RESUMO

Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1a) and of five benzofuran derivatives (2a, 2b, 2c, 2f and 2g) by single crystal X-Ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2b, 2e, and 2g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition > 60%). Compound 2e showed an IC50 of 0.2 µM and was selected for further analysis, results reinforce its anticancer potential.

RESUMO

Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.

Assuntos

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Anxiety disorders, characterized by high prevalence rates, cause psychiatric disabilities and are related to impairments in serotoninergic system function. Frequent anxiety recurrence, resistance, and drug adverse effects have driven searches for new therapies. We initially evaluated the anxiolytic-like activity of 3-selanyl-benzo[b]furan compounds (SeBZF1-5) (50 mg/kg, i.g.) in male Swiss mice using the light-dark test (LDT). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) exhibited anxiolytic-like activity. SeBZF3 anxiolytic-like effects were also observed in the novelty-suppressed feeding test (NSFT) (50 mg/kg) and elevated plus-maze test (EPMT) (25 and 50 mg/kg). In the EPMT, anxiolytic-like effects of SeBZF3 (50 mg/kg) were abolished by pretreatment with p-chlorophenylalanine, a selective tryptophan hydroxylase inhibitor (100 mg/kg, i.p. for 4 days), suggesting the involvement of serotonergic mechanisms. Furthermore, we conducted experiments to investigate the synergistic effects of SeBZF3 subeffective doses (5 mg/kg, i.g.) in combination with fluoxetine (a selective serotonin reuptake inhibitor, 5 mg/kg, i.p.) or buspirone (a partial agonist of the 5-HT1A receptor, 2 mg/kg, i.p.). This coadministration resulted in pronounced synergistic effects. We also examined the effects of repeated oral treatment with SeBZF3 at doses of 1 and 5 mg/kg over 14 days and both reduced anxiety signals. In vitro and ex vivo findings revealed that SeBZF3 inhibited cerebral MAO-A activity. These findings collectively imply the potential involvement of serotonergic mechanisms in the anxiolytic-like activity of SeBZF3 in mice. These data offer contributions to the research field of organoselenium compounds and anxiolytics, encouraging the broadening of the search for new effective drugs while offering improved side effect profiles.

RESUMO

Despite the recent promising results of MDMA (3,4-methylenedioxy-methamphetamine) as a psychotherapeutic agent and its history of misuse, little is known about its molecular mode of action. MDMA enhances monoaminergic neurotransmission in the brain and its valuable psychoactive effects are associated to a dual action on the 5-HT transporter (SERT). This drug inhibits the reuptake of 5-HT (serotonin) and reverses its flow, acting as a substrate for the SERT, which possesses a central binding site (S1) for antidepressants as well as an allosteric (S2) one. Previously, we characterized the spatial binding requirements for MDMA at S1. Here, we propose a structure-based mechanistic model of MDMA occupation and translocation across both binding sites, applying ensemble binding space analyses, electrostatic complementarity, and Monte Carlo energy perturbation theory. Computed results were correlated with experimental data (r = 0.93 and 0.86 for S1 and S2, respectively). Simulations on all hSERT available structures with Gibbs free energy estimations (ΔG) revealed a favourable and pervasive dual binding mode for MDMA at S2, i.e., adopting either a 5-HT or an escitalopram-like orientation. Intermediate ligand conformations were identified within the allosteric site and between the two sites, outlining an internalization pathway for MDMA. Among the strongest and more frequent interactions were salt bridges with Glu494 and Asp328, a H-bond with Thr497, a π-π with Phe556, and a cation-π with Arg104. Similitudes and differences with the allosteric binding of 5-HT and antidepressants suggest that MDMA may have a distinctive chemotype. Thus, our models may provide a framework for future virtual screening studies and pharmaceutical design and to develop hSERT allosteric compounds with a unique psychoactive MDMA-like profile.

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The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL-1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL-1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.

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The repurposing or repositioning of previously-approved drugs has become an accepted strategy for the expansion of the pharmacopeia for neglected diseases. Accordingly, amiodarone, an inexpensive and extensively- used class III antiarrhythmic has been proposed as a treatment for Chagas' disease and leishmaniasis. Amiodarone has a potent trypanocidal and leishmanicidal action, mainly acting through the disruption of parasite intracellular Ca2+ homeostasis, which is a recognized target of different drugs that have activity against trypanosomatids. Amiodarone collapses the mitochondrial electrochemical potential (Δφm) and induces the rapid alkalinization of parasite acidocalcisomes, driving a large increase in the intracellular Ca2+ concentration. Amiodarone also inhibits oxidosqualene cyclase activity, a key enzyme in the ergosterol synthesis pathway that is essential for trypanosomatid survival. In combination, these three effects lead to parasite death. Dronedarone, a drug synthesized to minimize some of the adverse effects of amiodarone, displays trypanocidal and leishmanicidal activity through the same mechanisms, but curiously, being more potent on Leishmaniasis than its predecessor. In vitro studies suggest that other recently-synthesized benzofuran derivatives can act through the same mechanisms, and produce similar effects on different trypanosomatid species. Recently, the combination of amiodarone and itraconazole has been used successfully to treat 121 dogs naturally-infected by T. cruzi, strongly supporting the potential therapeutic use of this combination against human trypanosomatid infections.

Assuntos

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Leishmaniasis is a parasitic disease representing an important problem of public health. Visceral leishmaniasis, resulting from infection with Leishmania donovani, causes considerable mortality and morbidity in the poorest region of the word. At present there is no current effective treatment, since the approved, drugs are expensive and are not free of undesirable side effects. Therefore, there is a need for the identification of new drugs. In this context, the parasite Ca2+ regulatory mechanisms in which mitochondria and acidocalcisomes are involved have been postulated as important targets for several trypanocidal drugs. Thus, amiodarone and dronedarone, common human antiarrythmics, exert its known action on these parasites through the disruption of the intracellular Ca2+ homeostasis. AMIODER is a benzofuran derivate based on the structure of amiodarone that recently demonstrates a significant effect on Trypanosoma cruzi. We now report the effect of AMIODER on Leishmania donovani demonstrating that it inhibit the growth of promastigotes and also of amastigotes inside macrophages, the clinically relevant stage of the parasite, obtaining IC50 values significantly lower than those reported for T. cruzi. We also show that this compound disrupted Ca2+ homeostasis in L. donovani, through its action on two organelles involved in the intracellular Ca2+ regulation and on the bioenergetics of the parasite. AMIODER totally collapsed the electrochemical membrane potential of the unique giant mitochondrion and simultaneously induced the alkalinization of acidocalcisomes, driving together to a large increase in the intracellular Ca2+ concentration of the parasite as the main mechanism of action of this benzofurane derivative.

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Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder that slowly destroys memory. The precise mechanism of AD is still not entirely understood and remains under discussion; it is believed to be a multifactorial disease in which a number of mechanisms are involved in its pathogenesis. Worldwide, near 37 million people suffer from the effects of AD. As a cause of death for elderly, it is predicted that AD will rank third in the coming years, just behind cancer and heart disease. Unfortunately, AD remains an incurable condition. Despite the devastating problems associated with AD, there are only four FDA approved drugs for palliative treatment of this pathology. Hence, renewed scientific efforts are required not only to uncover more insights into the AD process but also to develop more efficient pharmacological tools against this disease. Due to the complexity and multiple mechanisms at play in the progression of AD, the development of drugs by rational design is extremely difficult. The existing drugs to fight against Alzheimer's have had limited success, mainly due to their ability to modulate only one of the mechanisms involved in AD. As opposed to single-targeted strategies, the identification of small molecules able to affect multiple pathways involved in Alzheimer's is a promising strategy to develop more efficient medicines against this disease. Central to existing efforts to develop pharmaceuticals controlling AD is the discovery of new chemicals displaying strong neuroactivity. Benzofurans are privileged oxygen containing heterocycles that have a strong neuroprotective behavior, inhibiting several of the important events involved in the AD process. In this review, an approach is presented that relies on expanding the neuroprotective chemical space of benzofuran scaffolds by accessing them from Andean-Patagonian fungi and synthetic sources (chemical libraries). The exploration of the neuroprotective chemical space of these scaffolds has the potential to allow the discovery of substitution patterns that display multi-target neuroactivity against multiple events involved in AD. This benzofuran chemical framework will establish a multi-target chemical space that could set the basis for the development of super drugs against AD.

RESUMO

In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔGbind) obtained for the Tam16 lead molecule was of -51.43 kcal/mol. When comparing this result with the ΔGbind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC50 = 0.19 µM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.

Assuntos

RESUMO

We have investigated gas-phase fragmentation reactions of protonated benzofuran neolignans (BNs) and dihydrobenzofuran neolignans (DBNs) by accurate-mass electrospray ionization tandem and multiple-stage (MSn ) mass spectrometry combined with thermochemical data estimated by Computational Chemistry. Most of the protonated compounds fragment into product ions B ([M + H-MeOH]+ ), C ([B-MeOH]+ ), D ([C-CO]+ ), and E ([D-CO]+ ) upon collision-induced dissociation (CID). However, we identified a series of diagnostic ions and associated them with specific structural features. In the case of compounds displaying an acetoxy group at C-4, product ion C produces diagnostic ions K ([C-C2 H2 O]+ ), L ([K-CO]+ ), and P ([L-CO]+ ). Formation of product ions H ([D-H2 O]+ ) and M ([H-CO]+ ) is associated with the hydroxyl group at C-3 and C-3', whereas product ions N ([D-MeOH]+ ) and O ([N-MeOH]+ ) indicate a methoxyl group at the same positions. Finally, product ions F ([A-C2 H2 O]+ ), Q ([A-C3 H6 O2 ]+ ), I ([A-C6 H6 O]+ ), and J ([I-MeOH]+ ) for DBNs and product ion G ([B-C2 H2 O]+ ) for BNs diagnose a saturated bond between C-7' and C-8'. We used these structure-fragmentation relationships in combination with deuterium exchange experiments, MSn data, and Computational Chemistry to elucidate the gas-phase fragmentation pathways of these compounds. These results could help to elucidate DBN and BN metabolites in in vivo and in vitro studies on the basis of electrospray ionization ESI-CID-MS/MS data only.