Search Results (49)

The indole scaffold represents a privileged structural motif in medicinal chemistry, celebrated for its remarkable chemical versatility, biological ubiquity, and clinical relevance. This review provides a comprehensive analysis of the recent research on the indole nucleus, emphasizing its physicochemical properties, reactivity patterns, and capacity to interact with a wide array of biological targets. Found in key endogenous compounds such as serotonin and melatonin, indole serves as a cornerstone in neurochemical signaling, circadian regulation, and chrono-metabolic homeostasis. Beyond its physiological roles, synthetic indole derivatives have shown extensive therapeutic potential across diverse domains, including oncology, infectious diseases, neurodegenerative disorders, immunomodulation, and metabolic syndromes. The review explores structure–activity relationships (SAR), pharmacokinetics, and the molecular mechanisms by which indole-based compounds exert their tremendous effects, that are ranging from enzyme inhibition to receptor modulation. Special focus is given to current clinical applications and emerging strategies for enhancing drug specificity, bioavailability, and safety through indolic frameworks. Additionally, we highlight the translational potential of indole-containing molecules in personalized medicine, underscoring opportunities for future drug discovery. By integrating insights from medicinal chemistry, biochemistry, pharmacology, and clinical science, this review affirms the indole ring’s enduring value as a central scaffold in therapeutic innovation. Full article

Fusarium oxysporum is the causal agent of Fusarium dry rot disease (FDR), which results in postharvest potato losses. Biological control agents (BCAs) and phytohormone melatonin have antifungal effects on fungal pathogens and can be used as alternatives to synthetic chemical fungicides. The aim of the study was to evaluate the integrated effects of melatonin (MEL) and Bacillus amyloliquefaciens (Bamy) on the postharvest quality of potato tubers. Bamy was integrated with six MEL concentrations and screened against F. oxysporum in vitro and in vivo. The effects of the best performing treatment were evaluated for antioxidant activity, phenolic content, ascorbic acid content, and protein content on potato tubers. In the in vitro screening trial, treatment with Bamy + MEL100 had the highest mycelial growth inhibition percentage (59.92%), followed by Bamy + MEL15 and Bamy + MEL50 (56.12% and 55.27%, respectively). Potato tubers treated with Bamy + MEL100 had the lowest disease severity of FDR (50.61%) and a pathogen penetration value of 6.39 mm. Bamy + MEL50 showed a disease severity percentage of 59.72%. The exogenous application of melatonin at a concentration of 100 µM combined with B. amyloliquefaciens was the most effective treatment with the highest phenolic content (144.1 mg GAE/g DW) and protein content (68 mg/g DM) compared to the untreated tubers (104.4 GAE/g DW phenolic content and 50.06 mg/g DM protein content). Tubers treated with melatonin had the highest ascorbic acid content (5.48 mg AAE/100g DM) compared to the untreated tubers (4.09 mg AAE/100 g DM). Overall, tubers treated with a combination of melatonin and B. amyloliquefaciens showed less severe symptoms of FDR across all concentrations. Based on these findings, it can be concluded that B. amyloliquefaciens and melatonin at 100 µM concentration can be used in combination to inhibit the growth of F. oxysporum. Full article

Cardiovascular disease (CVD) remains the leading cause of global mortality, despite advances in adult-focused prevention and therapy. Mounting evidence supports the Developmental Origins of Health and Disease (DOHaD) paradigm, which identifies early-life exposures as critical determinants of long-term cardiovascular health. Among the key mechanistic pathways, oxidative stress and gut microbiota dysbiosis have emerged as central, interrelated contributors to cardiovascular programming. Prenatal and postnatal insults can induce sustained redox imbalance and disrupt microbial homeostasis. This disruption creates a feed-forward loop that predisposes offspring to CVD later in life. Antioxidants offer a promising reprogramming strategy by targeting both oxidative stress and gut microbiota composition. Preclinical studies demonstrate that maternal antioxidant interventions—such as vitamins, amino acids, melatonin, polyphenols, N-acetylcysteine, and synthetic agents—can restore redox homeostasis, modulate gut microbial communities, and attenuate cardiovascular risk in offspring. This review synthesizes current evidence on how oxidative stress and gut microbiota act together to shape cardiovascular trajectories. It also examines how antioxidant-based therapies may disrupt this pathological axis during critical developmental windows. Although human data remain limited due to ethical and practical constraints, advancing microbiota-targeted antioxidant interventions may offer a transformative approach to prevent CVD at its origins. Full article

Chronobiotics represent a pharmacologically diverse group of substances, encompassing both experimental compounds and those utilized in clinical practice, which possess the capacity to modulate the parameters of circadian rhythms. These substances influence fluctuations in various physiological and biochemical processes, including the expression of core “clock” genes in model organisms and cell cultures, as well as the expression of clock-controlled genes. Despite their chemical heterogeneity, chronobiotics share the common ability to alter circadian dynamics. The concept of chronobiotic drugs has been recognized for over five decades, dating back to the discovery and detailed clinical characterization of the hormone melatonin. However, the field remains fragmented, lacking a unified classification system for these pharmacological agents. The current categorizations include natural chrononutrients, synthetic targeted circadian rhythm modulators, hypnotics, and chronobiotic hormones, yet no comprehensive repository of knowledge on chronobiotics exists. Addressing this gap, the development of the world’s first curated and continuously updated database of chronobiotic drugs—circadian rhythm modulators—accessible via the global Internet, represents a critical and timely objective for the fields of chronobiology, chronomedicine, and pharmacoinformatics/bioinformatics. The primary objective of this study is to construct a relational database, ChronobioticsDB, utilizing the Django framework and PostGreSQL as the database management system. The database will be accessible through a dedicated web interface and will be filled in with data on chronobiotics extracted and manually annotated from PubMed, Google Scholar, Scopus, and Web of Science articles. Each entry in the database will comprise a detailed compound card, featuring links to primary data sources, a molecular structure image, the compound’s chemical formula in machine-readable SMILES format, and its name according to IUPAC nomenclature. To enhance the depth and accuracy of the information, the database will be synchronized with external repositories such as ChemSpider, DrugBank, Chembl, ChEBI, Engage, UniProt, and PubChem. This integration will ensure the inclusion of up-to-date and comprehensive data on each chronobiotic. Furthermore, the biological and pharmacological relevance of the database will be augmented through synchronization with additional resources, including the FDA. In cases of overlapping data, compound cards will highlight the unique properties of each chronobiotic, thereby providing a robust and multifaceted resource for researchers and practitioners in the field. Full article

In recent years, an increasing number of case reports have mentioned the presence of illicit nootropics, smart drugs or mind doping products on the market. To better understand the extent of the problem, a market surveillance study was organised by the General European Official Medicines Control Laboratory Network and associated member Australia to detect substandard, falsified or illegal medicines or dietary supplements containing unauthorised nootropic molecules of natural or synthetic origin. From January 2020 to September 2024, 159 different samples were documented, which yielded a comprehensive dataset of 166 molecular identification entries. Within this dataset, 34 distinct molecules were identified. Most samples were sold or presented as dietary supplements (49%) or medicines (32%). The vast majority (69%) were collected from the illegal market. Prescription drugs and non-authorised drugs only available on prescription in Russia were found in pharmacological quantities; some of the latter (noopept, phenylpiracetam and phenibut) were intercepted as large bulk quantities of raw material. Unauthorised novel foods, prescription or higher amounts of melatonin, and clinically uncharacterised research molecules were also reported. This study highlights the need for more active monitoring and screening of such products, as consumption of some of the reported samples could have detrimental health effects. Furthermore, as a large number of the samples were presented as dietary supplements, consumers may not be aware of the possible dangers and side-effects of these products. Full article

Yeast metabolism significantly contributes to functional beverage production by generating bioactive compounds such as tryptophan derivatives (dTRPs). While Saccharomyces cerevisiae is traditionally used, non-Saccharomyces yeasts like Torulaspora delbrueckii and Zygosaccharomyces bailii are gaining interest for their ability to enhance aroma profiles and influence metabolite synthesis. This study evaluated the dTRP production of T. delbrueckii CBS1146^T and Z. bailii ATCC36947^T in synthetic medium and Cabernet Sauvignon must supplemented with 100 mg/L tryptophan. LC-MS/MS analysis revealed strain-dependent differences in metabolite profiles, with a predominance of kynurenine pathway compounds and the first identification of two tryptophan-ethylester (TEE) isomers. T. delbrueckii exhibited significant TEE production, correlating with the consumption of dTRPs; conversely, Z. bailii synthesized diverse metabolites, including 5OH-tryptophan and kynurenic acid. Notably, melatonin was not detected. The fermentation matrix strongly influenced dTRP biosynthesis, with must conditions enhancing TEE and kynurenic acid accumulation. These findings highlight the role of growth medium composition in modulating yeast metabolism and support the potential of non-Saccharomyces yeasts for functional beverage development. Full article

In these times and with the pace of life that we have developed, many people need help falling asleep due to poor sleep hygiene, among other reasons. Thus, in mild cases, it is recommended to use natural therapies, such as phytotherapy, avoiding in the first instance the use of drugs. Melatonin is considered a versatile molecule widely used today. It is included as a main ingredient in dietary supplements that are, in some cases, accompanied by medicinal plants as botanical mixes, generating beneficial products for sleep disorders among other conditions. The dietary phytotherapeutic supplements evaluated in this work contain various concentrations of melatonin and other products, resulting in different effects on sleep therapy. The aim of this work is to reveal the quantitative differences that exist between the melatonin contents labeled in the products and those analyzed. The degradation rate of this hormone at three years in the phytotherapeutic supplements is also studied in order to re-evaluate the expiration dates of these products. In conclusion, the mixture between synthetic melatonin and different botanical mixes is very common in the supplements studied here and aimed at improving sleep. However, the most natural thing would be to be able to use only plants with sufficient phytomelatonin content to eliminate the inclusion of chemically synthesized melatonin in preparation. We propose the use of a particular raw plant material with excellent characteristics for this purpose. Full article

Melatonin is indispensable for the homeostasis of plants and animals. In humans, it can help prevent or be an adjuvant treatment for several diseases mainly related to the immune system, inflammation, and oxidative stress. Moreover, a melatonin-rich diet is linked to several health benefits, such as regulation of circadian rhythm, regulation of the immunological system, epilepsy control, delaying the aging process, and diminishing hormones related to cancer. This review aimed to show the effects of melatonin in diseases beyond its traditional use. The results showed it can present scavenging of free radicals, reducing inflammatory cytokines, and modulating the immune system. Moreover, it can improve insulin resistance, blood pressure, LDL-c, adipose tissue mass, adhesion molecules, endothelial impairment, and plaque formation. These effects result in neuro- and cardioprotection, improvement of liver diseases, rheumatoid arthritis, dermatitis, COVID-19, polycystic ovaries, and sepsis. We conclude that plant melatonin can benefit patients with many diseases besides sleep problems and neurodegeneration. Plant melatonin may be more cost-effective and present fewer adverse events than synthetic. However, more clinical trials should be performed to show adequate doses, formulation, and treatment time. Full article

Alzheimer’s disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) is emerging as a promising target for AD therapy. In this study, by combining a PDE9 inhibitor C33 with the antioxidant melatonin, we designed and discovered a series of pyrazolopyrimidinone derivatives that simultaneously inhibit PDE9 and possess antioxidant activities. Molecular docking, together with dynamics simulations, were applied to accelerate compound design and reduce synthetic work. Four out of the 14 compounds were validated as effective PDE9 inhibitors with comparable antioxidant activity. Notably, compounds 17b and 17d demonstrated IC₅₀ values of 91 and 89 nM against PDE9, respectively, with good antioxidant activities (ORAC (Trolox) of 2.00 and 2.60). This work provides a new approach for designing MTDLs for the treatment of AD and offers insights for further structural modifications of PDE9 inhibitors with antioxidant capacities. Full article

Background/Objectives: Exogenous melatonin adsorbed onto PEG microspheres can modulate the functional activity of phagocytes in colostrum, but no data are available on the activity of melatonin found in colostrum. Therefore, the objective of this study was to extract melatonin from human colostrum, develop and characterize PEG microspheres with the extracted melatonin adsorbed onto them, and evaluate the effects of this system on the oxidative metabolism of colostrum phagocytes. Methods: Thirty colostrum samples were collected; ten were used for melatonin extraction, while twenty were used to obtain phagocytes. Melatonin was extracted from the colostrum supernatant through affinity chromatography and quantified by ELISA. The polyethylene glycol microspheres produced were analyzed using fluorescence microscopy and flow cytometry. Oxidative metabolism was assessed by measuring the release of the superoxide anion and superoxide enzymes. A control was conducted using commercial melatonin. Results: The fluorescence microscopy and flow cytometry analyses demonstrated that PEG microspheres can adsorb melatonin. There was an increase in superoxide release in phagocytes incubated with colostrum-derived or synthetic melatonin. When exposed to bacteria, colostrum phagocytes treated with colostrum melatonin adsorbed to PEG microspheres exhibited increased superoxide, accompanied by a decrease in the release of superoxide dismutase (SOD) and a lower SOD-to-superoxide ratio. In contrast, synthetic melatonin reduced the release of superoxide and increased the release of the enzyme and the SOD-to-superoxide ratio. Conclusions: These data highlight the importance of melatonin on cellular metabolism and suggest that colostrum-derived melatonin may be a more effective option for controlling oxidative metabolism, particularly during infectious processes. Full article

Melatonin, an endogenous indolamine derived from tryptophan, is primarily synthesized by the pineal gland in mammals and regulated by a complex neural system. Its release follows a circadian rhythm, which is crucial for regulating physiological processes in response to light–dark cycles in both humans and animals. In this review, we report that the presence of this hormone in bovine milk, with significant differences in concentration between daytime and nighttime milking, has increased interest in milk as a natural source of bioactive molecules. Melatonin lowers cortisol levels at night, reduces body temperature and blood pressure, coinciding with decreased alertness and performance, acts as an antioxidant and anti-inflammatory agent, modulates the immune system, offers neuroprotective benefits, and supports gastrointestinal health by scavenging free radicals and reducing oxidative stress in dairy cows. Many factors influence the release of melatonin, such as the intensity of artificial lighting during nighttime milking, the frequency of milkings, milk yield, and genetic differences between animals. Nocturnal milking under low-intensity light boosts melatonin, potentially reducing oxidative damage and mastitis risk. Additionally, ultra-high temperature (UHT) treatment does not significantly affect the melatonin content in milk. However, further research on its stability during milk processing and storage is crucial for ensuring product efficacy. In some countries, nighttime milk with naturally elevated melatonin content is already commercialized as a natural aid for sleep. Thus, naturally melatonin-rich milk may be a promising alternative to synthetic supplements for promoting better sleep and overall well-being. Full article

Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian reserve suppression and estrogen deficiency result in reduced quality of life for cancer patients and are frequently the cause of infertility and early menopause. Classic alkylating cytostatics are among the most toxic chemotherapeutics in this regard. They cause DNA damage in ovarian follicles and the cells they contain, and they can also induce oxidative stress or affect numerous signaling pathways. In vitro tests, animal models, and a few studies among women have investigated the effects of various agents on the protection of the ovarian reserve during classic chemotherapy. In this review article, we focused on the possible beneficial effects of selected hormones (anti-Müllerian hormone, ghrelin, luteinizing hormone, melatonin), agents affecting the activity of apoptotic pathways and modulating gene expression (C1P, S1P, microRNA), and several natural (quercetin, rapamycin, resveratrol) and synthetic compounds (bortezomib, dexrazoxane, goserelin, gonadoliberin analogs, imatinib, metformin, tamoxifen) in preventing gynotoxic effects induced by commonly used cytostatics. The presented line of research appears to provide a promising strategy for protecting and/or improving the ovarian reserve in the studied group of cancer patients. However, well-designed clinical trials are needed to unequivocally assess the effects of these agents on improving hormonal function and fertility in women treated with ovotoxic anticancer drugs. Full article

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies. Full article

Melatonin is a tryptophan derivative synthesized in plants and animals. In humans, melatonin acts on melatonin MT₁ and MT₂ receptors belonging to the G protein-coupled receptor (GPCR) family. Synthetic melatonin receptor agonists are prescribed for insomnia and depressive and circadian-related disorders. Here, we tested 25 commercial plant extracts, reported to have beneficial properties in sleep disorders and anxiety, using cellular assays (2─[¹²⁵I]iodomelatonin binding, cAMP inhibition, ERK1/2 activation and β-arrestin2 recruitment) in mock-transfected and HEK293 cells expressing MT₁ or MT₂. Various melatonin receptor-dependent and -independent effects were observed. Extract 18 (Ex18) from Pistacia vera dried fruits stood out with very potent effects in melatonin receptor expressing cells. The high content of endogenous melatonin in Ex18 (5.28 ± 0.46 mg/g extract) is consistent with this observation. Ex18 contains an additional active principle that potentiates the effect of melatonin on G_i protein-dependent pathways but not on β-arrestin2 recruitment. Further active principles potentiating exogenous melatonin were detected in several extracts. In conclusion, we identified plant extracts with various effects in GPCR-based binding and signalling assays and identified high melatonin levels and a melatonin-potentiating activity in Pistacia vera dried fruit extracts that might be of therapeutic potential. Full article

Due to its endogenously high oxygen consumption, the central nervous system (CNS) is vulnerable to oxidative stress conditions. Notably, the activity of several CNS-targeting compounds, such as antidepressant and hypnotic drugs, or endogenous mediators, such as melatonin, is indeed linked to their ability of mitigating oxidative stress. In this work, we report the synthesis of two organoselenium compounds of which the structure was inspired by CNS-targeting psychotropic drugs (zolpidem and fluoxetine) and an endogenous mediator (melatonin). The molecules were designed with the aim of combining the ROS-scavenging properties, which were already assessed for the parent compounds, with a secondary antioxidant action, a glutathione peroxidase (GPx) mimic role empowered by the presence of selenium. The compounds were obtained through a facile three-step synthesis and were predicted by computational tools to passively permeate through the blood–brain barrier and to efficiently bind to the GABA A receptor, the macromolecular target of zolpidem. Of note, the designed synthetic pathway enables the production of several other derivatives through minor modifications of the scheme, paving the way for structure–activity relationship studies. Full article