ATRA within their core after dispersion. Pharmacokinetic parameters after oral administration of SEDDS-TRF-ATRA-BZT in mice were improved compared with what was seen for an ATRA solution. Moreover, SEDDS-TRF-ATRA-BZT had improved activity against HL-60 cells compared with SEDDS without TRF. SEDDS-TRF-ATRA-BZT is a promising therapeutic choice over ATRA conventional medicine.
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http://dx.doi.org/10.2217/nnm-2020-0061DOI Listing
June 2020

Virtual screening of antibacterial compounds by similarity search of Enoyl-ACP reductase (FabI) inhibitors.

Future Med Chem 2020 01 15;12(1):51-68. Epub 2019 Nov 15.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, Brazil 31270-901.

Antibiotic resistance is an alarming issue, as multidrug-resistant bacteria are growing worldwide, hence the decrease of therapeutic potential of available antibiotic arsenal. Among these bacteria, was pointed by the WHO in the pathogens list to be prioritized in drug development. We report the use of chemical similarity models for the virtual screening of new antibacterial with structural similarity to known inhibitors of FabI. The potential inhibitors were experimentally evaluated for antibacterial activity and membrane disrupting capabilities. These models led to the finding of four new compounds with antibacterial activity, one of which having antimicrobial activity already reported in the literature.
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http://dx.doi.org/10.4155/fmc-2019-0158DOI Listing
January 2020

Purity determination of a new antifungal drug candidate using quantitative H NMR spectroscopy: Method validation and comparison of calibration approaches.

Magn Reson Chem 2020 01 1;58(1):97-105. Epub 2019 Sep 1.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Quantitative nuclear magnetic resonance (qNMR) is an analytical technique that offers numerous advantages in pharmaceutical applications including minimum sample preparation and rapid data collection times with no need for response factor corrections, being a powerful tool for assaying drug content in both drug discovery and early drug development. In the present work, we have applied qNMR, using both the internal standard and the electronic reference to access in vivo concentrations 2 calibration methods, to assess the purity of RI76, a novel antifungal drug candidate. NMR acquisition and processing parameters were optimized in order to obtain spectra with intense, well-resolved signals of completely relaxed nuclei. The analytical method was validated following current guidelines, demonstrating selectivity, linearity, accuracy, precision, and robustness. The calibration approaches were statistically compared, and no significant difference was observed when comparing the obtained results and their dispersion in terms of relative standard deviation. The proposed qNMR method may, therefore, be used for both qualitative and quantitative assessments of RI76 in early drug development and for characterization of this compound.
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http://dx.doi.org/10.1002/mrc.4936DOI Listing
January 2020

Anti- Activity of Thiazolylhydrazone Derivatives in Invertebrate and Murine Models.

J Fungi (Basel) 2018 Dec 12;4(4). Epub 2018 Dec 12.

Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte-Minas Gerais 31270-901, Brasil.

Candidiasis is an opportunistic fungal infection with being the most frequently isolated species. Treatment of these infections is challenging due to resistance that can develop during therapy, and the limited number of available antifungal compounds. Given this situation, the aim of this study was to evaluate the antifungal activity of four thiazolylhydrazone compounds against . Thiazolylhydrazone compounds , , , and were found to exert antifungal activity, with MICs of 0.125⁻16.0 μg/mL against . . The toxicity of the compounds was evaluated using human erythrocytes and yielded LC > 64 μg/mL. The compounds were further evaluated using the greater wax moth as an in vivo model. The compounds prolonged larval survival when tested between 5 and 15 mg/kg, performing as well as fluconazole. Compound was evaluated in murine models of oral and systemic candidiasis. In the oral model, compound reduced the fungal load on the mouse tongue; and in the systemic model it reduced the fungal burden found in the kidney when tested at 10 mg/kg. These results show that thiazolylhydrazones are an antifungal towards with in vivo efficacy.
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http://dx.doi.org/10.3390/jof4040134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308944PMC
December 2018

In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives.

J Mol Graph Model 2019 01 12;86:106-112. Epub 2018 Oct 12.

Department of Pharmaceutical Products, Pharmacy Faculty, Federal University of Minas Gerais, 6627 Antônio Carlos AVE, 31270-901, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

The antioxidant potential of a series of thiazolylhydrazone derivatives was investigated using three different methods namely DPPH, ABTS and FRAP assays. In general, the tested compounds showed higher or comparable activity to that of curcumin, used as positive control. Chemometric analyses demonstrated that the presence of hydrazone moiety is required for the activity of this class of compounds. From these results, compound 4 was identified as the most promising molecule and was then selected for further studies. The antiproliferative effect of compound 4 was evaluated, being active in three (T47D, MDA-MB-231 and SKMEL) of the six cancer cell lines tested, with IC values ranging from 15.9 to 31.3 μM. Compound 4 exhibited no detectable cytotoxic effect on peripheral blood mononuclear cells (PBMC) when tested at a concentration of 100 μM, demonstrating good selectivity. From these results, it is possible to infer that there is a correlation between antioxidant capacity and anticancer effects.
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http://dx.doi.org/10.1016/j.jmgm.2018.10.007DOI Listing
January 2019

In vivo and in vitro activity of a bis-arylidenecyclo-alkanone against fluconazole-susceptible and -resistant isolates of Candida albicans.

J Glob Antimicrob Resist 2018 09 30;14:287-293. Epub 2018 Apr 30.

Department of Microbiology, Institute of Biological Sciences, University Federal of Minas Gerais, Av. Antônio Carlos 6627, P.O. Box 486, 31270-901 Belo Horizonte, MG, Brazil. Electronic address:

Objectives: Candida albicans is a commensal organism and opportunistic pathogen associated both with superficial (mucosal and cutaneous) and systemic infections. Extensive use of antifungal agents has led to reduced susceptibility to the few existing drugs, which has encouraged the search for novel antifungal agents. Therefore, the present study investigated the antifungal activity of 2,6-bis[(E)-(4-pyridyl)methylidene]cyclohexanone (PMC) against C. albicans.

Methods: The in vitro activity of PMC was evaluated against C. albicans. Additionally, an invertebrate infection model in Caenorhabditis elegans as well as two infected murine models of oral and systemic candidiasis were used to determine the antifungal efficacy of PMC in vivo.

Results: Minimum inhibitory concentrations (MICs) of PMC ranged from 4-32μg/mL against nine clinical and two reference C. albicans isolates. Interestingly, PMC inhibited filamentation in vitro at subinhibitory concentrations similar to fluconazole. PMC also showed low toxicity against murine macrophages and human erythrocytes. In the invertebrate infection model, PMC was efficient in prolonging survival of C. elegans infected with C. albicans SC5314. Treatment with PMC was efficient both in murine models of systemic and oral candidiasis and was similar to that observed with conventional drug treatments (nystatin and fluconazole).

Conclusions: The results of this study indicate the therapeutic potential of PMC as it was able to inhibit filamentation of C. albicans in vitro. These alterations to the fungi by PMC resulted in a reduction of oral and systemic infection in mice. In conclusion, we present promising evidence of the anticandidal activity of PMC in vitro and in vivo.
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http://dx.doi.org/10.1016/j.jgar.2018.04.012DOI Listing
September 2018

Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives.

Eur J Med Chem 2018 May 31;151:248-260. Epub 2018 Mar 31.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address:

In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.083DOI Listing
May 2018

Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations.

J Comput Aided Mol Des 2018 05 21;32(5):591-605. Epub 2018 Mar 21.

Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, MG, CEP 31270-901, Brazil.

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.
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http://dx.doi.org/10.1007/s10822-018-0112-3DOI Listing
May 2018

Thiazole derivatives act on virulence factors of Cryptococcus spp.

Med Mycol 2019 Jan;57(1):84-91

Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Cryptococcosis is an opportunistic or primary fungal infection considered to be the most prevalent fatal fungal disease worldwide. Owing to the limited number of available drugs, it is necessary to search for novel antifungal compounds. In the present work, we assessed the antifungal efficacy of three thiazole derivatives (1, 2, and 3). We conducted in vitro and in vivo assays to investigate their effects on important virulence factors, such as capsule and biofilm formation. In addition, the phagocytosis index of murine macrophages exposed to compounds 1, 2, and 3 and the in vivo efficacy of 1, 2, and 3 in Galleria mellonella infected with Cryptococcus spp. were evaluated. All compounds exhibited antifungal activity against biofilms and demonstrated a reduction in biofilm metabolic activity by 43-50% for C. gattii and 26-42% for C. neoformans. Thiazole compounds promoted significant changes in the capsule thickness of C. gattii compared to that of C. neoformans. Further examination of these compounds suggests that they can improve the phagocytosis process of peritoneal murine macrophages in vitro, causing an increase in the phagocytosis rate. Survival percentage was examined in the invertebrate model Galleria mellonella larvae, and only compound 3 could increase the survival at doses of 5 mg/kg after infection with C. gattii (P = .0001) and C. neoformans (P = .0007), similar to fluconazole at 10 mg/kg. The results demonstrated that thiazole compounds, mainly compound 3, have potential to be used for future studies in the search for new therapeutics for cryptococcosis.
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http://dx.doi.org/10.1093/mmy/myx158DOI Listing
January 2019

Novel nitroaromatic compound activates autophagy and apoptosis pathways in HL60 cells.

Chem Biol Interact 2018 Mar 6;283:107-115. Epub 2017 Dec 6.

Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address:

N-(2-butanoyloxyethyl)-4-(chloromethyl)-3-nitrobenzamide (NBCN) is a nitroaromatic bioreducible compound with cytotoxic effects in cancer cell lines. The aim of this work was to investigate the molecular mechanisms involved in cell death promoted by NBCN in HL60 cells. We observed that NBCN treatment increased intracellular ROS and reduced mitochondria membrane potential (ΔΨm). NBCN treatment also induced morphological changes, phosphatidylserine exposure, cell cycle arrest in G2/M-phase, DNA condensation and fragmentation, but it did not show cytotoxic effects on normal human peripheral blood mononuclear cells (PBMCs). NBCN-induced caspase 3- and 9-dependent DNA fragmentation, which was blocked by pretreatment with the broad-spectrum caspase inhibitor, z-VAD-fmk. Flow cytometry analysis demonstrated that NBCN also increased of the number of autophagic vesicles in HL60 cells, which was not observed when cells were pre-treated with bafilomycin A1. Taken together, these results indicate that NBCN triggered the mitochondrial apoptotic pathway and led to the onset of autophagic cell death, which contributed to its cytotoxic effects.
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http://dx.doi.org/10.1016/j.cbi.2017.12.012DOI Listing
March 2018

Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex.

Antimicrob Agents Chemother 2017 08 25;61(8). Epub 2017 Jul 25.

Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Human cryptococcosis can occur as a primary or opportunistic infection and develops as an acute, subacute, or chronic systemic infection involving different organs of the host. Given the limited therapeutic options and the occasional resistance to fluconazole, there is a need to develop novel drugs for the treatment of cryptococcosis. In this report, we describe promising thiazole compounds 1, 2, 3, and 4 and explore their possible modes of action against To this end, we show evidence of interference in the antioxidant system. The tested compounds exhibited MICs ranging from 0.25 to 2 μg/ml against strains H99 and KN99α. Interestingly, the knockout strains for Cu oxidase and sarcosine oxidase were resistant to thiazoles. MIC values of thiazole compounds 1, 2, and 4 against these mutants were higher than for the parental strain. After the treatment of ATCC 24067 (or ) and strain L27/01 (or ) with thiazoles, we verified an increase in intracellular reactive oxygen species (ROS). Also, we verified the synergistic interactions among thiazoles and menadione, which generates superoxides, with fractional inhibitory concentrations (FICs) equal to 0.1874, 0.3024, 0.25, and 0.25 for the thiazole compounds 1, 2, 3, and 4, respectively. In addition, thiazoles exhibited antagonistic interactions with parasulphonatephenyl porphyrinato ferrate III (FeTPPS). Thus, in this work, we showed that the action of these thiazoles is related to an interference with the antioxidant system. These findings suggest that oxidative stress may be primarily related to the accumulation of superoxide radicals.
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http://dx.doi.org/10.1128/AAC.02700-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527588PMC
August 2017

Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification.

Bioorg Med Chem 2017 03 9;25(6):1889-1900. Epub 2017 Feb 9.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address:

Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC values ranging from 15 to 125µM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC=15µM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC=67.7µM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC=3.1µM) with remarkable selectivity index (SI=128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.
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http://dx.doi.org/10.1016/j.bmc.2017.02.009DOI Listing
March 2017

Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro.

Eur J Med Chem 2015 Sep 17;102:233-42. Epub 2015 Jul 17.

Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address:

Human cryptococcosis can occur as a primary or opportunistic infection and develop as an acute, subacute, or chronic, systemic infection involving different host organs. We evaluated the antifungal activity of thirteen compounds against Cryptococcus gattii and Cryptococcus neoformans in vitro, by assessing the toxicity of the compounds showing the greatest antifungal activity in VERO cells and murine macrophages. From these results, four compounds were considered promising for further studies because they displayed low cytotoxicity and significant antifungal activity. The heterocyclic compounds 1b, 1c, 1d, and 1m have antifungal activity levels between that of amphotericin B and fluconazole in vitro. The death curve of Cryptococcus spp. treated with these four compounds was similar to the curve obtained for amphotericin B, in that we observed a significant reduction in cell viability within the first 24 h of treatment. Additionally, we found that there was no effect when these compounds were combined with amphotericin and fluconazole, except for 1c, which antagonized the effect of amphotericin B against C. gattii, also reflected in the reduction of the post-antifungal effect (PAFE); however, this interaction did not alter the ergosterol content. The results shown in this paper reveal the discovery of novel thiazole compounds, which are easy to synthesize, and with potentially exhibit antifungal activity, and display low cytotoxicity in normal mammalian cells. These compounds can be used as prototypes for the design of new antifungal drugs against C. gattii and C. neoformans.
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http://dx.doi.org/10.1016/j.ejmech.2015.07.032DOI Listing
September 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

Synthesis of nitroaromatic compounds as potential anticancer agents.

Anticancer Agents Med Chem 2015 ;15(2):206-16

Department of Pharmaceutical Products, Pharmacy Faculty, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

Twenty-seven nitrated and non-nitrated compounds have been synthesized and tested for their growth inhibitory activity on three human cancer cells lines. Fourteen compounds were able to inhibit more than 50% of the growth of at least one of the cancer cell lines and five compounds exhibited high antiproliferative activity on human cancer cell lines (IC50 < 8.5 μM). The cytotoxicity of the compounds on Vero cell line was established in vitro to evaluate the selectivity. All active compounds have a good leaving group (bromide or chloride) at the benzylic position, indicating that the mechanism of action of these compounds is related to their alkylating properties. Two compounds (3 and 24) were selected for further studies in mice with Ehrlich solid tumors and display significant antitumor effects in vivo.
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http://dx.doi.org/10.2174/1871520614666141114201749DOI Listing
October 2015

Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue.

J Biomed Nanotechnol 2013 Nov;9(11):1939-44

Faculty of Pharmacy, Department of Pharmaceutical Products, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil.

Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.
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http://dx.doi.org/10.1166/jbn.2013.1674DOI Listing
November 2013

Stability-indicating HPLC-UV for the determination of 4-bromomethyl-3-nitrobenzoic acid, a bioactive nitrocompound.

J Chromatogr Sci 2014 Jul 20;52(6):526-31. Epub 2013 Jun 20.

Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.

The nitroaromatic compound 4-bromomethyl-3-nitrobenzoic acid (ANB) is a promising antitumoral agent whose activity has recently been investigated. Forced degradation studies were conducted on ANB with a high-performance liquid chromatography-ultraviolet assay to establish its stability and selectivity. ANB was subjected to degradation studies under hydrolytic (acid and alkaline), oxidative and light exposition conditions. The compound showed greater lability only in acid and alkaline conditions by forming a major degradation product. The chromatographic separation of ANB and its degradation product was achieved on an octadecylsilane column using a mobile phase of methanol-water (80:20, v/v), pH 4.0 adjusted with formic acid, flow rate of 0.7 mL/min, ultraviolet diode array detection at λ 271 nm, injection volume of 20 µL and temperature of 30°C. The method was validated according to International Conference on Harmonization guidelines with respect to precision (average relative standard deviation 0.67%), accuracy (average 99.97%), linearity (y = 118730x + 12912; coefficient of determination > 0.999), specificity and robustness (p > 0.05). The degradation product formed as a result from the hydrolysis of nitrobenzyl bromide, corresponded to its benzyl alcohol, 4-hydroxymethyl-3-nitrobenzoic acid (ANOH) and was characterized by co-elution with a synthetic ANOH working standard.
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http://dx.doi.org/10.1093/chromsci/bmt077DOI Listing
July 2014

Amphotericin B-loaded nanocarriers for topical treatment of cutaneous leishmaniasis: development, characterization, and in vitro skin permeation studies.

J Biomed Nanotechnol 2012 Apr;8(2):322-9

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brasil.

Topical treatment of cutaneous leishmaniasis represents an exciting alternative for reducing toxicity associated with parenteral administration of conventional amphotericin B. This work aims to develop and to characterize amphotericin B-loaded new carriers and to investigate their potential for topical delivery by conducting permeation studies with pig ear skin in comparison with marketed formulations. Among other formulations, nanoemulsions were developed and characterized for size, encapsulation efficiency, and zeta potential. To mimic use conditions in topical therapy of cutaneous leishmaniasis, in vitro skin permeation experiments were conducted using a damaged skin model. High encapsulation efficiency (95%) and low particle size (239 nm) were obtained for amphotericin B-loaded nanoemulsion by employing an ion pairing between the drug and stearylamine. Amphotericin B permeation after 24 h across the dermal membrane was low, regardless of the type of formulation tested. In contrast, amphotericin B penetration into dermal membranes (microg/cm2) from solution (control), aqueous Amphocil, hydroalcoholic Amphocil, Fungizone, mixture Fungizone-Lipofundin, and NE was 17.5 +/- 4, 15.2 +/- 3, 9.6 +/- 3, 3.5 +/- 1, 1.7 +/- 0.3, and 1.1 +/- 0.1, respectively. Amphocil provided the best results, highlighted by its high improvement of dermal penetration of amphotericin B.
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http://dx.doi.org/10.1166/jbn.2012.1385DOI Listing
April 2012

The activity of a metronidazole analogue and its β-cyclodextrin complex against Trypanosoma cruzi.

Mem Inst Oswaldo Cruz 2011 Dec;106(8):1055-7

Departamento de Produtos Farmacêuticos, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.

In this study we prepared an inclusion complex between an iodide analogue of metronidazole (MTZ-I) and cyclodextrin (CD) to develop a safer and more effective method of treating Trypanosoma cruzi infections. According to our results, MTZ-I and MTZ-I:β-CD were 10 times more active than MTZ, demonstrating that the presence of an iodine atom on the side chain increased the trypanocidal activity while maintaining its cytotoxicity. The selective index shows that MTZ-I was 10 times more active against T. cruzi than it was against mammalian cells. The modification of MTZ side chains provides a promising avenue for the development of new drugs.
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http://dx.doi.org/10.1590/s0074-02762011000800027DOI Listing
December 2011

Synthesis and in vitro cytotoxic activity of compounds with pro-apoptotic potential.

Molecules 2009 Dec 24;15(1):12-26. Epub 2009 Dec 24.

Laboratório de Química de Produtos Naturais, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Av. Augusto de Lima 1715, Belo Horizonte, MG 30190-002, Brazil.

In our search for new anticancer therapies, some compounds synthesized in our lab were selected and their potential cytotoxic activity was evaluated in vitro against two cancer cells lines including a solid tumor (UACC-62, melanoma) and a human lymphoma (JURKAT). Compounds showing cytotoxic activity were subjected to an apoptosis assay. Two compounds showed promising results.
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http://dx.doi.org/10.3390/molecules15010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256932PMC
December 2009
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