Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.
The histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson’s, and Alzheimer’s diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01 series) molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pKi 6.40), while the chlorinated compound LINS01007 has moderate affinity for H4R (pKi 6.06). In addition, BRET assays to assess the functional activity of Gi1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg) than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.
The histamine receptors (HRs) are members of G-protein-coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H R and H R have been explored as targets for drug discovery, including in the search for dual-acting H R/H R ligands. The H R, the most recent histamine receptor, is a promising target for novel anti-inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H R/H R ligands herein. The results showed the compounds presented affinity (K ) for H R/H R in micromolar range, and they are more selective to H R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl-substituted compound LINS01005 has shown the higher affinity of the set for H R, but no considerable selectivity toward this receptor over H R. LINS01005 showed interesting anti-inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX-2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti-inflammatory agents.
Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.
Recebido em 12/6/12; aceito em 7/12/12; publicado na web em 12/3/13 STUDY OF THE STRUCTURE-ACTIVITY RELATIONSHIPS OF PARABENS: A PRACTICAL CLASS. Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify theircorrelation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes.Keywords: parabens; drug synthesis; SAR. INTRODUÇÃOOs conservantes são usados em muitos cosméticos para aumentar a vida útil dos produtos, impedindo o desenvolvimento de microrganismos que podem causar doenças ou, simplesmente, prejudicar o bom aspecto do produto final. Um conservante ideal deve ser efetivo em uma concentração baixa e não tóxica; apresentar boa solubilidade em água; compatibilidade com outros excipientes; não ter características organolépticas adequadas; apresentar um amplo espectro de atividade para bactérias e fungos; e custo razoável. 1Dentre os conservantes mais utilizados em formulações farmacêu-ticas e cosméticas, destacam-se os parabenos. Parabenos são ésteres do ácido p-hidroxibenzoico que apresentam características como amplo espectro de atividade, boa solubilidade em água e são incolores, inodoros e insípidos.1,2 Sabe-se que a atividade antimicrobiana desses compostos aumenta com o aumento da cadeia carbônica do substituinte do éster, entretanto sua solubilidade em água decresce proporcionalmente.3 São mais ativos contra fungos do que contra bactérias.1 Entre os parabenos mais utilizados como conservantes, estão o metilparabeno (1) e o propilparabeno (3) (Figura 1).O mecanismo de ação antimicrobiana dos parabenos é desconhecido, porém bastante complexo. Propõe-se que os parabenos apresentam ação sobre a síntese de DNA e RNA, 4 sobre enzimas-chave como ATPases e fosfotransferases 5 ou, ainda, sobre os mecanismos de transporte pelas membranas. 6O estudo das relações entre estrutura química e atividade bioló-gica (REA) de moléculas bioativas é uma prática muito comum em Química Farmacêutica Medicinal. Os primeiros estudos deste tipo foram feitos por Crum-Brown e Fraser em 1869, 7 quando demonstraram que compostos contendo uma amina terciária (como a estricnina, morfina, atropina e nicotina) se tornavam bloqueadores neuromusculares quando metilados e, assim, transformados nos respectivos quaternários de amônio. Desta forma, concluíram (mesmo que de maneira precipitada) que o grupo amônio quaternário era necessário para a atividade bloqueadora neuromuscular. 8 A partir de então, a exploração de grupos funcionais em moléculas biologicament...
Mesoporous gamma-aluminas (γ-Al 2 O 3 ) were synthesized starting from an unusual precursor of polyoxohydroxide aluminum (POHA). This precursor was obtained from aluminum oxidation in alkaline water-ethanol solvent in the presence of d-glucose that induces the formation of a gel, which leads to the POAH powder after ethanolic treatment. Precipitated POHAs were calcined at different temperatures (300, 400, 700 and 900 °C) resulting in the metastable γ-Al 2 O 3 phase. Whereas at 300 °C no γ-Al 2 O 3 phase was formed, unexpectedly, mesoporous γ-Al 2 O 3 was obtained at 400 ºC having a high specific surface area (282 m 2 /g) and a narrow pore size distribution. At higher temperatures, the aluminas had the expected decrease in surface area: 166 m 2 /g (700 °C) and 129 m 2 /g (900 °C), respectively. The structural change from POHA to alumina calcined at 400 ºC occurs directly without the need to isolate the hydroxide or oxyhydroxide aluminum precursors. Both POHA and transition aluminas were characterized by Fourier Transform Infrared spectroscopy (FTIR), X-ray diffraction (XRD), N 2 sorption and Scanning Electron Microscopy (SEM). These findings show an alternative route to produce high standard aluminas.
Iodocyclization of 2-allylphenols is a suitable method to access furans and dihydrofurans with adequate yields. Several methodologies to iodocyclization are reported in the literature; however, since some data about the conditions are conflicting, a more systematic approach is needed to define the best conditions. In this work, we performed a full 2
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