Synergizing structure and function: Cinnamoyl hydroxamic acids as potent urease inhibitors.

The current investigation encompasses the structural planning, synthesis, and evaluation of the urease inhibitory activity of a series of molecular hybrids of hydroxamic acids and Michael acceptors, delineated from the structure of cinnamic acids. The synthesized compounds exhibited potent urease inhibitory effects, with IC50 values ranging from 3.8 to 12.8 µM. Kinetic experiments unveiled that the majority of the synthesized hybrids display characteristics of mixed inhibitors. Generally, derivatives containing electron-withdrawing groups on the aromatic ring demonstrate heightened activity, indicating that the increased electrophilicity of the beta carbon in the Michael Acceptor moiety positively influences the antiureolytic properties of this compounds class. Biophysical and theoretical investigations further corroborated the findings obtained from kinetic assays. These studies suggest that the hydroxamic acid core interacts with the urease active site, while the Michael acceptor moiety binds to one or more allosteric sites adjacent to the active site.

The GNE-KLH anti-cocaine vaccine protects dams and offspring from cocaine-induced effects during the prenatal and lactating periods.

Protecting children from prenatal cocaine exposure is a significant challenge for physicians and childbearing women with cocaine use disorder. Cocaine use is highly prevalent among reproductive-aged women and prenatal cocaine exposure produces obstetric, foetal neurodevelopmental and long-term behavioural impairments. Cocaine crosses the maternal and foetal blood-brain barrier and the placenta by diffusion. The best approach to prevent prenatal cocaine exposure is to stop cocaine use. However, only 25% of cocaine users can discontinue their use during pregnancy. Anti-cocaine vaccination decreases cocaine passage through the blood-brain barrier. This study describes an innovative approach for preventing prenatal cocaine exposure using the GNE-KLH anti-cocaine vaccine, a novel use for the named anti-drug vaccines. Here, we show that anti-cocaine vaccination with GNE-KLH produced and maintained anti-cocaine IgG antibody titres and avidity during pregnancy. These antibodies protected the pregnant rats and their pups against prenatal cocaine damage during pregnancy until weaning. The present work is the first preclinical evidence of the efficacy of an innovative mechanism to prevent prenatal cocaine exposure damage, a worldwide public health care issue. In the future, this mechanism may be useful in pregnant women with cocaine use disorder. Further studies to understand the mechanisms of how anti-cocaine antibodies exert their protective effects in pregnancy are warranted.

Special issue: The Brazilian Meeting on Organic Synthesis.

The 18th Brazilian Meeting on Organic Synthesis (18th BMOS) was planned to be held in Tiradentes, Brazil from October 2020. Due to the pandemic caused by the new coronavirus, the event was initially postponed until 2021 and will finally take place in late 2022. This Special Collection of The Chemical Record is organized together with Guest Editors Ângelo de Fátima and Eufrânio N. da Silva Júnior from Federal University of Minas Gerais and features contributions by present and previous participants of the conferene in the field of Organic Synthesis.

Calix[n]arene-Catalyzed Three-Component Povarov Reaction: Microwave-Assisted Synthesis of Julolidines and Mechanistic Insights.

A new one-pot cascade reaction-based application of Povarov reactions with a p-sulfonic acid calix[4]arene catalyst for the synthesis of a series of 34 julolidine derivatives with substituents at C8 or C9 in good to excellent yields is reported. These microwave-assisted reactions proceeded efficiently, had short reaction times, were metal-free, were low cost, and used an inexpensive, easily available and nontoxic catalyst. These advantages, along with a simple workup procedure, make this protocol a very efficient and green alternative to the traditional methods for constructing these types of N-heterocyclic skeletons. In addition, this protocol allows the formation of julolidine structures, which requires the construction of four new C-C bonds and two C-N bonds. A mechanism for the Povarov reaction involving a stepwise sequence via ionic intermediates was proposed and validated.

Quinolines: Microwave-assisted synthesis and their antifungal, anticancer and radical scavenger properties.

An efficient method for the synthesis of quinolines using microwave irradiation was developed providing 28 quinolines with good yields. The reaction procedures are environmentally friendly, convenient, mild and of easy work-up. Quinolines were evaluated for their antifungal, anticancer and antioxidant properties and exhibited high activities in all tests performed.

Xanthenones: calixarenes-catalyzed syntheses, anticancer activity and QSAR studies.

An efficient method is proposed for obtaining tetrahydrobenzo[a]xanthene-11-ones and tetrahydro-[1,3]-dioxolo[4,5-b]xanthen-9-ones. The method is based on the use of p-sulfonic acid calix[n]arenes as catalysts under solvent-free conditions. The antiproliferative activity of fifty-nine xanthenones against six human cancer cells was studied. The capacity of all compounds to inhibit cancer cell growth was dependent on the histological origin of the cells. QSAR studies indicate that among compounds derived from ß-naphthol the most efficient compounds against glioma (U251) and renal (NCI-H460) cancer cells are those having higher hydrogen bonding donor ability.

2-(benzylideneamino)phenol: a promising hydroxyaldimine with potent activity against dermatophytoses.

Infections caused by dermatophytes, mainly Trichophyton rubrum,are often vulnerable to relapses upon cessation of antifungal therapy, reinforcing the need of new antifungals. Aldimines have potential biological activities, but there are few reports on their antifungal profile. The aim of this study was to evaluate the antifungal activity of 2-(benzylideneamino)phenol (3A3) and 4-(benzylideneamino)phenol (3A4) against dermatophytes. We determined the minimum inhibitory concentration, minimum fungicidal concentration, time-kill curves and fractional inhibitory concentration of the combination of 3A3, 3A4 and itraconazole against a set of isolates of T. rubrum and T. interdigitale. 3A3 was tested in a murine model of dermatophytoses caused by T. rubrum, and the effect on phagocytosis was assessed. The MIC values ranged from 8 to 32 µg/mL for 3A3 and from 64 to 256 µg/mL for 3A4. The interaction between 3A3 and 3A4 with itraconazole proved to be synergistic and indifferent, respectively. 3A3 was as efficient as itraconazole in reducing the fungal burden on the skin of mice, being this effect associated with the influx of neutrophil and macrophage. Also, 3A3 was able to increase the internalization of conidia by macrophages. Altogether, our data encourage future clinical studies with 3A3 to treat dermatophytoses.

Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy.

Pancreatic cancer ranks fourth among cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage tumors. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression, resistance and metastasis. The main goal of this study was to define the mechanisms by which calix[6]arene, but not other calixarenes, efficiently decreases the aggressiveness of a drug resistant human pancreas carcinoma cell line (Panc-1). Calix[6]arene was more potent in reducing Panc-1 cell viability than gemcitabine and 5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and retinoblastoma proteins. Importantly, calix[6]arene abolished signal transduction of Mer and AXL tyrosine kinase receptors, both of which are usually overexpressed in pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these proteins are positively modulated by Mer and AXL. Despite decreasing the phosphorylation of AKT at Thr308, calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α provide a molecular basis explaining the capacity of calix[6]arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight calix[6]arene as a potential candidate for overcoming pancreatic cancer aggressiveness. Importantly, we provide evidence that calix[6]arene affects a broad array of key targets that are usually dysfunctional in pancreatic cancer, a highly desirable characteristic for chemotherapeutics.

Synthesis, antinociceptive activity and pharmacokinetic profiles of nicorandil and its isomers.

Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K(+) channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.

Exposure to the psychedelic substance 25 H-NBOMe disrupts maternal care in lactating rats and subsequently impairs the social play behavior of the offspring.

Given the critical role of maternal care in the neurodevelopment of offspring, this study aimed to investigate the effects of the psychedelic substance 25 H-NBOMe on maternal behavior in lactating rats and its subsequent impact on the social and neurodevelopmental behavior of the offspring. We administered two different dosages of 25 H-NBOMe (0.3 mg/kg and 1.0 mg/kg; i,p,) to lactating rats and observed changes in maternal behaviors, such as nest-building and pup retrieval, and in offspring behaviors, including social play. Behavioral assessments were complemented by physiological measurements to rule out general health or nutritional decline. 25 H-NBOMe significantly disrupted maternal behaviors, including nest-building and pup retrieval, without affecting the weight of dams or offspring. Offspring of exposed dams exhibited reduced social play behavior. Higher doses led to more pronounced disruptions, while lower doses, despite not visibly affecting maternal behavior, still impacted offspring behavior, suggesting potential direct effects of 25 H-NBOMe. The study highlights the potential risks associated with the use of 25 H-NBOMe during lactation, emphasizing its detrimental impact on maternal care and offspring development. These findings contribute to understanding the neurobiological effects of psychedelic substances during critical developmental periods and underscore the importance of avoiding their use.

Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks.

Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 µM; p ã€ˆ0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and - 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer.

An innovative approach for selective and robust screening of NBOHs, NBOMes, and LSD in forensic samples using a 3D-Printed electrochemical double cell.

Lysergic acid diethylamide (LSD) and two phenethylamine classes (NBOHs and NBOMes) are the main illicit drugs found in seized blotter papers. The preliminary identification of these substances is of great interest for forensic analysis. In this context, this work constitutes the inaugural demonstration of an efficient methodology for the selective detection of LSD, NBOHs, and NBOMes, utilizing a fully 3D-printed electrochemical double cell (3D-EDC). This novel 3D-EDC enables the use of two working electrodes and/or two supporting electrolytes (at different pHs) in the same detection system, with the possibility of shared or individual auxiliary and pseudo-reference electrodes. Thus, the selective voltammetric detection of these substances is proposed using two elegant strategies: (i) utilizing the same 3D-EDC platform with two working electrodes (boron-doped diamond (BDD) and 3D-printed graphite), and (ii) employing two pH levels (4.0 and 12.0) with 3D-printed graphite electrode. This comprehensive framework facilitates a fast, robust, and uncomplicated electrochemical analysis. Moreover, this configuration enables a rapid and sensitive detection of LSD, NBOHs, and NBOMes in seized samples, and can also provide quantitative analysis. The proposed method showed good stability of the electrochemical response with RSD <9 % for Ip and <5 % for Ep, evaluating all oxidation processes observed for studied analytes (n = 7) at two pH levels, using the same and different (n = 3) working electrodes. It demonstrates a broad linear range (20-100 and 20-70 µmol L-1) and a low LOD (1.0 µmol L-1) for quantification of a model molecule (LSD) at the two pHs studied. Hence, the 3D-EDC combined with voltammetric techniques using BDD and 3D-printed graphite electrodes on the same platform, or only with this last sensor at two pH values, provide a practical and robust avenue for preliminary identification of NBOHs, NBOMes, and LSD. This method embodies ease, swiftness, cost-efficiency, robustness, and selectivity as an on-site screening tool for forensic analysis.

Psychedelic 25H-NBOMe attenuates post-sepsis depression in rats.

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis.

New anti-SARS-CoV-2 aminoadamantane compounds as antiviral candidates for the treatment of COVID-19.

Here, the antiviral activity of aminoadamantane derivatives were evaluated against SARS-CoV-2. The compounds exhibited low cytotoxicity to Vero, HEK293 and CALU-3 cells up to a concentration of 1,000 µM. The inhibitory concentration (IC50) of aminoadamantane was 39.71 µM in Vero CCL-81 cells and the derivatives showed significantly lower IC50 values, especially for compounds 3F4 (0.32 µM), 3F5 (0.44 µM) and 3E10 (1.28 µM). Additionally, derivatives 3F5 and 3E10 statistically reduced the fluorescence intensity of SARS-CoV-2 protein S from Vero cells at 10 µM. Transmission microscopy confirmed the antiviral activity of the compounds, which reduced cytopathic effects induced by the virus, such as vacuolization, cytoplasmic projections, and the presence of myelin figures derived from cellular activation in the face of infection. Additionally, it was possible to observe a reduction of viral particles adhered to the cell membrane and inside several viral factories, especially after treatment with 3F4. Moreover, although docking analysis showed favorable interactions in the catalytic site of Cathepsin L, the enzymatic activity of this enzyme was not inhibited significantly in vitro. The new derivatives displayed lower predicted toxicities than aminoadamantane, which was observed for either rat or mouse models. Lastly, in vivo antiviral assays of aminoadamantane derivatives in BALB/cJ mice after challenge with the mouse-adapted strain of SARS-CoV-2, corroborated the robust antiviral activity of 3F4 derivative, which was higher than aminoadamantane and its other derivatives. Therefore, aminoadamantane derivatives show potential broad-spectrum antiviral activity, which may contribute to COVID-19 treatment in the face of emerging and re-emerging SARS-CoV-2 variants of concern.

Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors.

This study presents the synthesis of 15 new tacrine dimers as well as the Ki and IC50 results, studies of the kinetic mechanism, and molecular docking analysis of the dimers in relation to the cholinesterases hAChE, hBChE, EeAChE and eqBChE. In addition to spectroscopic characterization, X-ray structure determination was performed for two of the new compounds. These new dimers were found to be mixed nanomolar inhibitors of the evaluated targets with a broad and significant selectivity profile, and these properties are dependent on both the type of the linker and the volume of the hydroacridine alicyclic ring. The results indicate that the aromatic linkers play a significant role in generating specific interactions with the half-gorge region of the catalytic center. Thus, these types of linkers can positively modulate the electronic properties of the tacrine dimers studied with an improvement of their cholinesterase inhibition activity.

Organocatalysis in the three-component Povarov reaction and investigation by mass spectrometry.

A diastereoselective three-component cascade reaction, catalyzed by p-sulfonic acid calix[4]arene, provides a unique method to access diverse julolidine derivatives in high yields. Additionally, the reaction was also monitored by mass spectrometry and the mechanistic pathway uncovered.

3-Benzoyl-1-[4-(methyl-sulfan-yl)phen-yl]thio-urea.

The title compound, C15H14N2OS2, adopts a helix conformation. An intra-molecular N-H⋯O hydrogen bond leads to a six-membered pseudo-ring [r.m.s. deviation = 0.0212 Å, maximum deviation = 0.033 (1) Šfor the N atom bearing the benzoyl group] in the central unit. The benzene and (methyl-sulfan-yl)benzene ring [r.m.s = 0.0028 Šand largest deviation of 0.067 (3) Šfor the methyl-sulfanyl C atom] make dihedral angles of 31.76 (8) and 54.68 (6)°, respectively, with the pseudo-ring plane. The dihedral angle between the benzene rings is 85.71 (8)°. In the crystal, pairs of weak N-H⋯S inter-actions form inversion dimers and mediate a linear chain along [001].

rac-5-(1-Methyl-eth-yl)-2-sulfanylidene-imidazolidin-4-one.

In the title compound, C6H10N2OS, the 2-sulfanylideneimidazolidin-4-one fragment is essentially planar (r.m.s. deviation = 0.0033 Å). In the crystal, one amino group is involved in N-H⋯O hydrogen bonding, which links pairs of mol-ecules into inversion dimers, while the other amino group generates weak N-H⋯S hydrogen bonds, which link these dimers into chains in [10-1]. The chains are further aggregated into layers parallel to the ac plane through weak C-H⋯O inter-actions.

Psychoactive substances 25H-NBOMe and 25H-NBOH induce antidepressant-like behavior in male rats.

Ring-substituted phenethylamines are believed to induce psychedelic effects primarily by interacting with 5-hydroxytryptamine 2 (5-HT2A) receptors in the brain. We assessed the effect of the psychedelic substances 25H-NBOMe and 25H-NBOH on the depressive-like behavior of male adult rats. Naive Wistar rats were divided into groups to assess the effects of different doses (0.1 mg/kg, 1 mg/kg, and 3 mg/kg) of 25H-NBOMe and 25H-NBOH. The substances were administered intraperitoneally and the hallucinogenic properties were evaluated using the head twitch response test (HTR). Additionally, we assessed their locomotor activity in the open field test (OFT) and depressive-like behavior in the forced swimming test (FST). Our data demonstrated that all doses of synthetic psychedelic substances evaluated exhibited hallucinogenic effects. Interestingly, we observed that both 25H-NBOMe and 25H-NBOH produced a significantly greater motivation to escape in the FST, compared to the control group. Furthermore, we found no significant differences in locomotor activity during the OFT, except for the dose of 3 mg/kg, which induced a reduction in locomotion. This study provides new insights into a potential psychedelic substance, specifically by demonstrating the previously unknown antidepressant properties of a single dose of both 25H-NBOMe and 25H-NBOH. These findings contribute to the ongoing progress of experimental psychiatry toward developing safe and effective clinical practices in the field of psychedelics research.