Antinociceptive Effect of Dillenia indica (Linn.) Mediated by Opioid and Cannabinoid Systems: Pharmacological and Chemical Studies.

Dillenia indica (Linn.) has been reported by several biological activities, including anti-inflammatory, antioxidant, antidiabetic, anti-hyperglycemic, antiproliferative, antimutagenic, anticholinesterase, and antimicrobial. In Brazilian traditional medicine, the fruits of D. indica have been used to treat general topical pain and inflammation, but with no scientific validation. Thus, aiming to study its chemical constitution and antinociceptive properties, the crude extract (CE) and fractions obtained from the fruits of D. indica were submitted to an in vivo pharmacological evaluation and a dereplication study by LC-MS/MS analysis, assisted by the Global Natural Product Social Molecular Networking (GNPS). The oral antinociceptive activity of the fruits of D. indica and the possible participation of the opioid and cannabinoid systems were demonstrated in the formalin-induced nociception model. The chemical dereplication study led us to identify several known chemical constituents, including flavonoids, such as caffeoylmalic acid, naringenin, quercetin, and kaempferol. According to literature data, our results are compatible with significant antinociceptive and anti-inflammatory activities. Therefore, the flavonoid constituents of the fruits of D. indica are probably responsible for its antioxidant, anti-inflammatory, and antinociceptive effects mediated by both opioid and cannabinoid systems, confirming its folk use in the treatment and relief of pain.

Proposals to promote health and prevent voice disorders in occupational voice users: A scoping review / Propostas de promoção da saúde e prevenção de distúrbios vocais para profissionais da voz: revisão de escopo

ABSTRACT Purpose: to characterize the actions of vocal health promotion and/or prevention of vocal disorders applied to voice professionals. Methods: a scoping review following the PRISMA-ScR guidelines in SciELO and PubMed databases was conducted. Articles that had as participants voice professionals without concomitant vocal treatment, that described proposals for health promotion or vocal disorders prevention, published between 2010 and 2023, were included. They were grouped into categories and data were presented descriptively. Literature Review: eighteen articles with artistic and non-artistic voice professionals, mostly teachers, were included. Most of the studies focused on healthy voices, aiming at primary prevention. Many articles presented guidance on vocal hygiene and health and used resources such as vocal enhancement, voice workshop, voice amplifiers and apps. All the articles positively mentioned their results, especially with regard to self-perception in relation to voice, vocal quality and quality of life, awareness of positive and harmful practices to the voice. Conclusion: the proposals contemplated different levels of prevention, but most focused on primary prevention, including vocally healthy participants; all articles indicated positive results in voice self-perception, voice quality and quality of life, and awareness of positive and harmful voice practices.

RESUMO Objetivo: caracterizar as ações de promoção de saúde vocal e/ou prevenção de distúrbios vocais aplicadas em profissionais da voz. Métodos: foi conduzida uma revisão de escopo seguindo as diretrizes do PRISMA-ScR nas bases de dados SciELO e PubMed. Foram incluídos artigos que tivessem como participantes profissionais da voz sem tratamento vocal concomitante, que descrevessem propostas de promoção da saúde ou prevenção de distúrbios vocais, publicados entre 2010 e 2023. Os artigos foram agrupados em categorias e os dados apresentados de forma descritiva. Revisão da Literatura: foram incluídos 18 artigos com profissionais da voz artística e não-artística, em sua maioria professores. A maior parte dos estudos tinha como foco vozes saudáveis, visando a prevenção primária. Muitos artigos apresentaram orientações sobre higiene e saúde vocal e utilizaram recursos como aprimoramento vocal, oficina de voz, amplificadores de voz e aplicativos. Todos os artigos mencionam resultados benéficos, principalmente no que se refere à autopercepção em relação a voz, qualidade vocal e de vida, conscientização de práticas positivas e prejudiciais à voz. Conclusão: as propostas contemplaram diferentes níveis de prevenção, mas a maioria tinha como foco a prevenção primária, incluindo participantes vocalmente saudáveis; todos os artigos indicaram resultados favoráveis na autopercepção em relação à voz, qualidade vocal e de vida e conscientização de práticas benéficas e prejudiciais à voz.

DISTRIBUTION AND ANTIMICROBIAL RESISTANCE OF STAPHYLOCOCCI ISOLATED FROM FREE-LIVING SOUTH AMERICAN COATI (NASUA NASUA) IN AN URBAN PARK IN MINAS GERAIS, BRAZIL.

The scientific information regarding staphylococci in procyonids is scarce. Hence, the aim of this study was to evaluate the frequency, distribution, and pattern of antimicrobial resistance of staphylococcal species isolated from free-roaming coatis (Nasua nasua) in an urban park in Belo Horizonte, Minas Gerais, Brazil. Rectal swabs from 55 free-living coatis were plated onto mannitol salt agar for isolating staphylococci, and species were identified using matrix-assisted laser desorption/ionization-time of flight mass spectrometry, polymerase chain reaction (PCR) of nuc, and sequencing of 16S rRNA and rpoB when needed. Antimicrobial susceptibility was investigated using the disk diffusion method, and the presence of the mecA gene was investigated by PCR. A total of 72.7% of the animals tested positive for staphylococci. Nine different species were identified, and Staphylococcus intermedius (60.4%) and S. delphini (20.9%) were the most frequently isolated species. Most of the isolates were susceptible to most of the antimicrobials evaluated, with a resistance pattern seen for penicillin (13.9%). One isolate was multidrug-resistant (MDR). The present study suggests that coatis are natural hosts of S. intermedius and S. delphini and, despite living in a heavily anthropized environment, the Staphylococcus spp. isolates showed a low incidence of drug resistance.

Piperine-Chlorogenic Acid Hybrid Inhibits the Proliferation of the SK-MEL-147 Melanoma Cells by Modulating Mitotic Kinases.

Melanoma is considered the most aggressive form of skin cancer, showing high metastatic potential and persistent high mortality rates despite the introduction of immunotherapy and targeted therapies. Thus, it is important to identify new drug candidates for melanoma. The design of hybrid molecules, with different pharmacophore fragments combined in the same scaffold, is an interesting strategy for obtaining new multi-target and more effective anticancer drugs. We designed nine hybrid compounds bearing piperine and chlorogenic acid pharmacophoric groups and evaluated their antitumoral potential on melanoma cells with distinct mutational profiles SK-MEL-147, CHL-1 and WM1366. We identified the compound named PQM-277 (3a) to be the most cytotoxic one, inhibiting mitosis progression and promoting an accumulation of cells in pro-metaphase and metaphase by altering the expression of genes that govern G2/M transition and mitosis onset. Compound 3a downregulated FOXM1, CCNB1, CDK1, AURKA, AURKB, and PLK1, and upregulated CDKN1A. Molecular docking showed that 3a could interact with the CUL1-RBX1 complex, which activity is necessary to trigger molecular events essential for FOXM1 transactivation and, in turn, G2/M gene expression. In addition, compound 3a effectively induced apoptosis by increasing BAX/BCL2 ratio. Our findings demonstrate that 3a is an important antitumor candidate prototype and support further investigations to evaluate its potential for melanoma treatment, especially for refractory cases to BRAF/MEK inhibitors.

Acoustic Measurements of Speech and Voice in Men with Angle Class II, Division 1, Malocclusion

Abstract Introduction The acoustic analysis of speech (measurements of the fundamental frequency and formant frequencies) of different vowels produced by speakers with the Angle class II, division 1, malocclusion can provide information about the relationship between articulatory and phonatory mechanisms in this type of maxillomandibular disproportion. Objectives To investigate acoustic measurements related to the fundamental frequency (F0) and formant frequencies (F1 and F2) of the oral vowels of Brazilian Portuguese (BP) produced by male speakers with Angle class II, division 1, malocclusion (study group) and compare with men with Angle class I malocclusion (control group). Methods In total, 60 men (20 with class II, 40 with class I) aged between 18 and 40 years were included in the study. Measurements of F0, F1 and F2 of the seven oral vowels of BP were estimated from the audio samples containing repetitions of carrier sentences. The statistical analysis was performed using the Student t-test and the effect size was calculated. Results Significant differences (p-values) were detected for F0 values in five vowels ([e], [i], [o], [o] and [u]), and for F1 in vowels [a] and [ɔ], with high levels for class II, division 1. Conclusion Statistical differences were found in the F0 measurements with higher values in five of the seven vowels analysed in subjects with Angle class II, division 1. The formant frequencies showed differences only in F1 in two vowels with higher values in the study group. The data suggest that data on voice and speech production must be included in the protocol's assessment of patients with malocclusion.

Acoustic Measurements of Speech and Voice in Men with Angle Class II, Division 1, Malocclusion.

Introduction The acoustic analysis of speech (measurements of the fundamental frequency and formant frequencies) of different vowels produced by speakers with the Angle class II, division 1, malocclusion can provide information about the relationship between articulatory and phonatory mechanisms in this type of maxillomandibular disproportion. Objectives To investigate acoustic measurements related to the fundamental frequency (F0) and formant frequencies (F1 and F2) of the oral vowels of Brazilian Portuguese (BP) produced by male speakers with Angle class II, division 1, malocclusion (study group) and compare with men with Angle class I malocclusion (control group). Methods In total, 60 men (20 with class II, 40 with class I) aged between 18 and 40 years were included in the study. Measurements of F0, F1 and F2 of the seven oral vowels of BP were estimated from the audio samples containing repetitions of carrier sentences. The statistical analysis was performed using the Student t -test and the effect size was calculated. Results Significant differences ( p -values) were detected for F0 values in five vowels ([e], [i], [ᴐ], [o] and [u]), and for F1 in vowels [a] and [ᴐ], with high levels for class II, division 1. Conclusion Statistical differences were found in the F0 measurements with higher values in five of the seven vowels analysed in subjects with Angle class II, division 1. The formant frequencies showed differences only in F1 in two vowels with higher values in the study group. The data suggest that data on voice and speech production must be included in the protocol's assessment of patients with malocclusion.

Occurrence and characterization of methicillin-resistant Staphylococcus spp. in diseased dogs in Brazil.

Staphylococcus pseudintermedius is a major commensal bacterium of the skin and mucosae of dogs and an opportunistic agent responsible for several clinical infections, such as pyoderma, otitis, and surgical wound infections. The emergence of methicillin-resistant S. pseudintermedius (MRSP) has become a problem of great concern in veterinary and human medicine because it is multidrug resistant (MDR) and can also infect humans. This study aimed to identify the occurrence of Staphylococcus spp. in infected patients and investigate the antimicrobial resistance profiles and molecular structure of MRSP isolates. Samples were obtained from two different veterinary clinics; suggestive colonies were submitted to matrix-assisted laser desorption ionization-time of flight (MALDI-ToF) mass spectrometry and confirmed at the species level by polymerase chain reaction (PCR). Sequencing of the 16S rRNA and rpoB genes were used in selected samples that were not identified by MALDI-ToF and by the species-specific PCR. Antimicrobial susceptibility and PCR detection of mecA were performed. MRSP isolates were subjected to multilocus sequence typing. Of all the clinical staphylococci (n = 131), 98 (74.8%) were identified as S. pseudintermedius. Multidrug resistance (resistance to ≥3 classes of antimicrobials) was observed in 63.2% of S. pseudintermedius isolates, and 24.5% of S. pseudintermedius isolates were methicillin-resistant. Half of the MRSP isolates were isolated from surgical site infections. Among the ten sequence types (ST) identified, nine were novel. ST71 was the most prevalent and associated with resistance to fluoroquinolones. Prior antimicrobial therapy, hospitalization, and surgical site infections seemed to be risk factors for MRSP acquisition. The present study showed a high rate of MDR staphylococci in infected dogs. MRSP was isolated from different clinical conditions, mainly surgical site infections. Additionally, this is the first study to extensively investigate the population structure of MRSP in Brazil, which revealed the dispersion of CC71 and nine novel ST. These findings raise concerns for both animal and human health due to the zoonotic potential of this species and limited therapeutic options available for MRSP infections.

Fecal Shedding of Multidrug Resistant Escherichia coli Isolates in Dogs Fed with Raw Meat-Based Diets in Brazil.

The practice of feeding dogs raw meat-based diets (RMBDs) is growing in several countries, and the risks associated with the ingestion of pathogenic and antimicrobial-resistant Escherichia coli in dogs fed these diets are largely unknown. We characterized E. coli strains isolated from dogs fed either an RMBD or a conventional dry feed, according to the phylogroup, virulence genes, and antimicrobial susceptibility profiles of the bacteria. Two hundred and sixteen E. coli strains were isolated. Dogs fed RMBDs shed E. coli strains from the phylogroup E more frequently and were positive for the E. coli heat-stable enterotoxin 1-encoding gene. Isolates from RMBD-fed dogs were also frequently positive for multidrug-resistant E. coli isolates including extended-spectrum beta-lactamase (ESBL) producers. Whole-genome sequencing of seven ESBL-producing E. coli strains revealed that they predominantly harbored blaCTX-M-55, and two strains were also positive for the colistin-resistant gene mcr-1. These results suggest that feeding an RMBD can affect the dog's microbiota, change the frequency of certain phylogroups, and increase the shedding of diarrheagenic E. coli. Also, feeding an RMBD seemed to be linked with the fecal shedding of multidrug-resistant E. coli, including the spread of strains harboring mobilizable colistin resistance and ESBL genes. This finding is of concern for both animal and human health.

Curcumin, Resveratrol and Cannabidiol as Natural Key Prototypes in Drug Design for Neuroprotective Agents.

Nowadays, neurodegenerative diseases (NDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a great challenge in different scientific fields, such as neuropharmacology, medicinal chemistry, molecular biology and medicine, as all these pathologies remain incurable, with high socioeconomic impacts and high costs for governmental health services. Due to their severity and multifactorial pathophysiological complexity, the available approved drugs for clinic have not yet shown adequate effectiveness and exhibited very restricted options in the therapeutic arsenal; this highlights the need for continued drug discovery efforts in the academia and industry. In this context, natural products, such as curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) have been recognized as important sources, with promising chemical entities, prototype models and starting materials for medicinal organic chemistry, as their molecular architecture, multifunctional properties and single chemical diversity could facilitate the discovery, optimization and development of innovative drug candidates with improved pharmacodynamics and pharmacokinetics compared to the known drugs and, perhaps, provide a chance for discovering novel effective drugs to combat NDs. In this review, we report the most recent efforts of medicinal chemists worldwide devoted to the exploration of curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) as starting materials or privileged scaffolds in the design of multi-target directed ligands (MTDLs) with potential therapeutic properties against NDs, which have been published in the scientific literature during the last 10 years of research and are available in PubMed, SCOPUS and Web of Science databases.

Acoustic Analysis of Voice and Speech in Men with Skeletal Class III Malocclusion: A Pilot Study.

OBJECTIVES: To assess the fundamental (f0) and first third formant (F1, F2, F3) frequencies of the 7 oral vowels of Brazilian Portuguese in men with skeletal class III malocclusion and to compare these measures with a control group of individuals with Angle's class I. METHODS: Sixty men aged 18-40 years, 20 with Angle's class III skeletal malocclusion and 40 with Angle's class I malocclusion were selected by speech therapists and dentists. The speech signals were obtained from sustained vowels, and the values of f0 and frequencies of F1, F2 and F3 were estimated. The differences were verified through Student's t test, and the effect size calculation was performed. RESULTS: In the class III group, more acute f0 values were observed in all vowels, higher values of F1 in the vowels [a] and [ε] and in F2 in the vowels [a], [e] and [i] and lower F1 and F3 values of the vowel [u]. CONCLUSION: More acute f0 values were found in all vowels investigated in the class III group, which showed a higher laryngeal position in the production of these sounds. The frequencies of the first 3 formants showed punctual differences, with higher values of F1 in the vowels [a] and [ε] and of F2 in [a], [e] and [i], and lower values of F1 and F3 in the vowel [u] in the experimental group. Thus, it is concluded that the fundamental frequency of the voice was the main parameter that differentiated the studied group from the control.

Alzheimer's Disease: Related Targets, Synthesis of Available Drugs, Bioactive Compounds Under Development and Promising Results Obtained from Multi-target Approaches.

We describe herein the therapeutic targets involved in Alzheimer's disease as well as the available drugs and their synthetic routes. Bioactive compounds under development are also exploited to illustrate some recent research advances on the medicinal chemistry of Alzheimer's disease, including structure-activity relationships for some targets. The importance of multi-target approaches, including some examples from our research projects, guides new perspectives in search of more effective drug candidates. This review comprises the period between 2001 and early 2020.

Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases.

It is essential to acknowledge the efforts made thus far to manage or eliminate various disease burden faced by humankind. However, the rising global trends of the so-called incurable diseases continue to put pressure on Pharma industries and other drug discovery platforms. In the past, drugs with more than one target were deemed as undesirable options with interest being on the one-drug-single target. Despite the successes of the single-target drugs, it is currently beyond doubt that these drugs have limited efficacy against complex diseases in which the pathogenesis is dependent on a set of biochemical events and several bioreceptors operating concomitantly. Different approaches have thus been proposed to come up with effective drugs to combat even the complex diseases. In the past, the focus was on producing drugs from screening plant compounds; today, we talk about combination therapy and multi-targeting drugs. The multi-target drugs have recently attracted much attention as promising tools to fight against most challenging diseases, and thus a new research focus area. This review will discuss the potential impact of multi-target drug approach on various complex diseases with focus on malaria, tuberculosis (TB), diabetes and neurodegenerative diseases as the main representatives of multifactorial diseases. We will also discuss alternative ideas to solve the current problems bearing in mind the fourth industrial revolution on drug discovery.

Fecal shedding of Salmonella spp., Clostridium perfringens, and Clostridioides difficile in dogs fed raw meat-based diets in Brazil and their owners' motivation.

The present study aimed to explore the motivations of Brazilian dog owners and their knowledge about the risks related to raw meat-based diets (RMBD) as well as to evaluate important enteropathogens such as Salmonella spp., C. perfringens, and C. difficile, in feces of dogs fed different diets. The majority of the pet owners (69.3%) reported to have chosen this diet for their dogs, considering it to be more "natural". A large number of owners declared that RMBD do not pose health risks for their animals (87.9%) or humans (98.8%), even though almost one third of the respondents (34.8%) declared having at least one individual at high risk of infection in contact with RMBD-fed dogs. Stool samples from 46 RMBD-fed dogs and 192 dogs fed commercial dry feed were collected. The present study revealed that dogs fed raw meat diets were almost 30 times more likely to be positive for Salmonella spp. than dogs on a conventional diet. Some of the serovars detected were commonly associated with human salmonellosis, such as S. Typhimurium and S. Saintpaul, and were multidrug resistant. RMBD-fed dogs were more likely to be positive for C. perfringens type A (p = 0.008) and one C. perfringens type F was isolated from these animals. Two toxigenic strains (4.3%) of C. difficile were isolated only from raw meat-fed dogs, all of which were under antibiotic therapy. These toxigenic C. difficile isolates were classified as RT106/ST54 and RT600/ST149, previously associated with infection in dogs and humans. The present work revealed that the owners have a tendency to ignore or are unaware of the risks associated with raw meat diets for dogs. Also, the higher fecal shedding of important enteropathogens in dogs fed RMBD suggests that this diet poses a risk for the animals and the people in contact with them.

An Acoustic Examination of Pitch Variation in Soprano Singing.

INTRODUCTION: The ability to perform acoustic inspection of data and to correlate the results with perceptual and physiological aspects facilitates vocal behavior analysis. The singing voice has specific characteristics and parameters that are involved during the phonation mechanism, which may be analyzed acoustically. OBJECTIVE: To describe and analyze the fundamental frequency and formants in pitch variation in the /a/ vowel in sopranos. METHODS: The sample consisted of 30 female participants between the ages of 20 to 45 years without vocal complaints. All sustained vowel sounds were recorded with the /a/ vowel sustained for 5 seconds, with three replications at low (C4-261 Hz), medium (Eb4-622 Hz), and high (Bb4-932 Hz) frequencies that were comfortable for the voice classification. In total, 90 samples were analyzed with digital extraction of the fundamental frequency (f0) and the first five formants (F1, F2, F3, F4, and F5) and manual confirmation. The middle segment was considered for analysis, whereas the onset and offset segments were not considered. Subsequently, FFT (fast Fourier transform) plots, LPC (linear predictive coding) graphs, and tube diagrams were created. The Shapiro-Wilks test was applied for adherence and the Friedman test was applied for comparison of paired samples. RESULTS: For vocalizations at low and medium pitches, higher values were observed for the first five formant frequencies than for the f0 value. Overlaying the LPC and FFT graphs revealed a similarity between F1 and F2 at the two pitches, with clustered harmonics in the F3, F4, and F5 region in the low pitch. At the medium pitch, there was similarity between F3 and F4, an F5 peak, and tuned harmonics. However, in the high-pitch vocalizations, there was an increase in the F2, F3, F4, and F5 values in relation to f0, and there was similarity between them along with synchrony between f0 and F1, H2 and F2, H3 and F3, H4 and F4, and H5 and F5. CONCLUSIONS: Pitch changes indicate differences in the behavior of the fundamental frequency and sound formants in sopranos. The comparison of the sustained vowels sounds in f0 at the three pitches revealed specific vocal tract changes on the LPC curve and FFT harmonics, with an extra gain range at 261 Hz, synchrony between peaks of formants and harmonics at 622 Hz, and equivalence of f0 and F1 at 932 Hz.

New multifunctional AChE inhibitor drug prototypes protect against Aß-induced memory deficit.

Alzheimer's disease (AD) is the most incident neurodegenerative disorder, characterized by accumulation of extracellular amyloid-ß (Aß), intracellular neurofibrillary tangles, and cognitive impairment. The current available treatments are mainly based on the use of reversible acetylcholinesterase (AChE) inhibitors, which only ameliorate the cognitive deficits. However, it is important to develop disease-modifying drugs with neuroprotective effects in order to hamper the progression of the disease. Here, we describe the effect of four promising new drugs with additional protective characteristics on AD-associated memory changes. C57Bl/6 mice treated with the compounds received an intra-hippocampal injection of Aß1-40 and were submitted to the novel object recognition test, to evaluate memory recovery. All the compounds prevented memory loss. Compounds PQM-56 (4c) and PQM-67 (4g) showed the best profile of memory recovery, representing potential drug candidates for AD treatment.

Radiographic study of the development of the pelvis and hip and the femorotibial joints in domestic cats.

OBJECTIVES: The aims of the present study were to monitor, by radiographic examination, the skeletal development of the pelvis and the femorotibial joints of the domestic cat from the first week of life until the closing of the growth plates. METHODS: Radiographic examinations were collected from 15 domestic cats at weekly intervals during the first month and every 2 weeks from the second to the fourth month of age. After that, examinations were performed monthly until the age of 18 months. RESULTS: The ischiopubic growth plate closed at 2 months of age, followed by the fusion of the iliopubic, ilioischial, proximal femoral, greater trochanter and proximal fibular growth plates. The distal femur and proximal tibial growth plates were the last to close, with fusion occurring at 18 months. The mean time to closure of the iliopubic, ilioischial and distal femoral growth plates was shorter in females. The ossification centers first appeared, in ascending order, beginning with the lesser trochanter, followed by the greater trochanter, proximal fibular epiphysis, tibial tuberosity, patella, ischial tuberosity and lateral sesamoid of the popliteus muscle. CONCLUSIONS AND RELEVANCE: The complete closure of the growth plates of domestic cats occurs at approximately 18 months of age. Skeletal maturation at approximately 18 months of age is an important parameter to be considered in radiographic evaluation of certain skeletal changes, evolution of fractures and nutritional imbalance.

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases.

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

Leishmanicidal and antimicrobial activity of primin and primin-containing extracts from Miconia willdenowii.

As a part of an ongoing bioprospective project, searching for potential medicinal plants from the Brazilian Atlantic Forest, Miconia willdenowii was selected for its potential leishmanicidal and antimicrobial activities. The crude ethanolic extract of M. willdenowii showed an inhibition of 99.7% of the promastigote forms of Leishmania amazonensis at the concentration of 80 µg/mL. Further investigation of its antimicrobial activity against pathogenic fungi and Gram positive and negative bacteria, revealed a significant antimicrobial activity. A bioguided study with its liquid-liquid partition fractions revealed the hexane fraction (Hex) as the most active against Leishmania, inhibiting 99.2% and 46.9% of the protozoan at concentrations of 40 and 20 µg/mL, respectively. Hex also showed significant antimicrobial activity against Staphylococcus aureus and Candida krusei with IC50 of 15.6 and 62.5 µg/mL, respectively. Purification of Hex led to the isolation of 2-methoxy-6-pentyl-benzoquinone (1, also known as primin) as the active metabolite, probably responsible for the observed antimicrobial and anti-leishmania effects. Primin (1) disclosed leishmanicidal activity (IC50 = 1.25 µM), showing higher potency than the standard drug amphotericin B (IC50 = 5.08 µM), with additional antifungal effects against all tested fungi species. Compound 1 also showed significant activity against S. aureus (IC50 = 8.94 µM), showing a comparable potency with the reference drug chloramphenicol (IC50 = 6.19 µM), but with a potential cytotoxicity towards peripheral human blood mononuclear cells (CC50 = 255.15 µM). Here in, the antimicrobial and anti-L. amazonensis effects of M. willdenowii are reported for the first time, as well as Primin (1) as its probable bioactive metabolite.

3-Hydroxy-piperidinyl-N-benzyl-acyl-arylhydrazone derivatives reduce neuropathic pain and increase thermal threshold mediated by opioid system.

Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a-d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6 h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects.

Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates.

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AßO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AßO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.