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Recebido em 27/9/06; aceito em 10/8/07; publicado na web em 19/3/08 STRUCTURE, REACTIVITY AND BIOLOGICAL PROPERTIES OF HIDANTOINES. Hydantoin (imidazolidine-2,4-dione) is a 2,4-diketotetrahydroimidazole discovered by Baeyer in 1861. Thiohydantoins and derivatives were prepared, having chemical properties similar to the corresponding carbonyl compounds. Some biological activities (antimicrobial, anticonvulsant, schistosomicidal) are attributed to the chemical reactivity and consequent affinity of hydantoinic rings towards biomacromolecules. Therefore, knowledge about the chemistry of hydantoins has increased enormously. In this review, we present important aspects such as reactivity of hydantoins, acidity of hydantoins, spectroscopy and cristallographic properties, and biological activities of hydantoin and its derivatives.Keywords: hydantoin; reactivity; biological properties. INTRODUÇÃOOs fármacos são substâncias usadas para impedir ou curar doenças em homens e animais. A introdução de novos fármacos na terapêutica é necessária para o aperfeiçoamento do tratamento de doenças já existentes ou recém-identificadas ou, ainda, para a implementação de tratamentos mais seguros e eficazes. Desde a Antigüidade, diversas civilizações possuíam coleções de produtos naturais que usavam como tratamentos para os diversos males. Em particular, no final do século XIX, a busca por medicamentos menos tóxicos resultou na introdução de substâncias sintéticas na terapêutica e seu uso foi amplamente disseminado no século XX. 1 Em estatísticas da área de química medicinal, 2 em 2001, cerca de 85% dos fármacos disponíveis na terapêutica moderna são de origem sintética, isto sem considerar aqueles oriundos de processos de semi-síntese. Neste contexto, diversas substâncias sintéticas são obtidas a partir de derivações de anéis heterocíclicos, dentre as quais, destaca-se a hidantoína (Figura 1a) devido à sua potencialidade como protótipo para o desenvolvimento de novos fármacos.A hidantoína foi descoberta por Baeyer, em 1861, enquanto pesquisava as reações do ácido úrico e corresponde ao 2,4-dicetotetra-hidro-imidazol, embora seja também denominada imidazolidina-2,4-diona. A primeira fórmula estrutural da hidantoína foi sugerida por Kolbe, em 1870, tendo sido modificada por Strecker, que, neste mesmo ano, propôs uma nova fórmula que é aceita até hoje. A partir dessa época, o sistema anelar hidantoínico tem sido intensivamente estudado tanto no tocante aos aspectos químicos, quanto biológicos. 3A substituição dos átomos de oxigênio carbonílicos da hidantoína por átomos de enxofre origina três tio-derivados: a 2-tio-hidantoína (2-tioxo-imidazolidin-4-ona) (Figura 1b), a 4-tiohidantoína (4-tioxo-imidazolidin-2-ona) (Figura 1c) e a 2,4-ditiohidantoína (imidazolidina-2,4-ditiona) (Figura 1d).A primeira tio-hidantoína sintética, a 2-tio-hidantoína (2-tioxoimidazolidin-4-ona), foi obtida por Klason (1890) pelo aquecimento do hidrocloreto de etil-aminoacetato em presença de tiocianato de potássio. 4 Mais tarde, em 1911, três novos trabalhos pub...

(Bromomethyl)dibromoindium(III), Br2InCH2Br, reacts with tetraethylammonium bromide, 1,4-dioxane (diox), or tetrahydrofuran (thf) to produce addition compounds of the general formula Br2In(L) n CH2Br (L = diox, thf, n = 2; L = Br-, n = 1) in which the ligand is directly attached to the indium atom. The crystal structure of the ionic derivative [(C2H5)4N][Br3InCH2Br] has been solved by X-ray diffraction methods:  cell constants a = 10.1710(1) Å, b = 10.1710(1) Å, and c = 35.1745(4) Å, space group P41212, V = 3638.78(7) Å3, Z = 8, R = 0.0519, R w = 0.0543 for 2374 independent reflections. Quantum mechanical calculations, by the PM3 method, on the parent molecule confirm the postulated strong intramolecular interaction between the bromomethylic bromine and the metal center. Complete intramolecular bromide transfer gives the tautomeric structure Br3Inδ-CH2 δ+. The calculations also satisfactorily predict the bond distances and angles in the Br3InCH2Br- anion. Preliminary investigations of the energetics and chemical properties of Br2In(diox)2CH2Br show that the molecule can decompose via elimination of methylene, which can be trapped by a suitable substrate (carboxylic acid, iodine), demonstrating the potential use of the compound as a methylene-transfer reagent.

Trypanosomatids are protozoan parasites responsible for leishmaniasis, Chagas disease and sleeping sickness. The design of new antitrypanosomatid drugs with trypanosomicidal and leishmanicidal activities is an effective perspective. The thiazolidinone ring is an important scaffold for several biological disorders. Herein, 4‐oxothiazolidine‐5‐acetic acids (1 a‐1 w) have been synthesized from respective thiosemicarbazone and maleic anhydride. Some of these 4‐oxothiazolidine‐5‐acetic acids were toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 1 e (IC50=10 μM), 1 u (IC50=8.94 μM), 1 g (IC50=5.65 μM) and 1 w (14.06 μM) showed the best anti‐T. cruzi activity for trypomastigote form, while 1 e, 1 u and 1 g showed SI higher than benznidazole (BZD). Similarly, against epimastigote the compound 1 q (IC50epi= 4.70 μM) has been found more selective and most active than benznidazole. However, evaluation against T. cruzi revealed that most of the active compounds have a low inhibition profile and weak leishmanicidal activity. In silico data suggests a good drug‐likeness profile, high chemical stability and demonstrate the use of these compounds in the designing of new anti‐T. cruzi and anti‐Leishmanial drugs.

BackgroundHarpalycin 2 (HP-2) is an isoflavone isolated from the leaves of Harpalyce brasiliana Benth., a snakeroot found in northeast region of Brazil and used in folk medicine to treat snakebite. Its leaves are said to be anti-inflammatory. Secretory phospholipases A2 are important toxins found in snake venom and are structurally related to those found in inflammatory conditions in mammals, as in arthritis and atherosclerosis, and for this reason can be valuable tools for searching new anti-phospholipase A2 drugs.MethodsHP-2 and piratoxin-III (PrTX-III) were purified through chromatographic techniques. The effect of HP-2 in the enzymatic activity of PrTX-III was carried out using 4-nitro-3-octanoyloxy-benzoic acid as the substrate. PrTX-III induced platelet aggregation was inhibited by HP-2 when compared to aristolochic acid and p-bromophenacyl bromide (p-BPB). In an attempt to elucidate how HP-2 interacts with PrTX-III, mass spectrometry, circular dichroism and intrinsic fluorescence analysis were performed. Docking scores of the ligands (HP-2, aristolochic acid and p-BPB) using PrTX-III as target were also calculated.ResultsHP-2 inhibited the enzymatic activity of PrTX-III (IC50 11.34 ± 0.28 μg/mL) although it did not form a stable chemical complex in the active site, since mass spectrometry measurements showed no difference between native (13,837.34 Da) and HP-2 treated PrTX-III (13,856.12 Da). A structural analysis of PrTX-III after treatment with HP-2 showed a decrease in dimerization and a slight protein unfolding. In the platelet aggregation assay, HP-2 previously incubated with PrTX-III inhibited the aggregation when compared with untreated protein. PrTX-III chemical treated with aristolochic acid and p-BPB, two standard PLA2 inhibitors, showed low inhibitory effects when compared with the HP-2 treatment. Docking scores corroborated these results, showing higher affinity of HP-2 for the PrTX-III target (PDB code: 1GMZ) than aristolochic acid and p-BPB. HP-2 previous incubated with the platelets inhibits the aggregation induced by untreated PrTX-III as well as arachidonic acid.ConclusionHP-2 changes the structure of PrTX-III, inhibiting the enzymatic activity of this enzyme. In addition, PrTX-III platelet aggregant activity was inhibited by treatment with HP-2, p-BPB and aristolochic acid, and these results were corroborated by docking scores.