Dalci José Brondani

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

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.

Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics

A new series of 1,2,4-oxadizoles 6a-g have been synthesised in good yields using the peptide synthesis strategy. The prepared compounds were tested for anti-inflammatory and antimicrobial activities. The anti-inflammatory activities were determined in the rat paw oedema induced by carrageenin. Compounds 6a, c, f and g (i.v.) significantly inhibited the rat paw oedema induced by carrageenin depending upon the dose employed. The compounds were also evaluated for their in vitro antimicrobial activity. Some compounds were found to have significant activity against Gram positive and Gram negative microorganisms.

Purificação e caracterização da beta-lapachona e estudo de estabilidade dos cristais em diferentes condições de armazenamento

The b-lapachone is a product obtained from the Ipe Roxo tree [Tabebuia avellandae], which has proved its excellent antineoplasic potential acting through a particular mechanism of apoptosis against various cancer types. This study aims at determining the identity card of b-lapachone by means of physico-chemical and pharmaco-technical characterization. A purifying process has been performed, as well as the isolation of a contaminant, its isomer a-lapachone. A stability study was also performed, determining the ideal storing conditions for b-lapachone, essential for the ongoing pre-formulation studies for obtaining the different classic pharmaceutical forms and modified release systems.

Synthesis and characterization of new amino acyl-4-thiazolidones

A series of heterocyclic compounds with a 4-thiazolidone nucleus and amino acyl moiety were synthesized by protection reaction of thiosemicarbazide using the symmetrical anhydride (Boc)2O and cyclization with chloroacetic acid under mild conditions. Trifluoroacetic acid was used to obtain 4-thiazolidone and the a-amino acid condensation reactions were carried out using strategies for peptide synthesis. The characterization of this new class of compounds was performed using IR and 1H-NMR spectroscopy.

Synthesis and antimicrobial activities of 5-Arylidene-thiazolidine-2,4-dione derivatives.

Antibiotic resistance is considered one of the worlds major public health concerns. The main cause of bacterial resistance is the improper and repeated use of antibiotics. To alleviate this problem, new chemical substances against microorganisms are being synthesized and tested. Thiazolidines are compounds having many pharmacological activities including antimicrobial activities. For this purpose some thiazolidine derivatives substituted at position 5 in the thiazolidine nucleus were synthesized and tested against several microorganisms. Using a disc diffusion method, antimicrobial activity was verified against Gram-positive, Gram-negative, and alcohol acid resistant bacteria and yeast. The minimum inhibition concentrations (MIC) and minimum bactericidal concentrations (MBC) were determined. All derivatives showed antimicrobial activity mainly against Gram-positive bacteria, with MIC values ranging from 2 to 16 µg/mL.

Novel Nitrofurazone Derivatives Endowed with Antimicrobial Activity

The N‐alkylated derivatives from nitrofurazone were synthesised and evaluated in vitro for their efficacy as antimicrobial agents against representative strains, including methicillin‐resistant Staphylococcus aureus (MRSA). The derivative 2a demonstrated greater activity than the prototype and was comparable to currently used antimicrobial drugs.

SYNTHESIS OF NEW 1,2,4-OXADIAZOLES-DERIVED DIPEPTIDOMIMETICS, A POTENTIAL CLASS OF ANTIINFLAMMATORY DRUGS

Substituted 1,2,4-oxadiazoles containing pseudopeptide moiety as the side chain have been synthesized as part of a program of a study aiming to discover potential antiinflammatory drugs. A simple and efficient strategy for the synthesis started with Boc-protected amino acids (Phe, Asp, Val, Asp, Glu, Leu and lie) and reactions conditions to allow the formation of dipeptidomimetics derivatives in good yields. Introduction 1,2,4-Oxadiazoles have attracted widespread attention due to their important pharmacological properties. These include antiviral (1), fungicide (2), herbicide (3), analgesic and antiinflammatory activities (4). Some of these also exhibited pronounced ß-adrenoreceptor blocking activity and moderate α-adrenoreceptor blocking properties (5). Oxadiazoles have also been used as dipeptidomimetics and their electrostatic and hydrogen bonding properties have been studied (6,7). It has been shown that therapeutically active agents with small peptides or amino acid residues reduce toxicity and enhance their therapeutic effect (8-10). Considering the potentiality of 1,2,4oxadiazoles, we undertook the synthesis of 8a-g employing a strategy from the peptide synthesis (11). This paper reports the synthesis of six such compounds for the first time and the confirmation of their structures by spectroscopic means.

SYNTHESIS OF NEW PEPTIDYL DERIVATIVES FROM 4-THIAZOLIDONE

Ana Cristina Lima Leite*, Luciene Maria F. Santos, Janaina Vers iani dos Anjos, Maria Patricia A lbuquerque de Farias, Ivone Antonia de Souza & Dalci Jose Brondani Laboratorio de Planejamento, Avaliafäo e Sintese de Färmacos LABSINFA Departamento de Ciencias Farmaceuticas, Rua Prof. Artur Sa s/n Cidade Universitäria Universidade Federal de Pernambuco, Recife-PEBrasil CEP: 50740-520 aclb@ufpe.br

N-pentyl-nitrofurantoin induces apoptosis in HL-60 leukemia cell line by upregulating BAX and downregulating BCL-xL gene expression

BACKGROUND Nitrofurantoin is a nitroderivative antibiotic that has bactericidal activity against pathogens causing urinary tract infection. A few studies have reported that nitrofurantoin has cytotoxic activity against cancer cells; however, nitrofurans remain a poorly explored class of compounds with respect to their anticancer potential. The aim of this study was to investigate the anticancer effects of a nitrofurantoin derivative, n-pentyl-nitrofurantoin (NFP), on HL-60 leukemia cells. METHODS Cytotoxicity was assayed by the MTT assay. Cell morphology and phosphatidylserine externalization were visualized after Giemsa-May-Grunwald and annexin V staining, respectively. DNA content and mitochondrial depolarization were measured by flow cytometry. BAX and BCL-xL expression was examined by RT-PCR. RESULTS NFP was 3.8-fold more cytotoxic against HL-60 leukemia cells than against normal cells. NFP reduced the number of viable cells 24h after the treatment with a concomitant increase in the number of apoptotic cells indicated by the externalization of phosphatidylserine, DNA fragmentation, and mitochondrial depolarization. The mRNA levels of BAX increased, whereas the mRNA levels of BCL-xL decreased. CONCLUSION The results indicate that NFP induces apoptosis in HL-60 cells by upregulating BAX and downregulating BCL-xL.