Homologous acetylenic acetogenins from Porcelia macrocarpa R.E. (Fries) displayed potent activity against amastigotes from Trypanosoma cruzi.

As part of our continuous study on the Annonaceae species Porcelia macrocarpa, in the present work, eight chemically related 2-alkyl-3-hydroxy-4-methyl-γ-lactones (1-8) were isolated. Their structures were characterised by NMR, MS, and VCD. Their antitrypanosomal activity was evaluated in vitro against intracellular amastigotes with EC values ranged from 13.

Tackling Neuroinflammation in Cognitive Disorders with Single-targeted and Multi-targeted Histamine H3 Receptor Modulators.

Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well.

Antihistamines H as Potential Anthelmintic Agents against the Zoonotic Parasite .

Infections caused by parasitic helminths pose significant health concerns for both humans and animals. The limited efficacy of existing drugs underscores the urgent need for novel anthelmintic agents. Given the reported potential of antihistamines against various parasites, including worms, this study conducted a screening of clinically available antihistamines against -a nematode with widespread implications for vertebrate hosts, including humans.

The histamine H receptor antagonist 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-4-methyl-piperazine(LINS01007) prevents the development of DSS-induced colitis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as HR antagonist (pK 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work.

Therapeutic potential of LINS01 histamine H receptor antagonists as antineoplastic agents for triple negative breast cancer.

The aims of this work were to evaluate the expression of histamine H receptor (HR) in triple negative breast cancer (TNBC) samples and to investigate the antitumoral efficacy and safety of the LINS01 series of HR antagonists, through in silico, in vitro, and in vivo approaches. Antitumor activity of LINS01009, LINS01010, LINS01022, LINS01023 was assayed in vitro in 4T1 and MDA-MB-231 TNBC cells (0.01-100 μM), and in vivo in 4T1 tumors orthotopically established in BALB/c mice (1 or 20 mg/kg).

Investigation of Structure-Activity Relationships for Benzoyl and Cinnamoyl Piperazine/Piperidine Amides as Tyrosinase Inhibitors.

Melanin is a substance that plays important roles in several organisms. Its function as an antioxidant and metal-complexing agent makes tyrosinase, the key enzyme that controls melanogenesis, an interesting target for designing inhibitors. In this article, we report a set of piperazine/piperidine amides of benzoic and cinnamic acid derivatives as tyrosinase inhibitors with improved potency and drug-likeness.

Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti- activity.

The absence of effective chronic treatment, expansion to non-endemic countries and the significant burden in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by . Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expansion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility.

Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in .

Chagas disease is an endemic tropical disease caused by the protozoan , which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need.

Toward anthelmintic drug candidates for toxocariasis: Challenges and recent developments.

Infections caused by parasitic helminths rank among the most prevalent infections of humans and animals. Toxocariasis, caused by nematodes of the genus Toxocara, is one of the most widespread and economically important zoonotic parasitic infections that humans share with dogs and cats. Despite the completion of the Toxocara canis draft genome project, which has been an important step towards advancing the understanding of this parasite and the search for drug targets, the treatment of toxocariasis has been dependent on a limited set of drugs, necessitating the search for novel anthelmintic agents, specially against Toxocara larvae in tissues.

Esterification of -Coumaric Acid Improves the Control over Melanoma Cell Growth.

Previous studies reported that p-coumaric acid modulates melanoma growth. Because the esterification of p-coumaric acid (p-CA) enhanced its activity as an antimelanogenic agent, we aimed to determine the antitumor potential of two derivatives, the ethyl and butyl esters, against the murine B16-F10 and the human SK-MEL-25 melanoma cells. Cell viability was determined in vitro by the lactate dehydrogenase release and violet crystal absorption assays.

Lethal action of Licarin A derivatives in Leishmania (L.) infantum: Imbalance of calcium and bioenergetic metabolism.

Natural metabolites present an extraordinary chemo-diversity and have been used as the inspiration for new drugs. Considering the need for new treatments against the neglected parasitic disease leishmaniasis, three semi-synthetic derivatives of natural neolignane licarin A were prepared: O-acetyl (1a), O-allyl (1b), and 5-allyl (1c). Using an ex vivo assay, compounds 1a, 1b, and 1c showed activity against the intracellular amastigotes of Leishmania (L.

Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H and dopamine D receptors.

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H and dopamine D receptors (HR and DR, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at HR and DR was done at 1 or 10 µM and 100 µM at AChE and BChE assays.

Neurotoxicity Assessment of 1-[(2,3-Dihydro-1-Benzofuran-2-yl)Methyl]Piperazine (LINS01 Series) Derivatives and their Protective Effect on Cocaine-Induced Neurotoxicity Model in SH-SY5Y Cell Culture.

Excessive levels of dopamine in the synaptic cleft, induced by cocaine for example, activates dopaminergic receptors, mainly DR, DR, and DR subtypes, contributing to neurotoxic effects. New synthetic 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine derivatives (the LINS01 compounds), designed as histaminergic receptor (HR) ligands, are also dopaminergic receptor ligands, mainly DR and DR. This study aims to evaluate the neurotoxicity of these new synthetic LINS01 compounds (LINS01003, LINS01004, LINS01011, and LINS01018), as well as to investigate their protective potential on a cocaine model of dopamine-induced neurotoxicity using SH-SY5Y cell line culture.

Orofacial myofunctional assessment and quality of life of individuals with Parkinson's disease.

Objectives: To characterize orofacial myofunctional structures of elders with Parkinson's disease (PD) and examine the relationship with the stages of PD, pharmacotherapy, and quality of life.

Methods: PD Group with 45 elders and a control group (CG) of 10 healthy elders of both sexes were included (60-86 years). Structured interviews, medical records, and clinical examination gathered information on health aspects such as the use of drugs, Hoehn & Yahr stages 1-4, and oral health status.

Evaluation of the histamine H receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies.

Histamine is involved in several central nervous system processes including cognition. In the last years, H receptor (H R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase.

Histamine research advancements in the second year of the COVID-19 pandemic: report of the European Histamine Research Society (EHRS).

In the light of cancellation of the 50th Annual Meeting of the European Histamine Research Society (EHRS) due to continuing challenges and restrictions imposed by the coronavirus disease 2019 (COVID-19) outbreak, the EHRS Council decided to organize a series of online events spread in 2021 to allow dissemination of histamine research progress and advancement among the Society members and beyond. This report summarizes the outcomes of the EHRS Council initiative that comprised the organization of four webinars, each focusing on a highly relevant histamine research scientific area. These included insights into novel therapeutic targets related to the histaminergic system in the eye, histamine intolerance, and the role of histamine and the histaminergic system in the regulation of the nervous system, as well as an update on studies leading to the development of novel methods for histamine detection.

Optimization of physicochemical properties is a strategy to improve drug-likeness associated with activity: Novel active and selective compounds against Trypanosoma cruzi.

Trypanosoma cruzi is the causing agent of Chagas disease, a parasitic infection without efficient treatment for chronic patients. Despite the efforts, no new drugs have been approved for this disease in the last 60 years. Molecular modifications based on a natural product led to the development of a series of compounds (LINS03 series) with promising antitrypanosomal activity, however previous chemometric analysis revealed a significant impact of excessive lipophilicity and low aqueous solubility on potency of amine and amide derivatives.

Bioisosteric modification on benzylidene-carbonyl compounds improved the drug-likeness and maintained the antifungal activity against Sporothrix brasiliensis.

Considering the emergence of antifungal resistance on Sporothrix brasiliensis, we aimed to assess new benzylidene-carbonyl compounds against feline-borne S. brasiliensis isolates. The compounds were designed as bioisosteres from previously reported benzylidene-ketones generating the p-coumaric (1), cinnamic (2), p-methoxycinnamic (3) and caffeic acid (4) analogues.

Histamine H receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands.

The role of histamine and acetylcholine in cognitive functions suggests that compounds able to increase both histaminergic and cholinergic neurotransmissions in the brain should be considered as promising therapeutic options. For this purpose, dual inhibitors of histamine H receptors (H R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H R/ChEs ligands using multitarget design approaches.

Metabolite profile of Nectandra oppositifolia Nees & Mart. and assessment of antitrypanosomal activity of bioactive compounds through efficiency analyses.

EtOH extracts from the leaves and twigs of Nectandra oppositifolia Nees & Mart. shown activity against amastigote forms of Trypanosoma cruzi. These extracts were subjected to successive liquid-liquid partitioning to afford bioactive CH2Cl2 fractions.

Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H and H receptors.

Histamine acts through four different receptors (HR-HR), the HR and HR being the most explored in the last years as drug targets. The HR is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while HR blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human HR/HR ligands as potential drug candidates.

The Novel HR Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma.

Background/aims: Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine H receptor (HR), whose role in several studies has already been demonstrated. Our group have explored the effects of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines as antagonists of HR, and herein the compounds LINS01005 and LINS01007 were studied with more details, considering the different affinity profile on HR and the anti-inflammatory potential of both compounds.

Relationship between polypharmacy, xerostomia, gustatory sensitivity, and swallowing complaints in the elderly: A multidisciplinary approach.

Oral dysfunctions are common in the elderly but the literature lacks a multidisciplinary approach on the relationship between polypharmacy, saliva flow, xerostomia, taste, and swallowing complaints. This cross-sectional study included 204 non-institutionalized elderly (>60 years; 123 women/81 men), free of severe disabilities and non-alcohol/tobacco consumers, from whom specific pharmacological therapies were evaluated, as well xerostomia (Xerostomia Inventory-XI) and swallowing complaints (EAT-10 questionnaire), salivary flow rate and gustatory sensitivity. Statistical analysis included Chi-square, Mann-Whitney, Two-way ANCOVA, and linear multiple regression.

Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives.

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which still has high prevalence worldwide. In addition, cases of drug resistance are frequently observed. In the search for new anti-TB drugs, compounds with antimycobacterial activity have been developed, such as derivatives of pyrazinoic acid, which is the main pyrazinamide metabolite.