Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives

A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

Importância do metabolismo no planejamento de fármacos

It is widely recognized that pharmacokinetic optimization needs to be addressed early in drug discovery to reduce the high failure rate in bringing drugs to market. Poor absorption, too short duration of action due to high elimination rate, or the presence of active metabolites are examples of properties that can potentially lead to unsuccessful clinical programmes. Here I describe a brief overview of advantages and molecular strategies for improving metabolic and pharmacokinetic properties applied to the discovery of fluconazol, beta-blockers, ritonavir and ezetimibe and to the development of the prodrugs enalapril and bambuterol.

Genetic relationship of diarrheagenic Escherichia coli pathotypes among the enteropathogenic Escherichia coli O serogroup

The genetic relationship among the Escherichia coli pathotypes was investigated. We used random amplified polymorphic DNA (RAPD) data for constructing a dendrogram of 73 strains of diarrheagenic E. coli. A phylogenetic tree encompassing 15 serotypes from different pathotypes was constructed using multilocus sequence typing data. Phylogram clusters were used for validating RAPD data on the clonality of enteropathogenic E. coli (EPEC) O serogroup strains. Both analyses showed very similar topologies, characterized by the presence of two major groups: group A includes EPEC H6 and H34 strains and group B contains the other EPEC strains plus all serotypes belonging to atypical EPEC, enteroaggregative E. coli (EAEC) and enterohemorrhagic E. coli (EHEC). These results confirm the existence of two evolutionary divergent groups in EPEC: one is genetically and serologically very homogeneous whereas the other harbors EPEC and non-EPEC serotypes. The same situation was found for EAEC and EHEC.

The evolution of purinergic receptors involved in recognition of a blood meal by hematophagous insects

Many blood feeders use adenine nucleotides as cues for locating blood meal. Structure-activity relationship of adenine nucleotides as phagostimulants varies between closely-related species of blood feeders. It is suggested that a preexisting diverse pool of nucleotide-binding proteins present in all living cells, serves as a source of receptor proteins for the gustatory receptors involved in blood detection. It is proposed that the selection of any such nucleotide-binding protein is random.

Molecular Modeling Approaches for Determining Gene Function: application to a Putative Poly-A Binding Protein from Leishmania amazonensis (LaPABP)

The great expansion in the number of genome sequencing projects has revealed the importance of computational methods to speed up the characterization of unknown genes. These studies have been improved by the use of three dimensional information from the predicted proteins generated by molecular modeling techniques. In this work, we disclose the structure-function relationship of a gene product from Leishmania amazonensis by applying molecular modeling and bioinformatics techniques. The analyzed sequence encodes a 159 aminoacids polypeptide (estimated 18 kDa) and was denoted LaPABP for its high homology with poly-A binding proteins from trypanosomatids. The domain structure, clustering analysis and a three dimensional model of LaPABP, basically obtained by homology modeling on the structure of the human poly-A binding protein, are described. Based on the analysis of the electrostatic potential mapped on the model's surface and conservation of intramolecular contacts responsible for folding stabilization we hypothesize that this protein may have less avidity to RNA than it's L. major counterpart but still account for a significant functional activity in the parasite. The model obtained will help in the design of mutagenesis experiments aimed to elucidate the mechanism of gene expression in trypanosomatids and serve as a starting point for its exploration as a potential source of targets for a rational chemotherapy.

Ambergris: perfume e síntese

Rules for the occurence of the ambergris odor is presented and discussed in terms of the relationship between chemical structure and odor. A general overview of the major approaches in the synthesis of Ambrox® , the key ambergris-type compound, is also presented.

A química medicinal de N-acilidrazonas: novos compostos-protótipos de fármacos analgésicos, antiinflamatórios e anti-trombóticos

In this article are described new bioactive N-acylhydrazone (NAH) derivatives, structurally designed as optimization of aryl hydrazones precursors planned by molecular hybridization of two 5-lipoxigenase inhibitors, e.g. CBS-1108 and BW-755c. The analgesic, antiedematogenic and anti-platelet aggregating profile of several isosteric compounds was investigated by using classic pharmacological assays in vivo and ex-vivo, allowing to identify new potent peripheric analgesic lead, a new anti-inflammatory and an antithrombotic agent. During this study was discovered dozen of active NAH compounds clarifying the structure-activity relationship for this series of NAH derivatives, indicating the pharmacophore character of the N-acylhydrazone functionality.

Seleção de variáveis em QSAR

The process of building mathematical models in quantitative structure-activity relationship (QSAR) studies is generally limited by the size of the dataset used to select variables from. For huge datasets, the task of selecting a given number of variables that produces the best linear model can be enormous, if not unfeasible. In this case, some methods can be used to separate good parameter combinations from the bad ones. In this paper three methodologies are analyzed: systematic search, genetic algorithm and chemometric methods. These methods have been exposed and discussed through practical examples.

Introdução a modelagem molecular de fármacos no curso experimental de química farmacêutica

Molecular Modeling is an important tool in drug design and it is very useful to predict biological activity from a library of compounds. A wide variety of computer programs and methods have been developed to visualize the tridimensional geometry and calculate physical properties of drugs. In this work, we describe a practical approach of molecular modeling as a powerful tool to study structure-activity relationships of drugs, including some antibacterials, hormones, cholinergic and adrenergic agents. At first, the students learn how to draw 3D structures and use them to perform conformational and molecular analysis. Thus, they compare drugs with similar pharmacological activity by superimposing one structure on the top of another and evaluate the geometry and physical properties.

Síntese e avaliação da atividade antimicrobiana de novas 4-tiazolidinonas obtidas a partir de formilpiridina tiossemicarbazonas

Twelve novel 4-thiazolidinone derivatives (2a-l) have been synthesized by reacting formilpyridine thiosemicarbazones (1a-l) and anhydride maleic in toluene. Their chemical structures were confirmed by IR, ¹H and 13C NMR. The new compounds were submitted to in vitro evaluation against pathogenic Gram-positive, Gram-negative bacteria and yeasts. The findings obtained showed that the compounds 2a, 2d, 2e and 2g were effective against some of the bacterial strains used, whereas the compounds 2d, 2e and 2i exhibited a moderate antifungal activity against the yeast strains evaluated. An initial structure activity relationship (SAR) was established.

Propriedades químico-quânticas empregadas em estudos das relações estrutura-atividade

In this work we show that structure-activity relationship studies are of great importance in modern chemistry and biochemistry. In order to obtain a significant correlation, it is crucial that appropriate descriptors be employed. Thus, quantum chemical calculations are an attractive source of new molecular descriptors which can, in principle, express all the electronic and geometric properties of molecules and their interactions with the biological receptor.

Química e farmacologia de quimioterápicos antineoplásicos derivados de plantas

This review demonstrates the importance of plants as sources of molecules used in anticancer therapies. The approach is performed by relating the active molecules to their origins, details, mechanisms of action, structure-activity relationship and chemical characteristics of chemotherapeutical medicines. It was also described the development of anticancer agents from plants by the pharmaceutical industry and the difficulties to release these compounds as a trademark. These include the well known paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, and other molecules that are undergoing clinical trials.

Hemoglobina extracelular gigante de Glossoscolex paulistus: um extraordinário sistema supramolecular hemoproteico

Giant extracellular hemoglobins are considered the summit of complexity in systems that carry oxygen, constituting an extraordinary model system to the study of hemoproteins. This class includes the hemoglobin of the annelid Glossoscolex paulistus that presents high cooperativity, great oligomeric and redox stabilities and ability of oligomeric reassociation. These properties have motivated evaluations about its utilization as prototype of artificial blood and biosensor. Kinetic studies involving autoxidation and detailed spectroscopic characterizations of its ferrous and ferric species have propitiated information about the structure-activity relationship of this macromolecule. The present review analyzes several biochemical issues, evaluating the state-of-art of this subject.

Application of GA-PLS and GA-KPLS calculations for the prediction of the retention indices of essential oils

Genetic algorithm and partial least square (GA-PLS) and kernel PLS (GA-KPLS) techniques were used to investigate the correlation between retention indices (RI) and descriptors for 117 diverse compounds in essential oils from 5 Pimpinella species gathered from central Turkey which were obtained by gas chromatography and gas chromatography-mass spectrometry. The square correlation coefficient leave-group-out cross validation (LGO-CV) (Q²) between experimental and predicted RI for training set by GA-PLS and GA-KPLS was 0.940 and 0.963, respectively. This indicates that GA-KPLS can be used as an alternative modeling tool for quantitative structure-retention relationship (QSRR) studies.

Desenhos de estruturas químicas correlacionam-se com propriedades biológicas: MIA-QSAR

Descriptors in multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) are pixels of bidimensional images of chemical structures (drawings), which were used to model the trichomonicidal activities of a series of benzimidazole derivatives. The MIA-QSAR model showed good predictive ability, with r², q² and r val. ext.² of 0.853, 0.519 and 0.778, respectively, which are comparable to the best values obtained by CoMFA e CoMSIA for the same series. A MIA-based analysis was also performed by using images of alphabetic letters with the corresponding numeric ordering as dependent variables, but no correlation was found, supporting that MIA-QSAR is not arbitrary.