Ana Luisa P. Miranda

Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives†

Abstract This work describes recent results from our research program aiming at the synthesis and pharmacological evaluation of new compounds acting as antiinflammatory, analgesic and platelet antiaggregatory. In this paper the synthesis and the pharmacological profile as analgesic, antiinflammatory and anti-platelet of new functionalized 2-pyridylarylhydrazone derivatives 5a–r are discussed. This class of N-heterocyclic derivatives represents a new series of prototype candidates with analgesic and antiinflammatory properties possessing also an important anti-aggregating activity. The pharmacological results herein disclosed suggest that the antiinflammatory and analgesic activities of these new pyridynehydrazone derivatives observed in the carrageenan pleurisy model and acetic acid writhing test, respectively, is probably due to an interference on the arachidonic acid (AA) metabolism. The most important antiinflammatory derivative 2-(2-formylfurane)pyridylhydrazone 5p presented a 79% inhibition of pleurisy at a dose of 80.1 μmol/kg. We also described the results concerning the mechanism of action of this series of N-heterocyclic derivatives in platelet aggregation which suggest a Ca2+ participation, probably by a complexation scavenger mechanism. Compound 2-(2-formylfurane)pyridylhydrazone 5p was able to complex Ca2+ in in vitro experiments at 100 μM concentration, indicating that this series of compounds can act as Ca2+ scavenger depending on the nature of the aryl moiety present at the imine subunit.

Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives

This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.

Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes

We describe herein the design, synthesis and pharmacological evaluation of novel 3-arylamine-imidazo[1,2-a]pyridine derivatives structurally designed as novel symbiotic prototypes presenting analgesic and anti-inflammatory properties. The derivatives obtained were submitted to in vivo assays of nociception, hyperalgesia and inflammation, and to in vitro assays of human PGHS-2 inhibition. These assays allowed the identification of compound LASSBio-1135 (3a) as an anti-inflammatory and analgesic symbiotic prototype. This compound inhibited moderately the human PGHS-2 enzyme activity (IC(50)=18.5 microM) and reverted the capsaicin-induced thermal hyperalgesia (100 micromol/kg, po) similarly to p38 MAPK inhibitor SB-203580 (2). Additionally, LASSBio-1135 (3a) presented activity similar to celecoxib (1) regarding the reduction of the carrageenan-induced rat paw edema (33% of inhibition at 100 micromol/kg, po). We also discovered derivatives LASSBio-1140 (3c) and LASSBio-1141 (3e) as analgesic and anti-inflammatory prototypes, which were able to attenuate the capsaicin-induced thermal hyperalgesia (100 micromol/kg, po) and reduce the carrageenan-induced paw edema (ED(50)=11.5 micromol/kg (3.3mg/kg) and 14.5 micromol/kg (4.1mg/kg), respectively), being both more active than celecoxib (1), despite the fact that their effects involve a different mechanism of action. Additionally, derivative LASSBio-1145 (3j) showed remarkable analgesic (ED(50)=22.7 micromol/kg (8.9 mg/kg)) and anti-inflammatory (ED(50)=8.7 micromol/kg (3.4 mg/kg)) profile in vivo (100 micromol/kg; po), in AcOH-induced abdominal constrictions in mice and carrageenan-induced rat paw edema models, respectively, being a novel orally-active anti-inflammatory drug candidate that acts as a selective PGHS-2 inhibitor (IC(50)=2.8 microM).

Purification and characterization of a phospholipase A2 isoenzyme isolated from Lachesis muta snake venom

A new phospholipase A2 (PLA2) isoenzyme was isolated from Lachesis muta crude venom, and was named LM-PLA2-II. This enzyme was purified by gel filtration on a Sephacryl S-200 HR column followed by reverse-phase chromatography on a C2/C18 column. LM-PLA2-II consists of a single polypeptide chain with an apparent molecular mass of 18 kDa and an isoelectric point at pH 5.4. The amino terminal sequence of the enzyme revealed a high degree of homology with other PLA2s from several sources. LM-PLA2-II has a high indirect hemolytic activity and a potent inhibitory effect on platelet aggregation induced by ADP and collagen. It also produces a significant paw edema reaction in rats. The edematous response in rats was abolished by pretreatment with either indomethacin or dexamethasone, suggesting the involvement of cyclo-oxygenase. Pretreatment of LM-PLA2-II with p-bromophenacyl bromide abolished all of these actions, clearly indicating that the biological activities, including the edematogenic effect, are dependent entirely on its enzymatic activity.

Synthesis and antinociceptive properties of new structurally planned imidazo[1,2-a]pyridine 3-acylarylhydrazone derivatives†

Abstract This paper describes recent results of a research program aiming at the synthesis and pharmacological evaluation of new N-heterocyclic functionalized acylarylhydrazone compounds, belonging to 3-acyl-(2-methyl-imidazo[1,2-a]pyridinyl)-arylhydrazone 2 series. These compounds were structurally planned applying classical ring bioisosterism strategies on previously described 4-acyl-(N-phenylpyrazolyl)-arylhydrazone 1, which presented important analgesic properties, in order to identify the pharmacophore contribution of the acylarylhydrazone moiety and investigate the structure—activity relationship (SAR) in these series. The results herein disclosed indicate that this strategy of molecular modification gave rise to a new series of analgesic and anti-inflammatory agents, where the activity seems to be more dependent on the nature of the para-substituent at the pharmacophore acylarylhydrazone (AAH) moiety, than the N-heterocyclic acyl-ring pattern.

Antinociceptive and hypothermic evaluation of the leaf essential oil and isolated terpenoids from Eugenia uniflora L. (Brazilian Pitanga)

Eugenia uniflora L. (Myrtaceae), known as Brazilian cherry tree, is a fruity tree spread all over Brazil used in popular medicine to treat inflammations, rheumatic pain and fever, as hypoglycemic, diuretic and has been widely used in the cosmetics industry. The present study discusses the chemical composition, the antinociceptive and hypothermic profile of the essential oil of pitangueira leaves. The chemical composition was evaluated by GC-MS and the main constituent of the oil was characterized, after isolation, as a mixture of atractylone (1) and 3-furanoeudesmene (2). The essential oil, its pentane fraction and the isolated mixture of sesquiterpenes (1 and 2), given orally, significantly inhibited the acetic acid-induced abdominal constrictions, increased the latency time in hot plate test and showed a hypothermic effect. The results suggest that the responsible for the antinociceptive and hypothermic effect were the isolated furanosesquiterpenes. These findings provided additional pharmacological information and may contribute for the use of Brazilian cherry tree as a phytomedicine.

Aspectos químicos, biológicos e etnofarmacológicos do gênero Cassia

Species of Cassia are widely distributed in tropical and subtropical regions throughout the world, and have been extensively investigated chemically and pharmacologically.They are known to be a rich source of phenolic derivatives, most of them with important biological and pharmacological properties. Some Asian, African and Indian tribes use these species as a laxative, purgative, antimicrobial, antipyretic, antiviral and anti-inflammatory agent. Among a number of other classes of secondary metabolites, such as anthracene derivatives, antraquinones, steroids and stilbenoids, biologically active piperidine alkaloids are an especially important bioactive class of compounds that showed to be restricted to a small group of Cassia species. In this paper we present an overview of the chemical, biological and ethnopharmacological data on Cassia piblished in the literature.

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.

New isoxazole derivatives designed as nicotinic acetylcholine receptor ligand candidates.

In this work we report the synthesis and evaluation of the analgesic properties of new isosteric heterocyclic derivatives, presenting the isoxazole nucleus, designed as nicotinic acetylcholine receptor ligand candidates, analogues to alkaloid epibatidine. Compound 2-(3-methyl-5-isoxazolyl)pyridine (3) presented the best analgesic profile of this series in hot plate test, which was partially prevented by pretreatment with nicotinic receptor antagonist mecamylamine.

Design and Synthesis of Novel Potent Antinociceptive Agents: Methyl-imidazolyl N-Acylhydrazone Derivatives

This paper describes recent results of design, synthesis and pharmacological evaluation of new N-heterocyclic functionalized N-acylhydrazone compounds, belonging to the 2-methyl-imidazolyl-3-acylhydrazone class (4a-e). These compounds were planned by applying the molecular simplification strategy to propose the structural modifications on the previously described functionalized imidazo [1,2-a]pyridine 3-acylhydrazone series (2), which presented an important analgesic profile. This new series (4) was synthesized in order to investigate the possible pharmacophoric contribution of the N-heteroaromatic ring and N-acylhydrazone moieties to the analgesic activity. Compounds 4a-b are the most potent antinociceptive agents from this series.