Publications by authors named "Jamerson Ferreira de Oliveira"

23 Publications

  • Page 1 of 1

Novel indole-thiazole and indole-thiazolidinone derivatives as DNA groove binders.

Int J Biol Macromol 2021 Feb 5;170:622-635. Epub 2021 Jan 5.

Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, 50670-901, Brazil; Laboratório de Biologia Molecular, Universidade de Pernambuco (UPE), Multicampi Garanhuns, Garanhuns, PE 55290-000, Brazil. Electronic address:

In this study, we report the synthesis of eight novel indole-thiazole and indole-thiazolidinone derivatives, as well as their ability to interact with DNA, analysed through the UV-vis absorption, fluorescence, circular dichroism (CD), viscosity techniques and molecular docking. The ctDNA interaction analysis demonstrated different spectroscopic effects and the affinity constants (Kb) calculated by the UV-vis absorption method were between 2.08 × 10 and 6.99 × 10 M, whereas in the fluorescence suppression constants (Ksv) ranged between 0.38 and 0.77 × 10 M and 0.60-7.59 × 10 M using Ethidium Bromide (EB) and 4',6-Diamidino-2-phenylindole (DAPI) as fluorescent probes, respectively. Most derivatives did not alter significantly the secondary structure of the ctDNA according to the CD results. None of the compounds was able to change the relative viscosity of the ctDNA. These results prove that compounds interact with ctDNA via groove binding, which was confirmed by A-T rich oligonucleotide sequence assay with compound JF-252, suggesting the importance of both the phenyl ring coupled to C-4 thiazole ring and the bromo-unsubstituted indole nucleus.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.12.153DOI Listing
February 2021

COVID-19 therapy: What weapons do we bring into battle?

Bioorg Med Chem 2020 12 10;28(23):115757. Epub 2020 Sep 10.

Laboratório de Química e Inovação Terapêutica (LQIT) - Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, PE, Brazil.

Urgent treatments, in any modality, to fight SARS-CoV-2 infections are desired by society in general, by health professionals, by Estate-leaders and, mainly, by the scientific community, because one thing is certain amidst the numerous uncertainties regarding COVID-19: knowledge is the means to discover or to produce an effective treatment against this global disease. Scientists from several areas in the world are still committed to this mission, as shown by the accelerated scientific production in the first half of 2020 with over 25,000 published articles related to the new coronavirus. Three great lines of publications related to COVID-19 were identified for building this article: The first refers to knowledge production concerning the virus and pathophysiology of COVID-19; the second regards efforts to produce vaccines against SARS-CoV-2 at a speed without precedent in the history of science; the third comprehends the attempts to find a marketed drug that can be used to treat COVID-19 by drug repurposing. In this review, the drugs that have been repurposed so far are grouped according to their chemical class. Their structures will be presented to provide better understanding of their structural similarities and possible correlations with mechanisms of actions. This can help identifying anti-SARS-CoV-2 promising therapeutic agents.
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http://dx.doi.org/10.1016/j.bmc.2020.115757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481143PMC
December 2020

New Oxazolidines Inhibit the Secretion of IFN-γ and IL-17 by PBMCS from Moderate to Severe Asthmatic Patients.

Med Chem 2021 ;17(3):289-297

Laboratorio de Imunomodulacao e Novas Abordagens Terapeuticas (LINAT), Nucleo de Pesquisa em Inovacao Terapeutica Suely Galdino (NUPIT-SG), Universidade Federal de Pernambuco, Recife, PE, Brazil.

Background: Moderate to severe asthma could be induced by diverse proinflammatory cytokines, as IL-17 and IFN-γ, which are also related to treatment resistance and airway hyperresponsiveness. Oxazolidines emerged as a novel approach for asthma treatment, since some chemical peculiarities were suggested by previous studies.

Objective: The present study aimed to evaluate the IL-17A and IFN-γ modulatory effect of two new oxazolidine derivatives (LPSF/NB-12 and -13) on mononucleated cells of patients with moderate and severe asthma.

Methods: The study first looked at potential targets for oxazolidine derivatives using SWISS-ADME. After the synthesis of the compounds, cytotoxicity and cytokine levels were analyzed.

Results: We demonstrated that LPSF/NB-12 and -13 reduced IFN-γ and IL-17 production in peripheral blood mononucleated cells from asthmatic patients in a concentrated manner. Our in silico analysis showed the neurokinin-1 receptor as a common target for both compounds, which is responsible for diverse proinflammatory effects of moderate and severe asthma.

Conclusion: The work demonstrated a novel approach against asthma, which deserves further studies of its mechanisms of action.
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http://dx.doi.org/10.2174/1573406416666200910151950DOI Listing
June 2021

Thiophene-thiosemicarbazone derivative (L10) exerts antifungal activity mediated by oxidative stress and apoptosis in C. albicans.

Chem Biol Interact 2020 Apr 28;320:109028. Epub 2020 Feb 28.

Laboratory of Synthesis and Drug Delivery, State University of Paraiba, 58071-160, Brazil.

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 μg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 μg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes.
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http://dx.doi.org/10.1016/j.cbi.2020.109028DOI Listing
April 2020

Novel indol-3-yl-thiosemicarbazone derivatives: Obtaining, evaluation of in vitro leishmanicidal activity and ultrastructural studies.

Chem Biol Interact 2020 Jan 15;315:108899. Epub 2019 Nov 15.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901, Recife, PE, Brazil. Electronic address:

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC values between 53.23 and 357.97 μM. Concerning the evaluation against L. amazonensis promastigote forms, IC values ranged between 12.31 and  > 481.52 μM, while the activity against L. infantum promastigotes obtained IC values between 4.36 and 23.35 μM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.
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http://dx.doi.org/10.1016/j.cbi.2019.108899DOI Listing
January 2020

Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.

Eur J Med Chem 2019 Nov 6;182:111592. Epub 2019 Aug 6.

Laboratório de Química e Inovação Terapêutica (LQIT), Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, PE, 50670-901, Brazil.

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 10 and 1.43 × 10, respectively, and DNA binding mode by intercalation. The IC values were obtained between 0.81 and 1.48 μM and topoisomerase inhibition results in 10 μM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2019.111592DOI Listing
November 2019

Topoisomerase inhibition and albumin interaction studies of acridine-thiosemicarbazone derivatives.

Int J Biol Macromol 2019 Oct 16;138:582-589. Epub 2019 Jul 16.

Universidade de Pernambuco (UPE), campus Garanhuns, Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), Garanhuns, PE, Brazil; Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, PE, Brazil. Electronic address:

In the present study, acridine-thiosemicarbazones (ATD) derivatives were tested for their interaction properties with BSA through UV-Vis absorption and fluorescence spectroscopic studies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated after the derivatives were added to the BSA. Values for the binding constant (K) ranged from 1.62 × 10 to 8.71 × 10 M and quenching constant (K) from 3.46 × 10 to 7.83 × 10 M indicating a good affinity to BSA protein. Complementary, two compounds were selected to assess their inhibition activity against topoisomerase IIα enzyme, of which derivative 3a presented the best result. Moreover, to evaluate protein-ligand interactions, as well as the antitopoisomerase potential of these compounds, tests of molecular modeling were performed between all compounds using the albumin and Topoisomerase IIα/DNA complex. Finally, in silico studies showed that all derivatives used in this research displayed good oral bioavailability potential.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.07.097DOI Listing
October 2019

Thiazolidinedione and thiazole derivatives potentiate norfloxacin activity against NorA efflux pump over expression in Staphylococcus aureus 1199B strains.

Bioorg Med Chem 2019 09 4;27(17):3797-3804. Epub 2019 Jul 4.

Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Av. Prof. Artur de Sá, s/n, Cidade Universitária, Recife, PE 54740-520, Brazil. Electronic address:

Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the Staphylococcus aureus 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the in silico study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC > 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent in vitro inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of -9.03 Kcal/mol and -9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against S. aureus SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells.
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http://dx.doi.org/10.1016/j.bmc.2019.07.006DOI Listing
September 2019

In vitro activity, ultrastructural studies and in silico pharmacokinetic properties of indol-3-yl-thiosemicarbazones derivatives and analogues against juvenile and adult worms of S. mansoni.

Eur J Pharm Sci 2019 Oct 5;138:104985. Epub 2019 Jul 5.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil. Electronic address:

The present work aimed to carry out in vitro biological assays of indol-3-yl derivatives thiosemicarbazones (2a-e) and 4-thiazolidinones (3a-d) against juvenile and adult worms of S. mansoni, as well as the in silico determination of pharmacokinetic parameters for the prediction of the oral bioavailability of these derivatives. All compounds were initially screened at a concentration of 200 μM against S. mansoni adult worms and the results evidenced the good activity of compounds 2b, 2d and 3b, which caused 100% mortality after 24, 48 and 72 h, respectively. Subsequent studies with these same compounds revealed that compound 2b was able to reduce the viability of the parasites by 85% and 83% at concentrations of 200 and 100 μM, respectively. In relation to the juvenile worms, all compounds (2b, 2d and 3b) were able to cause mortality, but compound 2b demonstrated better activity causing 100% mortality in 48 h. Additionally, it was possible to observe reduction in the viability of juvenile worms of 85%, 81% and 64% at concentrations of 200, 100 and 50 μM, respectively. Several ultrastructural damages were observed when adult and juvenile S. mansoni worms were exposed to compound 2b (200 μM) that was characterized by extensive destruction by the integument, which may justify the mortality rate of cultured parasites. In the DNA interaction assay, fragmentation of the genetic material of adult worms when treated with compound 2b (200 μM) was evidenced, indicating the apoptosis process as mechanism of parasite death. Regarding pharmacokinetic properties, all derivatives are according to the required parameters, predicting good oral bioavailability for the studied compounds. The results presented in this study reveal the good activity of compound 2b in both adult and juvenile worms of S. mansoni, pointing this compound as promising in the development of further studies on schistosomicidal activity.
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http://dx.doi.org/10.1016/j.ejps.2019.104985DOI Listing
October 2019

Synthesis, DNA and protein interactions and human topoisomerase inhibition of novel Spiroacridine derivatives.

Bioorg Med Chem 2018 12 29;26(22):5911-5921. Epub 2018 Oct 29.

Laboratório de Síntese e Vetorização de Moléculas, Universidade Estadual da Paraíba, Departamento de Ciências Biológicas, João Pessoa, PB, Brazil; Departamento de Ciências Farmacêuticas, Centro de Ciências Biológicas e da Saúde, Universidade Estadual da Paraíba - Bodocongó, Campina Grande, PB, Brazil.

Nine new spiroacridine derivatives were synthetized by introducing cyano-N-acylhydrazone group between the acridine and phenyl-substituted rings followed by spontaneous cyclization. The new compounds were assayed for their DNA binding properties, human topoisomerase IIα inhibition and bovine serum albumin (BSA) interaction. Besides, docking analysis were performed in order to better understanding the biomolecule-compounds interactions. All compounds interacted with BSA which was demonstrated by the fluorescence suppression constant of 10 M. Compounds with chloro and NO substituents at that para-position on phenyl ring demonstrated the best results for BSA interaction. DNA binding constant determined by UV-vis data demonstrated high values for AMTAC-11 and AMTAC-14, 1.1 × 10 M and 4.8 × 10 M, respectively, and all others presented constant values of 10 M. AMTAC-06 with chloro at para-position on phenyl ring presented a topoisomerase II inhibition of 84.34% in comparison to the positive controls used. Docking studies indicated that AMTAC-06 is able to intercalate the DNA base pairs at topoisomerase IIα active site, preventing DNA connection after break, in a process known as poisoning. Topoisomerase enzyme inhibition result was correlated to BSA interaction profile, since AMTAC-06 showed the best results in both analysis. The findings obtained here proved that methoxy or chloro substitution on phenyl ring at para-position is fundamental for in vitro activity of new spiroacridine derivatives, and indicates that AMTAC-06 is a promising entity and should serve as a lead compound in the development of new DNA and protein binders, as well as human topoisomerase II inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2018.10.038DOI Listing
December 2018

Synthesis, in vitro and in vivo biological evaluation, COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives.

Bioorg Med Chem 2018 11 17;26(20):5388-5396. Epub 2018 Jul 17.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901 Recife, PE, Brazil. Electronic address:

The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a-j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5 h of carrageenan injection at the 30 mg kg dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process.
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http://dx.doi.org/10.1016/j.bmc.2018.07.024DOI Listing
November 2018

New thiophene-acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies.

Chem Biol Drug Des 2018 06 25;91(6):1141-1155. Epub 2018 Mar 25.

Laboratório de Síntese e Vetorização de Moléculas, Departamento de Ciências Biológicas, Universidade Estadual da Paraíba, João Pessoa, PB, Brazil.

In this study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT and ACS -ACS ). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS and ACS derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC values of 9.60 ± 3.19 and 10.95 ± 3.96 μm. Additionally, these two derivatives were effective against antimony-resistant Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 10  m . In partial least-squares studies, it was observed that the most active compounds (ACS and ACS ) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene-acridine derivatives are promising molecules as potential drug candidates.
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http://dx.doi.org/10.1111/cbdd.13176DOI Listing
June 2018

New 1,3-benzodioxole derivatives: Synthesis, evaluation of in vitro schistosomicidal activity and ultrastructural analysis.

Chem Biol Interact 2018 Mar 31;283:20-29. Epub 2018 Jan 31.

Keizo Asami Immunopathology Laboratory (LIKA), Federal University of Pernambuco, 50740-465, Recife, PE, Brazil. Electronic address:

Schistosomiasis is considered a serious public health problem in 78 countries and territories located in Africa, Asia and America and it is estimated in more than 249 million people infected by any of the species of Schistosoma. The exclusive use of praziquantel (PZQ), effective drug against all species of Schistosoma, has been the basis of the development of a possible resistance against the strains of this parasite. In addition, PZQ is not effective against young forms of worms. Thus, there is a need for the development of new drugs with schistosomicidal activity. The objective of this work was to synthesize and to evaluate the therapeutic potential of new benzodioxole derivatives (3-14) candidates for schistosomicidal drugs. All compounds synthesized showed in vitro schistosomicidal activity. The derivative 12 was considered the best compound, since it took 100% of worms to mortality in the first 72 h of exposure at the concentration of 100 μM and 83.3% at the concentration of 50 μM. Furthermore, male and female adult worms, incubated for 24 h with the compound 12 showed tegument damages characterized by extensive desquamation and edema, tuber destruction, bubble formation and exposure of the muscle layer. This compound has a restricted structure, where the thiazolidinone is attached to the 4-position of the 1,3-benzodioxol ring. The structural conformation of derivative 12 was probably responsible for the promising schistosomicidal activity, where the presence of an electron/conformational restriction of the thiazolidine ring, as well as the action of bromine as a bulk substitute, favored an increase in biological activity. In addition, tegumentary changes caused by derivative 12 may also have been responsible for the death of adult worms of Schistosoma mansoni. Therefore, we verified that the results obtained in this study make benzodioxole derivatives possible candidates for prototypes of new schistosomicidal drugs.
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http://dx.doi.org/10.1016/j.cbi.2018.01.016DOI Listing
March 2018

DNA binding and Topoisomerase inhibition: How can these mechanisms be explored to design more specific anticancer agents?

Biomed Pharmacother 2017 Dec 22;96:1538-1556. Epub 2017 Nov 22.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901, Recife, PE, Brazil. Electronic address:

DNA is considered one of the most promising targets of molecules with anticancer activity potential. Its key role in various cell division mechanisms, which commands the intense multiplication of tumor cells, is considered in studies with compounds whose mechanisms of action suggest likeliness of interaction. In addition, inhibition of enzymes that actively participate in biological functions of cells such as Topoisomerase, is seen as a primary factor for conducting several events that result in cell death. Discovery of new anticancer chemotherapeutical capable of interacting with DNA and inhibiting Topoisomerase enzymes is highlighted in anticancer research. The present review aims at showing through distinct biological tests the performance of different candidates to anticancer drugs and their respective chemical modifications, which are crucial and/or determinant for DNA affinity and inhibition of important enzymes in cells' vital processe to either separately or synergistically optimize anticancer activity.
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http://dx.doi.org/10.1016/j.biopha.2017.11.054DOI Listing
December 2017

Synthesis of novel indole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerase I activities.

Eur J Med Chem 2017 Aug 4;136:511-522. Epub 2017 May 4.

Laboratório de Química e Inovação Terapêutica, Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil.

Molecules bearing indole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated both to DNA and protein interactions. This study focused on the synthesis of new indole derivatives with thiazolidines and imidazolidine rings condensed as side chains as well as the evaluation of their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized and their structures were elucidated by mass spectrometry (MS), infrared (IR), spectroscopy H NMR, C NMR, COSY H-H and HSQC H-C. The antitumor activity was evaluated against different cancer cell lines using the antiproliferative MTT assay. DNA binding ability was analyzed by absorption spectroscopy and fluorescence technique using ethidium bromide (EB) as a fluorescent probe. Changes were observed in spectroscopic properties of the compounds after interacting with ctDNA (calf thymus DNA), with hypochromic and hyperchromic effects, besides blue or red shifts in the maxima of spectra. The indole derivative 5-(1H-Indol-3-ylmethylene)-thiazolidin-2,4-dione (4c) presented the best results in antitumor assay against the breast line tested (T47D), with IC value lower than the positive control, doxorubicin (1.93 and 4.61 μM, respectively). On the other hand, the compound 3-amino-5-(1H-indol-3-ylmethylene)-2-thioxo-thiazolidin-4-one (4a) was active against leukemia cell lines (HL60 and K562) with the high value of the DNA binding constant, Kb of 5.69 × 10. However, this compound (4a) did not inhibit the topoisomerase-I activity evaluated by relaxation assay. These results show that the indole nucleus contribute to the incorporation of molecules into the DNA. Moreover, it was highlighted that basic side chains, such as thiazolidines and imidazolidines, and free amino group, are relevant for design of promising antitumor and DNA binding compounds.
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http://dx.doi.org/10.1016/j.ejmech.2017.05.012DOI Listing
August 2017

Synthesis and in vitro anticancer activity of new 2-thioxo-oxazolidin-4-one derivatives.

Pharmacol Rep 2017 Aug 18;69(4):633-641. Epub 2017 Mar 18.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Núcleo de Pesquisa para Inovação Terapêutica Suely Galdino (NUPIT-SG) - Federal University of Pernambuco (UFPE), Recife, Brazil; Laboratório de Planejamento e Síntese de Fármacos (LPSF), Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT-SG) - Federal University of Pernambuco (UFPE), Recife, Brazil. Electronic address:

Background: Oxazolidinones derivatives exhibit different biological properties, including anticancer activity. This work aimed to investigate the anticancer potential of five novel 2-Thioxo-oxazolidin-4-one derivatives.

Methods: Cytotoxicity assays were performed in human peripheral blood mononuclear cells (PBMCs) from healthy individuals and seven tumor cell lines. Apoptosis detection and cell cycle were evaluated by flow cytometry and the expression of genes involved in cell death processes by Real-Time PCR.

Results: All oxazolinedione derivatives were not cytotoxic in PBMCs. NB-5 showed the best results in cancer cells, inhibiting the growth of all tumor cell lines tested. NB-4 exhibited the highest cytotoxicity in Jurkat cells (IC=15.19μM) and NB-3 showed better anticancer effects in HL-60 (17.84μM). Only NB-4 significantly induced apoptosis in acute leukemia cells (p=0.001). All compounds caused a significant increase in expression of pro-apoptotic gene BID (p<0.05) and BECN1 (p<0.05). NB-3 significantly modulated the expression of RIPK3 (p=0.02) and DDIT3 (p=0.014), while NB-2 induced an increase of CDKN1A (p=0.03) and NB-4 induced PPARγ gene (p=0.0006).

Conclusion: NB-5 showed antitumor effects in solid and hematopoietic cancer cells, while other derivatives produced higher activity against hematopoietic cells. In acute leukemia cells, oxazolidinone derivatives modulated the expression of genes involved in apoptosis, ER stress, necroptosis and inflammation.
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http://dx.doi.org/10.1016/j.pharep.2017.03.005DOI Listing
August 2017

Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay.

Eur J Med Chem 2017 Aug 8;136:305-314. Epub 2017 May 8.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901, Recife, PE, Brazil. Electronic address:

In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI values ranging between 1.1 μM (2b) - 84.65 μM (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI = 0.01 μM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 μM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 μM) was able to interact with ctDNA and inhibited topoisomerase IIα activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2017.05.023DOI Listing
August 2017

Medicinal chemistry of antischistosomal drugs: Praziquantel and oxamniquine.

Bioorg Med Chem 2017 07 27;25(13):3259-3277. Epub 2017 Apr 27.

Laboratório de Química e Inovação Terapêutica (LQIT), Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego s/n, Cidade Universitária, 50670-901 Recife, PE, Brazil. Electronic address:

Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study.
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http://dx.doi.org/10.1016/j.bmc.2017.04.031DOI Listing
July 2017

Synthesis, cytotoxicity and antifungal activity of 5-nitro-thiophene-thiosemicarbazones derivatives.

Chem Biol Interact 2017 Jun 4;272:172-181. Epub 2017 May 4.

Laboratory of Synthesis and Drug Delivery, State University of Paraiba, 58071-160, Brazil.

In the present work, twelve N-substituted 2-(5-nitro-thiophene)-thiosemicarbazones derivatives (L1-12) were synthesized, characterized and their in vitro cytotoxic and antifungal activities were evaluated against Candida sp. and Cryptococcus neoformans. The probable mechanisms of action have been investigated by sorbitol and ergosterol assays. Additionally, ultrastructural study by Scanning Electron Microscopy was performed with the L10 compound. All compounds were obtained in good yield and their chemical structures were characterized on basis of their physico-chemical and Nuclear Magnetic Resonance - NMR, Spectrophotometric Absorption in the Infrared - IR and High-resolution Mass Spectrometry - HRMS data. The results showed that all strains were more sensitive to the compound L10 except Candida tropicalis URM 6551. On the other hand, the cytotoxicity assay by incorporation of tritiated thymidine showed moderate cytotoxic activity on L8 of the 50 μg/mLat which had the best MIC-cytotoxicity relationship. Concerning the study of the possible mechanism of action, the compounds were not able to bind to ergosterol in the membrane, do not act by inhibiting the synthesis of fungal cell wall (sorbitol assay). However, the Scanning Electron Microscopy - SEM analysis shows significant morphological changes in shape, size, number of cells and hyphae, and cell wall indicating a possible mechanism of action by inhibition of enzymes related to the ergosterol biosynthesis pathway. Our results demonstrate that N-substituted 2-(5-nitro-thiophene)-thiosemicarbazones derivatives are potential antifungal agents with activity associated with inhibition of enzymes related to biosynthesis of ergosterol.
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http://dx.doi.org/10.1016/j.cbi.2017.05.005DOI Listing
June 2017

Synthesis and biological evaluation of novel imidazolidine derivatives as candidates to schistosomicidal agents.

Rev Inst Med Trop Sao Paulo 2017 Apr 3;59:e8. Epub 2017 Apr 3.

Universidade Federal de Pernambuco, Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisas em Inovação Terapêutica Suely Galdino, Recife, Pernambuco, Brazil.

Introduction:: Schistosomiasis is an infectious parasitic disease caused by trematodes of the genus Schistosoma, which threatens at least 258 million people worldwide and its control is dependent on a single drug, praziquantel. The aim of this study was to evaluate the anti-Schistosoma mansoni activity in vitro of novel imidazolidine derivatives.

Material And Methods: : We synthesized two novel imidazolidine derivatives: (LPSF/PTS10) (Z)-1-(2-chloro-6-fluorobenzyl)-4-(4-dimethylaminobenzylidene)-5-thioxoimidazolidin-2-one and (LPSF/PTS23) (Z)-1-(2-chloro-6-fluoro-benzyl)-5-thioxo-4-(2,4,6-trimethoxy-benzylidene)-imidazolidin-2-one. The structures of two compounds were determined by spectroscopic methods. During the biological assays, parameters such as motility, oviposition, mortality and analysis by Scanning Electron Microscopy were performed.

Results: : LPSF/PTS10 and LPSF/PTS23 were considered to be active in the separation of coupled pairs, mortality and to decrease the motor activity. In addition, LPSF/PTS23 induced ultrastructural alterations in worms, after 24 h of contact, causing extensive erosion over the entire body of the worms.

Conclusion: : The imidazolidine derivatives containing the trimetoxy and benzylidene halogens showed promising in vitro schistosomicidal activity.
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http://dx.doi.org/10.1590/S1678-9946201759008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441159PMC
April 2017

In vivo study of schistosomicidal action of 1-benzyl-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one.

Biomed Pharmacother 2016 Oct 18;83:502-507. Epub 2016 Jul 18.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901, Recife, PE, Brazil. Electronic address:

Praziquantel has been the drug most widely used therapy against different forms of schistosomiasis around the world. However, this treatment has shown ineffective in humans and in experimental models of Schistosoma mansoni. New therapeutic alternatives have been tested, including the imidazolidine derivative LPSF/PT-09, which has shown high therapeutic potential in vitro. In this work, we tested the schistosomal activity of this derivative in doses of 250mg/kg and 200mg/kg in mice experimentally infected with a high parasite load of S. mansoni. Parasitological evaluations related to the number of S. mansoni worms and their oviposition were performed during the acute phase of the disease and have demonstrated moderate effectiveness of 30-54,4%. However, LPSF/PT-09 did not influence oviposition of the parasites or the embryonic development of the eggs. The results obtained in this model showed that the imidazolidine derivative LPSF/PT-09 presented significant antischistosomal activity in vivo, posing as a potential candidate for this class of drugs. However, a better understanding of the pharmacokinetics and pharmacodynamics of the imidazolidine derivative LPSF/PT-09 is needed.
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http://dx.doi.org/10.1016/j.biopha.2016.07.008DOI Listing
October 2016

Evaluation of anti-inflammatory effect of derivative (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone.

Biomed Pharmacother 2016 May 9;80:388-392. Epub 2016 Apr 9.

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil. Electronic address:

The present study aimed to further investigate the anti-inflammatory activity of (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone (BTTSC) as well as its antinociceptive effects. The anti-inflammatory activity was assessed using the model of ear edema induced by croton oil-induced and also evaluated in models of paw edema carrageenan-induced and by compound 48/80. Evaluation of the antinociceptive effect was performed through formalin test. In the nociception test induced by formalin the BTTSC showed activity in both phases of the pain, highlighting inflammatory pain, where it was able to reduce the time to paw lick 62.3, 84.30 and 100% at doses of 30, 100 and 300mgkg(-1). The anti-inflammatory activity was performed ear edema induced by croton oil, where none of the doses tested was capable of significantly regress edema. The paw edema carrageenan-induced showed activity compound, where the edema was reduced by 81.9 and 83.2% in the first two times of the experiment at the highest dose used. The paw edema assay induced by compound 48/80, showed that BTTSC after 15min of the inoculum phlogistic agent showed significant reduction of edema with values of 56.53% at a dose of 30mgkg(-1). Our results suggesting this compound exerts its antinociception effects connected with peripheral mechanisms. Furthermore, the compound was able to act in two phases of inflammation carrageenan-induced, highlighting the initial phase. This suggests an action on the early mediators of inflammation. The paw edema assay induced by compound 48/80 confirmed our hypothesis indicating action of the compound via histamine.
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http://dx.doi.org/10.1016/j.biopha.2016.03.047DOI Listing
May 2016

Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities.

Eur J Med Chem 2015 Nov;104:148-56

Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil. Electronic address:

A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 μM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 μM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies.
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http://dx.doi.org/10.1016/j.ejmech.2015.09.036DOI Listing
November 2015
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