Publications by authors named "Marcelo Zaldini Hernandes"

22 Publications

  • Page 1 of 1

Streptomyces hygroscopicus UFPEDA 3370: A valuable source of the potent cytotoxic agent nigericin and its evaluation against human colorectal cancer cells.

Chem Biol Interact 2021 Jan 4;333:109316. Epub 2020 Dec 4.

Departamento de Antibióticos, Rua Prof. Moraes Rego, 1235, Universidade Federal de Pernambuco, Recife, Pernambuco, 50670-901, Brazil. Electronic address:

Streptomyces hygroscopicus UFPEDA 3370 was fermented in submerged cultivation and the biomass extract was partitioned, obtaining a fraction purified named EB1. After purification of EB1 fraction, nigericin free acid was obtained and identified. Nigericin presented cytotoxic activity against several cancer cell lines, being most active against HL-60 (human leukemia) and HCT-116 (human colon carcinoma) cell lines, presenting IC and (IS) values: 0.0014 μM, (30.0) and 0.0138 μM (3.0), respectively. On HCT-116, nigericin caused apoptosis and autophagy. In this study, nigericin was also screened both in vitro and in silico against a panel of cancer-related kinases. Nigericin was able to inhibit both JAK3 and GSK-3β kinases in vitro and its binding affinities were mapped through the intermolecular interactions with each target in silico.
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http://dx.doi.org/10.1016/j.cbi.2020.109316DOI Listing
January 2021

Immunogenicity of Potential CD4 and CD8 T Cell Epitopes Derived From the Proteome of .

Front Immunol 2019 14;10:3145. Epub 2020 Feb 14.

Department of Immunology, Fundação Oswaldo Cruz, Recife, Brazil.

A safe and effective vaccine against human leishmaniasis still requires the identification of better antigens for immunization and adequate models to evaluate the immune response. To support vaccine development, this work tested the immunogenicity of 10 different peptides derived from the proteome of , which were selected by their affinity to MHC complexes. Comparative cell proliferation assays were performed by culturing, in the presence of each peptide, PBMC cells from subclinical subjects (SC), cutaneous leishmaniasis patients with active disease (AD), post-treatment (PT) individuals, and healthy controls. Culture supernatants were then used for Th1, Th2, and Th17 cytokine measurements. Cells from selected PT samples were also used to assess the expression, by T cells, of the T-bet Th1 transcription factor. A robust cell proliferation was observed for the SC group, for all the tested peptides. The levels of Th1 cytokines were peptide-dependent and had substantial variations between groups, where, for instance, IFN-γ and TNF levels were some of the highest, particularly on PT cultures, when compared to IL-2. On the other hand, Th2 cytokines displayed much less variation. IL-6 was the most abundant among all the evaluated cytokines while IL-4 and IL-10 could be found at much lower concentrations. IL-17 was also detected with variations in SC and AD groups. T-bet was up-regulated in CD4 and CD8 T cells from the PT group after stimulation with all peptides. The peptide epitopes can differentially stimulate cells from SC, AD, and PT individuals, leading to distinct immune responses.
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http://dx.doi.org/10.3389/fimmu.2019.03145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033680PMC
November 2020

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.

Pharmaceuticals (Basel) 2019 Nov 17;12(4). Epub 2019 Nov 17.

Departamento de Antibióticos, Centro de Biociências, Universidade Federal de Pernambuco, Recife, PE, 50740-520, Brazil.

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds and were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, inhibited seven different kinases and strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that and caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).
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http://dx.doi.org/10.3390/ph12040169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958387PMC
November 2019

A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90.

Sci Rep 2019 10 14;9(1):14756. Epub 2019 Oct 14.

Gonçalo Moniz Institute, FIOCRUZ, Laboratory of Parasite - Host Interaction and Epidemiology, Salvador, 40296-710, Brazil.

Leishmaniasis is a neglected disease that affects millions of individuals around the world. Regardless of clinical form, treatment is based primarily on the use of pentavalent antimonials. However, such treatments are prolonged and present intense side effects, which lead to patient abandonment in many cases. The search for chemotherapeutic alternatives has become a priority. Heat Shock Protein 90 (Hsp90) inhibitors have recently come under investigation due to antiparasitic activity in Plasmodium sp., Trypanosoma sp. and Leishmania sp. Some of these inhibitors, such as geldanamycin and its analogs, 17-AAG and 17-DMAG, bind directly to Hsp90, thereby inhibiting its activity. Previous studies have demonstrated that different parasite species are more susceptible to some of these inhibitors than host cells. We hypothesized that this increased susceptibility may be due to differences in binding of Hsp90 inhibitors to Leishmania protein compared to host protein. Based on the results of the in silico approach used in the present study, we propose that geldanamycin, 17-AAG and 17-DMAG present an increased tendency to bind to the N-terminal domain of Leishmania amazonensis Hsp83 in comparison to human Hsp90. This could be partially explained by differences in intermolecular interactions between each of these inhibitors and Hsp83 or Hsp90. The present findings demonstrate potential for the use of these inhibitors in the context of anti-Leishmania therapy.
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http://dx.doi.org/10.1038/s41598-019-51239-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791876PMC
October 2019

Anti-hypersensitivity effects of the phthalimide derivative N-(4methyl-phenyl)-4-methylphthalimide in different pain models in mice.

Biomed Pharmacother 2017 Dec 13;96:503-512. Epub 2017 Oct 13.

Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Santa Catarina, Brazil. Electronic address:

The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1β, bradykinin, prostaglandin E or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target.
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http://dx.doi.org/10.1016/j.biopha.2017.10.048DOI Listing
December 2017

Combination of In Silico Methods in the Search for Potential CD4(+) and CD8(+) T Cell Epitopes in the Proteome of Leishmania braziliensis.

Front Immunol 2016 29;7:327. Epub 2016 Aug 29.

Department of Immunology, Fundação Oswaldo Cruz , Recife, Pernambuco , Brazil.

The leishmaniases are neglected tropical diseases widespread throughout the globe, which are caused by protozoans from the genus Leishmania and are transmitted by infected phlebotomine flies. The development of a safe and effective vaccine against these diseases has been seen as the best alternative to control and reduce the number of cases. To support vaccine development, this work has applied an in silico approach to search for high potential peptide epitopes able to bind to different major histocompatibility complex Class I and Class II (MHC I and MHC II) molecules from different human populations. First, the predicted proteome of Leishmania braziliensis was compared and analyzed by modern linear programs to find epitopes with the capacity to trigger an immune response. This approach resulted in thousands of epitopes derived from 8,000 proteins conserved among different Leishmania species. Epitopes from proteins similar to those found in host species were excluded, and epitopes from proteins conserved between different Leishmania species and belonging to surface proteins were preferentially selected. The resulting epitopes were then clustered, to avoid redundancies, resulting in a total of 230 individual epitopes for MHC I and 2,319 for MHC II. These were used for molecular modeling and docking with MHC structures retrieved from the Protein Data Bank. Molecular docking then ranked epitopes based on their predicted binding affinity to both MHC I and II. Peptides corresponding to the top 10 ranked epitopes were synthesized and evaluated in vitro for their capacity to stimulate peripheral blood mononuclear cells (PBMC) from post-treated cutaneous leishmaniasis patients, with PBMC from healthy donors used as control. From the 10 peptides tested, 50% showed to be immunogenic and capable to stimulate the proliferation of lymphocytes from recovered individuals.
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http://dx.doi.org/10.3389/fimmu.2016.00327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002431PMC
September 2016

New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi.

Eur J Med Chem 2016 Oct 24;121:387-398. Epub 2016 May 24.

Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil. Electronic address:

In previous studies, the compound 3-(bromopropiophenone) thiosemicarbazone was described as a potent anti-Trypanosoma cruzi and cruzain inhibitor. In view to optimize this activity, 1,3-thiazole core was used as building-block strategy to access new lead generation of anti T. cruzi agents. In this way a series of thiazole derivatives were synthesized and most of these derivatives exhibited antiparasitic activity similar to benznidazole (Bzd). Among them, compounds (1c) and (1g) presented better selective index (SI) than Bzd. In addition, compounds showed inhibitory activity against the cruzain protease. As observed by electron microscopy, compound (1c) treatment caused irreversible and specific morphological changes on ultrastructure organization of T. cruzi, demonstrating that this class of compounds is killing parasites.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.050DOI Listing
October 2016

Thiosemicarbazones as Aedes aegypti larvicidal.

Eur J Med Chem 2015 Jul 28;100:162-75. Epub 2015 May 28.

Quantum Theory Project, University of Florida, 2234 New Physics Building, Gainesville, PO Box 118435, Florida, USA.

A set of aryl- and phenoxymethyl-(thio)semicarbazones were synthetized, characterized and biologically evaluated against the larvae of Aedes aegypti (A. aegypti), the vector responsible for diseases like Dengue and Yellow Fever. (Q)SAR studies were useful for predicting the activities of the compounds not included to create the QSAR model as well as to predict the features of a new compound with improved activity. Docking studies corroborated experimental evidence of AeSCP-2 as a potential target able to explain the larvicidal properties of its compounds. The trend observed between the in silico Docking scores and the in vitro pLC50 (equals -log LC50, at molar concentration) data indicated that the highest larvicidal compounds, or the compounds with the highest values for pLC50, are usually those with the higher docking scores (i.e., greater in silico affinity for the AeSCP-2 target). Determination of cytotoxicity for these compounds in mammal cells demonstrated that the top larvicide compounds are non-toxic.
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http://dx.doi.org/10.1016/j.ejmech.2015.04.061DOI Listing
July 2015

Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities.

Eur J Med Chem 2015 20;96:491-503. Epub 2015 Apr 20.

Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.

The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups.
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http://dx.doi.org/10.1016/j.ejmech.2015.04.041DOI Listing
February 2016

2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation.

Eur J Med Chem 2014 Oct 6;86:48-59. Epub 2014 Aug 6.

Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.

The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3-thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease.
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http://dx.doi.org/10.1016/j.ejmech.2014.08.012DOI Listing
October 2014

Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity.

ChemMedChem 2014 Jan 7;9(1):177-88. Epub 2013 Nov 7.

Universidade Federal de Pernambuco (UFPE), Departamento de Química Fundamental, 50670-901, Recife, PE (Brazil); Fundação Oswaldo Cruz (Fiocruz), Centro de Pesquisas Gonçalo Moniz, CEP 40296-710, Salvador, BA (Brazil).

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.
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http://dx.doi.org/10.1002/cmdc.201300354DOI Listing
January 2014

Sulfonamide-metal complexes endowed with potent anti-Trypanosoma cruzi activity.

J Enzyme Inhib Med Chem 2014 Apr 25;29(2):230-6. Epub 2013 Feb 25.

Department of Chemistry, Bahauddin Zakariya University , Multan , Pakistan .

In this article, we describe that mononuclear complexes composed of (5-chloro-2-hydroxybenzylidene)aminobenzenesulfonamides (L1-3) of general formula (L2(M)2H2O, where M is Co, Cu, Zn, Ni or Mn) reduced epimastigote proliferation and were found cidal for trypomastigotes of Trypanosoma cruzi Y strain. Complexes C5 and C11 have IC50 of 2.7 ± 0.27 and 4.8 ± 0.47 µM, respectively, for trypomastigotes, when the positive control Nifurtimox, which is also an approved drug for Chagas disease, showed IC50 of 2.7 ± 0.25 µM. We tested whether these complexes inhibit the enzyme T. cruzi trypanothione reductase or acting as DNA binders. While none of these complexes inhibited trypanothione reductase, we observed some degree of DNA binding, albeit less pronounced than observed for cisplatin in this assay. Unfortunately, most of these complexes were also toxic for mouse splenocytes. Along with the present studies, we discuss a number of interesting structure-activity relationships and chemical features for these metal complexes, including computational calculations.
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http://dx.doi.org/10.3109/14756366.2013.766608DOI Listing
April 2014

Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice.

J Med Chem 2012 Dec 7;55(24):10918-36. Epub 2012 Dec 7.

Departamento de Química Fundamental, Centro de Ciências Exatas and da Natureza, Universidade Federal de Pernambuco, 50670-901, Recife, PE, Brazil.

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.
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http://dx.doi.org/10.1021/jm301518vDOI Listing
December 2012

Quercetin as an inhibitor of snake venom secretory phospholipase A2.

Chem Biol Interact 2011 Jan 4;189(1-2):9-16. Epub 2010 Nov 4.

Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato 255, Campinas, SP, Brazil.

As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors.
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http://dx.doi.org/10.1016/j.cbi.2010.10.016DOI Listing
January 2011

Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents.

Bioorg Med Chem 2010 Nov 29;18(22):7826-35. Epub 2010 Sep 29.

Department of Pharmaceutical Sciences, Centre for Health Science, Federal University of Pernambuco, 50740-520 Recife, PE, Brazil.

In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.
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http://dx.doi.org/10.1016/j.bmc.2010.09.056DOI Listing
November 2010

Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands.

Bioorg Med Chem 2010 Jun 21;18(11):3805-11. Epub 2010 Apr 21.

Grupo de Pesquisa em Inovação Terapêutica-GPIT, Universidade Federal de Pernambuco, Pernambuco, Brazil.

Eight new 5-arylidene-3-benzyl-thiazolidine-2,4-diones with halide groups on their benzyl rings were synthesized and assayed in vivo to investigate their anti-inflammatory activities. These compounds showed considerable biological efficacy when compared to rosiglitazone, a potent and well-known agonist of PPARgamma, which was used as a reference drug. This suggests that the substituted 5-arylidene and 3-benzylidene groups play important roles in the anti-inflammatory properties of this class of compounds. Docking studies with these compounds indicated that they exhibit specific interactions with key residues located in the site of the PPARgamma structure, which corroborates the hypothesis that these molecules are potential ligands of PPARgamma. In addition, competition binding assays showed that four of these compounds bound directly to the ligand-binding domain of PPARgamma, with reduced affinity when compared to rosiglitazone. An important trend was observed between the docking scores and the anti-inflammatory activities of this set of molecules. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, explained why the 3-(2-bromo-benzyl)-5-(4-methanesulfonyl-benzylidene)-thiazolidine-2,4-dione compound had the best activity and the best docking score. Almost all of the stronger hydrophilic interactions occurred between the substituted 5-arylidene group of this compound and the residues of the binding site.
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http://dx.doi.org/10.1016/j.bmc.2010.04.045DOI Listing
June 2010

Halogen atoms in the modern medicinal chemistry: hints for the drug design.

Curr Drug Targets 2010 Mar;11(3):303-14

Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco (UFPE), 50740-520, Recife, PE, Brazil.

A significant number of drugs and drug candidates in clinical development are halogenated structures. For a long time, insertion of halogen atoms on hit or lead compounds was predominantly performed to exploit their steric effects, through the ability of these bulk atoms to occupy the binding site of molecular targets. However, halogens in drug - target complexes influence several processes rather than steric aspects alone. For example, the formation of halogen bonds in ligand-target complexes is now recognized as a kind of intermolecular interaction that favorably contributes to the stability of ligand-target complexes. This paper is aimed at introducing the fascinating versatility of halogen atoms. It starts summarizing the prevalence of halogenated drugs and their structural and pharmacological features. Next, we discuss the identification and prediction of halogen bonds in protein-ligand complexes, and how these bonds should be exploited. Interesting results of halogen insertions during the processes of hit-to-lead or lead-to-drug conversions are also detailed. Polyhalogenated anesthetics and protein kinase inhibitors that bear halogens are analyzed as cases studies. Thereby, this review serves as one guide for the virtual screening of libraries containing halogenated compounds and may be a source of inspiration for the medicinal chemists.
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http://dx.doi.org/10.2174/138945010790711996DOI Listing
March 2010

Synthesis, Cruzain docking, and in vitro studies of aryl-4-oxothiazolylhydrazones against Trypanosoma cruzi.

ChemMedChem 2007 Sep;2(9):1339-45

Laboratório de Planejamento, Avaliação e Síntese de Fármacos-LABSINFA, Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, Rua Prof. Artur Sá S/N, Cidade Universitária, 50740-520, Recife, PE, Brazil.

Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target. Herein we describe a small library of aryl-4-oxothiazolylhydrazones that have been tested in assays against T. cruzi cell cultures. The docking studies carried out suggest that these compounds are potential ligands for the TCC enzyme. The most promising compound of this series, N-(4-oxo-5-ethyl-2'-thiazolin-2-yl)-N'-phenylthio-(Z)-ethylidenehydrazone (6 f), was shown to be very active at non-cytotoxic concentrations in in vitro assays with mammalian cells and has a potency comparable with reference drugs such as nifurtimox (Nfx) and benznidazole (Bdz).
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http://dx.doi.org/10.1002/cmdc.200700022DOI Listing
September 2007

Synthesis, biological evaluation and molecular modeling studies of arylidene-thiazolidinediones with potential hypoglycemic and hypolipidemic activities.

Eur J Med Chem 2007 Oct 3;42(10):1263-71. Epub 2007 Mar 3.

Departamento de Química, Universidade Católica de Pernambuco, Brazil.

New arylidene-thiazolidinediones (ATZDs) were synthesized and evaluated in the alloxan-induced hyperglycemia mice model. The molecular target taken into consideration is the nuclear PPAR-gamma whose crystallographic structure is available on the PDB database as 2PRG. Thus the hypoglycemic and hypolipidemic activities of compounds were compared with the result of their docking after removal of the co-crystallized ligand present in the 2PRG structure. Molecular modeling studies were carried out using the Autodock 3.0.5 and ADT 1.1 programs.
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http://dx.doi.org/10.1016/j.ejmech.2007.02.015DOI Listing
October 2007

Synthesis, docking, and in vitro activity of thiosemicarbazones, aminoacyl-thiosemicarbazides and acyl-thiazolidones against Trypanosoma cruzi.

Bioorg Med Chem 2006 Jun 3;14(11):3749-57. Epub 2006 Feb 3.

Avaliação e Síntese de Fármacos-LABSINFA, Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, Rua Prof. Artur Sá S/N, Cidade Universitária, 50740-520 Recife, PE, Brazil.

A novel series of thiosemicarbazone and aminoacyl-thiazolidones derivatives were synthesized. Their structure suggests that these compounds could have anti-Trypanosoma cruzi activity. Biological evaluation indicates that some of these compounds are able to inhibit the growth of T. cruzi in concentrations non-cytotoxic to mammalian cells. Docking studies were carried out in order to investigate the binding pattern of these compounds for the T. cruzi cruzain (TCC) protein, and these showed a significant correlation with experimental data.
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http://dx.doi.org/10.1016/j.bmc.2006.01.034DOI Listing
June 2006

Chemometric study of liquid water simulations. I. The parameters of the TIP4P model potential.

J Comput Chem 2003 Jun;24(8):973-81

Departamento de Química Fundamental, Universidade Federal de Pernambuco, 50740-540 Recife (PE), Brazil.

The multivariate chemometric techniques two level factorial design (TLFD) and principal component analysis (PCA) were used to investigate the TIP4P model potential behavior with respect to perturbations on all intermolecular interaction parameters. The effects of these perturbations were calculated for the enthalpy of vaporization, the density, the first maximum of the radial distribution functions of the O-H and O-O pairs, and the second maximum of the radial distribution function of the O-H pair obtained from Monte Carlo simulations of liquid water at 25 degrees C. The principal effects were quantified and rationalized in terms of the pair-wise interaction potential of the TIP4P model. They also corroborate previously published sensitivity analysis results using molecular dynamics and other model potentials. In addition, significant interaction effects between some parameters of the TIP4P model potential were observed and quantified, which hardly could be obtained without such a statistic approach. These interaction effects are very regular and systematic, and their behavior has not been encountered in other chemometric studies and cannot be rationalized in terms of the functional form of the pair-wise potential.
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http://dx.doi.org/10.1002/jcc.10273DOI Listing
June 2003
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