Antinociceptive effect and mechanism of action of isatin, N-methyl isatin and oxopropyl isatin in mice.

AIMS: There has been growing interest in the synthesis of new derivatives from isatin, found in Isatis genus. Our objectives were to characterize the antinociceptive mechanism of action of isatin, N-methyl-isatin (MI) and N-methyl-3-(2-oxopropyl)-3-hydroxy-2-oxindole (MOI). MATERIALS AND METHODS: Substances (0.1-10mg/kg, p.o.) were studied in chemical (paw licking induced by formalin, capsaicin or glutamate) or thermal (hot plate) models of nociception. The involvement of several systems was evaluated using different receptor antagonists. KEY FINDINGS: All three substances inhibit both phases of formalin-induced licking, increase the area under the curve and MI and MOI have a higher effect than that of morphine (in hot plate). Capsaicin and glutamate-induced licking were also reduced by all three substances. In the hot plate model, the antinociceptive effect of isatin was reduced by naloxone and atropine; naloxone, atropine and L-NAME reduced MI effect while naloxone, atropine, L-NAME, mecamylamine and ondansetron reduced MOI effect. SIGNIFICANCE: Our results suggest that isatin, MI and MOI: 1) present activity in models of nociception; 2) capsaicin and glutamate receptors seems to participate in the mechanism of action; 3) opioid, cholinergic, serotoninergic, nitrergic and adrenergic systems may be involved, at least in part, in the mechanism of action of some of these substances.

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase.

Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman's test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease.

["Doliarina and iron powder": an important medicine at Peckolt Pharmacy]. / "Pós de doliarina e ferro": um dos remédios importantes da Farmácia Peckolt.

The pharmacist Theodoro Peckolt was one of the most important figures in the history of the chemistry of natural Brazilian products. Like other nineteenth-century pharmacists in Brazil, he developed formulations and sold them at his pharmacy in Rio de Janeiro, and these enjoyed great prestige in the eyes both of the public and the medical community. The article discusses the relation between the illness originally called "opilação" (ancylostomiasis, or hookworm) and nineteenth-century treatment. It focuses especially on Peckolt Pharmacy's "Doliarina and iron powder," a formulation extracted from the Ficus gomelleira rubber plant. One of the article's goals is to use modern methods to analyze Ficus gomelleira and identify the chemical composition of the drug.

“Pós de doliarina e ferro”: um dos remédios importantes da Farmácia Peckolt / “Doliarina and iron powder”: an important medicine at Peckolt Pharmacy

O farmacêutico Theodoro Peckolt é uma das mais importantes figuras da história da química de produtos naturais brasileira. Como outros farmacêuticos do século XIX que atuavam no Brasil, desenvolveu formulações que comercializava em sua farmácia, localizada no Rio de Janeiro, e que tiveram grande prestígio junto à população e à classe médica. O texto apresenta a relação entre a doença identificada inicialmente como opilação e a terapêutica utilizada no século XIX, destacando uma das formulações da Farmácia Peckolt – “Pós de doliarina e ferro”. O produto tem sua origem no látex da espécie Ficus gomelleira(figueira-branca ou gameleira). O artigo tem entre seus objetivos revelar a composição química, feita por métodos modernos de análise do látex deFicus gomelleira.(AU)

The pharmacist Theodoro Peckolt was one of the most important figures in the history of the chemistry of natural Brazilian products. Like other nineteenth-century pharmacists in Brazil, he developed formulations and sold them at his pharmacy in Rio de Janeiro, and these enjoyed great prestige in the eyes both of the public and the medical community. The article discusses the relation between the illness originally called “opilação” (ancylostomiasis, or hookworm) and nineteenth-century treatment. It focuses especially on Peckolt Pharmacy’s “Doliarina and iron powder,” a formulation extracted from the Ficus gomelleira rubber plant. One of the article’s goals is to use modern methods to analyze Ficus gomelleira and identify the chemical composition of the drug.(AU)

"Pós de doliarina e ferro": um dos remédios importantes da Farmácia Peckolt / "Doliarina and iron powder": an important medicine at Peckolt Pharmacy

Resumo O farmacêutico Theodoro Peckolt é uma das mais importantes figuras da história da química de produtos naturais brasileira. Como outros farmacêuticos do século XIX que atuavam no Brasil, desenvolveu formulações que comercializava em sua farmácia, localizada no Rio de Janeiro, e que tiveram grande prestígio junto à população e à classe médica. O texto apresenta a relação entre a doença identificada inicialmente como opilação e a terapêutica utilizada no século XIX, destacando uma das formulações da Farmácia Peckolt – “Pós de doliarina e ferro”. O produto tem sua origem no látex da espécie Ficus gomelleira(figueira-branca ou gameleira). O artigo tem entre seus objetivos revelar a composição química, feita por métodos modernos de análise do látex deFicus gomelleira.

Abstract The pharmacist Theodoro Peckolt was one of the most important figures in the history of the chemistry of natural Brazilian products. Like other nineteenth-century pharmacists in Brazil, he developed formulations and sold them at his pharmacy in Rio de Janeiro, and these enjoyed great prestige in the eyes both of the public and the medical community. The article discusses the relation between the illness originally called “opilação” (ancylostomiasis, or hookworm) and nineteenth-century treatment. It focuses especially on Peckolt Pharmacy’s “Doliarina and iron powder,” a formulation extracted from the Ficus gomelleira rubber plant. One of the article’s goals is to use modern methods to analyze Ficus gomelleira and identify the chemical composition of the drug.

Docking of the alkaloid geissospermine into acetylcholinesterase: a natural scaffold targeting the treatment of Alzheimer's disease.

Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole-indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode between GSP and AChE, in which GSP functional groups may perform specific interactions with residues in the enzyme active site, according to the ligand-protein contacts detected by the LPC/CSU server. Four hydrogen bonds were detected between GSP and Tyr121, Ser122, Ser200, and His440, in which the last two residues belong to the catalytic triad (Ser200···His440···Glu327). Hydrophobic and π-π stacking interactions were also detected between GSP and Phe330 and Trp84, respectively; these are involved in substrate stabilization at the active site. This study provides the basis to propose structural changes to the GSP structure, such as molecular simplification and isosteric replacement, in order to aid the design of new potential AChE inhibitors that are relevant to the treatment of Alzheimer's disease.

Characterization of the antinociceptive and anti-inflammatory activities of fractions obtained from Copaifera multijuga Hayne.

ETHNOPHARMACOLOGICAL RELEVANCE: Copaifera multijuga Hayne (Leguminosae) is a tree that produces an oleoresin, which is extensively commercialized in Brazil as capsules or crude oil for the treatment of several disorders. Ethnopharmacological studies show a diversity of indications such as anti-inflammatory and epidermal wound cicatrization. AIM OF THE STUDY: In the present work three fractions obtained from Copaifera multijuga oleoresin (hexane (HF), chloroform (CF), and methanol (MF) from a KOH impregnated silica gel column chromatography, representing the three main classes of compounds in the Copaifera genus (hydrocarbon sesquiterpenes, oxygenated sesquiterpenes and acidic diterpenes), were evaluated using antinociceptive and anti-inflammatory models. MATERIALS AND METHODS: HF, CF, and MF (doses ranging between 1 and 150 mg/kg, depending on the model used), Copaifera multijuga oleoresin (CMO, 100mg/kg, p.o.) and the reference drug morphine (5mg/kg, p.o.) were evaluated using models for analgesia (acetic acid-induced contortions and tail flick) or inflammation (rat paw oedema and increase in vascular permeability). To elucidate the mechanism of action from the fractions, animals were pre-treated with naloxone (opioid receptor antagonist, 5mg/kg, i.p.). RESULTS: Fractions significantly inhibited (in a concentration-dependant way) the number of contortions induced by acetic acid and the second phase of formalin-induced licking response. Similar results were observed in the tail flick model. The central antinociceptive effect for HF and CF at the doses of 50 and 100mg/kg was higher than the one observed for morphine (1mg/kg). Administration of naloxone inhibited the antinociceptive effect of fractions indicating that HF, CF, and MF may be acting on opioid receptors. All three fractions also inhibited rat paw oedema and the increase in vascular permeability induced by several phlogistic agents (carrageenan, histamine, and serotonin). CONCLUSIONS: Our results indicate that fractions obtained from Copaifera multijuga Hayne demonstrate an antinociceptive effect probably mediated by opioid receptors, and anti-inflammatory activity through inhibition of histaminergic and serotoninergic pathways.

Antineoplasic activity of Copaifera multijuga oil and fractions against ascitic and solid Ehrlich tumor.

The aim of this study was to investigate the effect of chronic treatment with C. multijuga oil on Ehrlich tumor evolution. C. multijuga was fractionated in a KOH impregnated silica gel column chromatography to give three distinct fractions, i.e., hexanic, chloroformic, and methanolic, mainly composed by hydrocarbon sesquiterpenes, oxygenated sesquiterpenes and acidic diterpenes, respectively. Results demonstrated that the C. multijuga oil, the hexanic, and chloroformic fractions did not develop toxic effects. The oil, hexanic and chloroformic fractions (doses varying between 100 and 200mg/kg) showed antineoplasic properties against Ehrlich ascitic tumor (EAT) and solid tumor during 10 consecutive days of treatment inhibiting ascitic tumor cell number, reverting medulla and blood cell counts to values similar to control group, and inhibiting the increase on several inflammatory mediators (total protein, PGE(2), nitric oxide, and TNF) on ascitic fluid. The treatment also inhibited the increase in paw volume on tumor-inoculated mice. In conclusion, C. multijuga as well as its fractions demonstrated antineoplasic effect even after oral administration confirming its use by traditional medicine.

Indole glucoalkaloids from Chimarrhis turbinata and their evaluation as antioxidant agents and acetylcholinesterase inhibitors.

As part of our study on bioactive agents from Brazilian rainforest plants, two new glucoalkaloids, 3,4-dehydro-strictosidine (1) and 3,4-dehydro-strictosidinic acid (2), were isolated from Chimarrhis turbinata, along with seven known glucoalkaloids, cordifoline (3), strictosidinic acid (4), strictosidine (5), 5 alpha-carboxystrictosidine (6), turbinatine (7), desoxycordifoline (8), and harman-3-carboxylic acid (9). The structures of the new alkaloids were established on the basis of comprehensive spectral analysis, mainly 1D and 2D NMR experiments, as well as high-resolution HRESIMS. Alkaloid 3 showed strong free-radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) as well as pronounced antioxidant activity evidenced by redox properties measured by ElCD-HPLC. Additionally, alkaloids 1-9 were submitted to TLC screening for acetylcholinesterase inhibitors. Both 7 and 8 were shown to be moderate acetylcholinesterase inhibitors at a concentration of 0.1 and 1.0 microM, respectively. In an in vitro rat brain assay, 7 showed moderate activity (IC(50) 1.86 microM), compared to the standard compound, galanthamine (IC(50) 0.92 microM).

Synthetic and theoretical studies on the reduction of electron withdrawing group conjugated olefins using the Hantzsch 1,4-dihydropyridine ester.

The Hantzsch 1,4-dihydropyridine ester (1) has been observed to be a useful selective reducing agent for the reduction of electron-withdrawing conjugated double bonds. The rate of this reaction was observed to be dependent upon the nature of the conjugated substituents and, consequently, the electronic nature of the unsaturated double bond. Theoretical calculations confirmed the importance of the HOMO-LUMO gap for this reaction and implicated a hydride transfer, agreeing with the experimentally observed reaction rate order. The calculations also revealed the importance of a boatlike structure of the 1,4-dihydropyridine nucleus as well as a trans arrangement of the ester groups to facilitate the hydride transfer.

Constituintes químicos de Burlemarxia rodriguesii Menezes & Semir (Velloziaceae)

Neste trabalho foi analisado o extrato apolar de Burlemarxia rodriguesii Menezes & Semir através da análise direta do extrato por métodos cromatográficos. Na análise por Cromatografia Gasosa de Alta Resolução (CGAR) e da Cromatografia de Alta Resolução acoplada à Espectrometria de Massas (CGAR-EM) foram detectados apenas os compostos majoritários. Para determinar os demais constituintes químicos presentes neste extrato foi realizado um pré-fracionamento no qual classes químicas como ácidos graxos, ésteres graxos, esteróis e terpenóides foram separados. A metodologia empregada permitiu a detecção e identificação de várias substâncias e séries homólogas através de co-injeções com padrões (em CGAR) e comparação de espectros (CGAR-EM).