Atypical antipsychotics olanzapine and clozapine increase bone loss in female rats with experimental periodontitis.

BACKGROUND AND OBJECTIVES: Periodontitis is a highly prevalent disease in psychiatric patients, including those undergoing symptomatic treatment with second-generation antipsychotics. Some of these drugs, such as clozapine (CLO) and olanzapine (OLA), have prominent metabolic effects such as weight gain, hyperglycemia, and dyslipidemia, which are risk factors for periodontitis. In addition to the metabolic effects, there are reports of changes in salivary flow, gingival bleeding, and caries. In this context, we aimed to evaluate if the metabolic effects of OLA and CLO alter periodontal parameters in an animal model of periodontitis without the environmental and psychosocial biases inherent to human diseases. METHODS: In the first set of experiments, male and female adult Wistar rats received oral administration of CLO, OLA, or vehicle for 45 days. They were evaluated for body mass composition and weight gain, blood glucose parameters (fasting and glucose tolerance and insulin resistance tests), and lipid profile (HDL, total cholesterol, and triglycerides). In a second set of experiments, the same measurements were performed in female rats exposed to the antipsychotics for 45 days and ligature-induced periodontitis on the 30th day of treatment. Macroscopic measurements of exposed roots, microtomography in the furcation region of the first molar, and histological evaluation of the region between the first and second molars were evaluated to assess bone loss. Additionally, gingival measurements of myeloperoxidase activity and pro-inflammatory cytokine TNF-α were made. RESULTS: Only females exposed to OLA had more significant weight gain than controls. They also exhibited differences in glucose metabolism. Ligature-induced periodontitis produced intense bone retraction without changing the density of the remaining structures. The bone loss was even higher in rats with periodontitis treated with OLA or CLO and was accompanied by a local increase in TNF-α caused by CLO. These animals, however, did not exhibit the same metabolic impairments observed for animals without periodontitis. CONCLUSION: The use of clozapine and olanzapine may be a risk factor for periodontal disease, independent of systemic metabolic alterations.

Zinc deficiency disrupts pain signaling promoting nociceptive but not inflammatory pain in mice.

Zinc (Zn) is an essential micronutrient involved in the physiology of nervous system and pain modulation. There is little evidence for the role of nutritional Zn alternations to the onset and progression of neuropathic (NP) and inflammatory pain. The study investigated the effects of a zinc restricted diet on the development of pain. Weaned mice were submitted to a regular (38 mg/kg of Zn) or Zn deficient (11 mg/kg of Zn) diets for four weeks, pain responses evaluated (mechanical, cold and heat allodynia; formalin- and carrageenan-induced inflammatory hypernociception), plasma and tissues collected for biochemical and metabolomic analysis. Zn deficient diet inhibited animal growth (37%) and changed mice sensitivity pattern, inducing an intense allodynia evoked by mechanical, cold and heat stimulus for four weeks. The inflammatory pain behavior of formalin test was drastically reduced or absent when challenged by an inflammatory stimulus. Zn restriction also reduce plasma TNF, increase neuronal activation, oxidative stress, indicating a disruption of the immune response. Liver metabolomic analyses suggest a downregulation of lipid metabolism of arachidonic acid. Zn restriction since weaned disrupts pain signaling considerably and reduce inflammatory pain. Zn could be considered a predisposing factor for the onset of chronic pain such as painful neuropathies.

Periodontal status, vascular reactivity, and platelet aggregation changes in rats submitted to hypercholesterolemic diet and periodontitis.

BACKGROUND AND OBJECTIVES: Periodontitis can corroborate with development and progression of atherosclerosis and a possible bidirectional interaction between both pathologies has been hypothesized. The aim of this work was to study the interactions between diet-induced hypercholesterolemia and ligature-induced periodontitis in Wistar rats submitted to both conditions. MATERIAL AND METHODS: Animals were divided into four experimental groups: C (control: standard diet without periodontitis), Perio (periodontitis plus standard diet), HC (high cholesterol diet without periodontitis), and HC + Perio (high cholesterol diet plus periodontitis). The diets were offered for 45 days and a silk ligature was applied in the lower first molars of Perio and HC-Perio animals on day 34 and maintained for 11 days until euthanasia. The mandibles were excised, and alveolar bone loss was determined by macroscopic and micro-tomographic (µ-CT) imaging. Blood samples were obtained, and platelet aggregation was induced in plasma rich in platelets by adenosine diphosphate (ADP) and collagen. Endothelium-dependent vascular reactivity and protein expression of endothelial (eNOS), phosphorylated endothelial (peNOS), and inducible (iNOS) nitric oxide synthases were evaluated in aorta samples. RESULTS: The HC diet combined with periodontitis (HC + Perio group) was associated with an increased alveolar bone loss, when compared to the other groups. Both in Perio and HC groups, platelet aggregation induced by ADP or collagen was increased, while maximum aortic relaxation induced by acetylcholine was decreased. Periodontitis or HC diet alone decreased the expression of peNOS and HC diet increased the expression of iNOS. In contrast, no additive or synergistic effects were found in vascular reactivity or in platelet aggregation when the two conditions were associated (HC + Perio group). CONCLUSION: Hypercholesterolemia accelerated the process of bone loss induced by periodontitis while a high cholesterol diet or periodontitis individually increased platelet aggregation and vascular reactivity in rats without additive or synergistic effects, when associated.

Geissoschizoline, a promising alkaloid for Alzheimer's disease: Inhibition of human cholinesterases, anti-inflammatory effects and molecular docking.

Due to the lack of effective pharmacotherapy options to treats Alzheimer's disease, new strategies have been approached in the search for multi-target molecules as therapeutic options. In this work, four indole alkaloids, geissoschizoline, geissoschizone, geissospermine, and 3',4',5',6'-tetradehydrogeissospermine were isolated from Geissospermum vellosii (Pao pereira) and evaluated for their anticholinesterase activities. While geissospermine inhibited only butyrylcholinesterase (BChE), the other alkaloids behaved as non-selective inhibitors of acetylcholinesterase (AChE) and BChE. In cell viability tests, only geissoschizoline was not cytotoxic. Therefore, geissoschizoline actions were also evaluated in human cholinesterases, where it was twice as potent inhibitor of hBChE (IC50 = 10.21 ± 0.01 µM) than hAChE (IC50 = 20.40 ± 0.93 µM). On enzyme kinetic studies, geissoschizoline presented a mixed-type inhibition mechanism for both enzymes. Molecular docking studies pointed interactions of geissoschizoline with active site and peripheral anionic site of hAChE and hBChE, indicating a dual site inhibitor profile. Moreover, geissoschizoline also played a promising anti-inflammatory role, reducing microglial release of NO and TNF-α at a concentration (1 µM) ten and twenty times lower than the IC50 values of hBChE and hAChE inhibition, respectively. These actions give geissoschizoline a strong neuroprotective character. In addition, the ability to inhibit hAChE and hBChE, with approximate inhibitory potencies, accredits this alkaloid for therapeutic use in the moderate to severe phase of AD. Thus, geissoschizoline emerges as a possible multi-target prototype that can be very useful in preventing neurodegeneration and restore neurotransmission.

Antinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction.

Geissospermum vellosii (Pao pereira) is a Brazilian tree whose stem barks are rich in indole alkaloids that present intense anticholinesterase activity. The present study evaluated the effects of a stem bark fraction (PPAC fraction) and ethanolic extract (EE) of Pao pereira in classic murine models of inflammation and pain. The EE and PPAC fraction, both at a dose of 30 mg/kg, significantly reduced mice abdominal constriction induced by acetic acid by 34.8% and 47.5%, respectively. In the formalin test, EE (30 mg/kg) and PPAC fraction (30 and 60 mg/kg) inhibited only the second phase, by 82.8%, 84.9% and 100%, respectively. Compared with indomethacin, similar doses of EE or PPAC fraction were approximately twice as effective in causing antinociception. PPAC fraction was not effective in the hot plate test but reduced the inflammatory response at the second (50.6%) and third (57.8%) hours of rat paw edema induced by carrageenan. Antihyperalgesic activity was observed within 30 min with a peak at 2 h (60.1%). These results demonstrate that compounds in PPAC fraction have anti-inflammatory and antinociceptive activity by a mechanism apparently unrelated to the opioid system. Regardless of similar responses to indomethacin, the effects of PPAC fraction are mainly attributed to acetylcholine actions.

Flavonoids and fractions from Saccharum officinarum L. juice: antinociceptive agents and molecular docking evaluations with µ-opioid receptor.

Opioid receptors mediate antinociceptive effects. Methanolic fractions from sugarcane varieties (MFSCf) were evaluated in classic nociception models. Interactions between bioactive compounds and the µ-opioid receptor (µOR) through docking analysis were also studied. Five methanolic fractions of sugarcane juice were obtained and analysed by LC-ESI-MS/MS. The fractions and standards of phenolic compounds were evaluated in a nociception model using the formalin test. All MFSCfs exhibited antinociceptive activity in the first phase of the formalin test. Docking analyses corroborates with the in vivo test results, suggesting that the phenolic substances are able to activate µOR. These results, for the first time, implicate phenolic constituents from sugarcane juice and other phenolic compounds in the activation of µOR. The antinociceptive activity of fractions from sugarcane juice suggests the potential pharmacological use of this species, widely cultivated in Brazil.

Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.

We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.

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).

Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazones: orally effective anti-inflammatory drug candidates.

We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives (1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 (1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED(50) of 97.8 micromol/kg, acting mainly as a non-selective COX inhibitor.

Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole.

In this work we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and platelet anti-aggregating properties of new 3-(arylideneamino)-2-methyl-6,7-methylenedioxy-quinazolin-4(3H)-one derivatives (3a-j), designed as conformationally constrained analogues of analgesic 1,3-benzodioxolyl-N-acylhydrazones (1) previously developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (2) as starting material. The pharmacological assays lead us to identify compounds LASSBio-1240 (3b) and LASSBio-1272 (3d) as new analgesic prototypes, presenting an antinociceptive profile more potent and effective than dipyrone and indomethacin used, respectively, as standards in AcOH-induced abdominal constrictions assay and in the formalin test. These results confirmed the success in the exploitation of conformation restriction strategy for identification of novel cyclic N-acylhydrazone analogues with optimized analgesic profile.

The selective TRPV4 channel antagonist HC-067047 attenuates mechanical allodynia in diabetic mice.

Painful diabetic neuropathy (PDN) is a serious symptom that compromises quality of life and remains without effective pharmacological treatment. The transient receptor vanilloid 4 (TRPV4) is a cation-permeable channel implicated in sensory transduction and pain signalling. Therefore, drugs that act on TRPV4 may have therapeutic applications to treat PDN. In the present work, we assessed the effect of the selective TRPV4 channel antagonist HC-067047 on painful neuropathy associated with streptozotocin (STZ)-induced diabetes in mice. STZ-treated animals presented both mechanical and cold allodynia at 6 weeks after diabetes induction. Notably, HC-067047 (1 mg/kg, s.c.) given daily between 2 and 6 weeks after diabetes induction significantly prevented the development of mechanical allodynia. Additionally, both single and repeated treatments with HC-067047 (10 mg/kg, s.c.) significantly reverted established mechanical allodynia induced by STZ. However, HC-067047 was not capable of affecting either thermal cold allodynia or hyperglycemia. Similarly, HC-067047 treatments showed no effect on body weight, temperature, locomotor activity or motor coordination of control mice. Immunohistochemistry assay showed that TRPV4 expression was not different in sciatic nerve, dorsal root ganglia (DRG) or hind paw plantar skin from diabetic and non-diabetic mice, suggesting that HC-067047 acts on constitutive receptors to inhibit mechanical allodynia. Taken together, the data generated in the present study show the potential relevance of using TRPV4 antagonists to treat painful neuropathy associated with diabetes.

Fish oil attenuates persistent inflammatory pain in rats through modulation of TNF-α and resolvins.

UNLABELLED: Fish oil (FO), source of omega-3 fatty acids (FA), has been widely studied in the treatment of inflammatory diseases and inflammatory pain (IP). Omega-3 FA give rise to eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, metabolized to eicosanoids and converted to resolvins with important anti-inflammatory action. AIMS: This study investigates the effects of oral doses of omega-3 FA from FO and concentrated fish oil (CFO) in a model of sub-chronic IP, induced by Complete Freund's Adjuvant (CFA). MAIN METHODS: IP was induced by intraplantar injection of CFA into the right hind paw of Wistar rats. Three groups were pre-treated with omega-3 FA: two groups received CFO (460mg of EPA/360mg of DHA and 690mg of EPA/540mg of DHA) and one group received natural FO (460mg EPA/300mg DHA), for 7days before IP induction (pre-treatment) and 5days after induction (treatment). KEY FINDINGS: TNF-α levels were reduced by CFO 690 (67.9%; p<0.01), CFO 460 (57.7%; p<0.01), FO 460 (26.2%), compared to the augment promoted by CFA (549.7%; p<0.001). Resolvin levels were increased in treated groups with respect to the CFA control group (CFO 690=3196.3%, p<0.01; CFO 460=3347.1%, p<0.01; FO=1653.5%). SIGNIFICANCE: The results indicate that the tested doses reduced inflammatory pain effectively in a short pre-treatment period, through modulation of TNF-α and resolvins and that CFO presented better results than FO. Therefore, Ω-3 FA from FO can be proposed for use as complementary medicine in the treatment of painful and inflammatory diseases.

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.

Novel potent imidazo[1,2-a]pyridine-N-Glycinyl-hydrazone inhibitors of TNF-α production: in vitro and in vivo studies.

In this work, we describe the design, synthesis and pharmacological evaluation of novel imidazo[1,2-a]pyridine-N-glycinyl-hydrazone derivatives (1a-k) intended for use as inhibitors of tumor necrosis factor alpha (TNF-α) production. The compounds were designed based on the orally active anti-inflammatory prototype LASSBio-1504 (2), which decreases the levels of the pro-inflammatory cytokine TNF-α in vitro and in vivo. The in vitro pharmacological evaluation of the imidazo[1,2-a]pyridine compounds (1) showed that substitution of the N-phenylpyrazole core present in prototype 2 by a bioisosteric imidazo[1,2-a]pyridine scaffold generated anti-TNF-α compounds that were more potent than the previously described N-phenylpyrazole derivative 2 and as potent as SB-203580, a p38 MAPK inhibitor. The most active derivative (E)-2-(2-tert-butylimidazo[1,2-a]pyridin-3-ylamino)-N'-(4-chlorobenzylidene) acetohydrazide, or LASSBio-1749 (1i) was orally active as an anti-inflammatory agent in a subcutaneous air pouch model, reducing expressively the levels in vivo of TNF-α and other pro-inflammatory cytokines at all of the tested doses.

Discovery of novel orally active anti-inflammatory N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that inhibit TNF-α production.

Herein, we describe the synthesis and pharmacological evaluation of novel N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that were designed as novel prototypes of p38 mitogen-activated protein kinase (MAPK) inhibitors. All of the novel synthesized compounds described in this study were evaluated for their in vitro capacity to inhibit tumor necrosis factor α (TNF-α production in cultured macrophages) and in vitro MAPK p38α inhibition. The two most active anti-TNF-α derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide (4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-(4-chlorobenzylidene)acetohydrazide (4f), were evaluated to determine their in vivo anti-hyperalgesic profiles in carrageenan-induced thermal hypernociception model in rats. Both compounds showed anti-inflammatory and antinociceptive properties comparable to SB-203580 used as a standard drug, by oral route at a dose of 100 µmol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-α levels in vivo by 57.3 and 55.8%, respectively.

Structure-based design and biological profile of (E)-N-(4-Nitrobenzylidene)-2-naphthohydrazide, a novel small molecule inhibitor of IκB kinase-ß.

In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-ß inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-ß active site, and a privileged structure template yielded a novel IKK-ß inhibitor scaffold with significant selectivity over IKK-α and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-ß inhibition, molecular dynamics simulations of LASSBio-1524 (3) were performed. The NAH derivative LASSBio-1524 (3), was able to suppress arachidonic acid-induced edema formation in a dose-dependent manner, demonstrating an in vivo anti-inflammatory effect. The molecular architecture of this novel, low-molecular weight IKK-ß inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates.

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.

Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.

We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.

Antinociceptive effects of an extract, fraction and an isolated compound of the stem bark of Maytenus rigida

The antinociceptive activity of the Maytenus rigida Mart. (Celastraceae) ethanol extract and its ethyl acetate fraction as well as of (-)-4'-methylepigallocatechin (1), a previously isolated compound, was demonstrated in vivo. ED50 for 1 in the writhing test was 14.14 mg/kg. The acetic acid-induced writhing was inhibited by 98.4, 84.4, and 58.3%, respectively, when mice were treated with the ethanol extract, ethyl acetate fraction, and 1. In the hot plate test, mice pretreated with 1 showed significantly increased reaction times (60-89%). Oral administration of 1 significantly inhibited first and second phases of the formalin-induced pain (50 and 26.5%, respectively), whereas indomethacin inhibited only the second phase of the test (41.2%). Ethanol extract and its fraction showed effects on inflammatory pain, while neurogenic and inflammatory pain suppression by 1 is a strong indication of the presence of both central and peripheral effects and suggests its analgesic and anti-inflammatory potential.

Design and synthesis of 3,4-methylenedioxy-6-nitrophenoxyacetylhydrazone derivatives obtained from natural safrole: new lead-agents with analgesic and antipyretic properties.

In this work, we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and antipyretic properties of new 2-(6-nitro-benzo[1,3]dioxol-5-yloxy)-acetylhydrazone derivatives (3), designed exploring molecular hybridization and isosteric replacement approaches between nimesulide (1) and carbanalogue NAH series (2) developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (4) as starting material. The evaluation of the antinociceptive properties of this series led us to discover a new potent prototype of analgesic and antipyretic agent, that is, NAH derivative 3c, named LASSBio-891, which showed to be more potent than dipyrone used as standard.