Search Results (56)

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to their diverse pharmacological activities. This study aimed to design, synthesize, and evaluate new hybrid heterocyclic systems, including 1,2,4-triazole, 1,3,4-oxadiazole, and thiadiazine motifs, targeting liver and breast cancer. Methods: A series of indolyl-based heterocyclic compounds was synthesized using efficient and environmentally friendly protocols. Indolyl-triazol-thiadiazin-6-ol 5 was prepared via solvent-free fusion of esters 2 and 3 or the corresponding acid 4. Oxadiazole derivatives were produced by reacting hydrazide intermediates with carbon disulfide. Triazole derivatives were synthesized via cylization of thiosemicarbazide 9 in aqueous KOH (4.0 N). Structural characterization was performed using Fourier Transform InfraRed (FTIR), ¹H and ¹³C NMR spectroscopy, and electron impact mass spectrometry (EIMS). Cytotoxic activity was evaluated against liver and breast cancer cell lines, and VEGFR-2 kinase inhibition was assessed for selected derivatives. Results: The synthesized compounds demonstrated notable cytotoxicity activity, with compounds 4, 5, and 9 exhibiting IC₅₀ values in the low micromolar range. Enzymatic assays revealed that compounds 4 and 9 showed strong VEGFR-2 inhibition (97.9% and 96.4%, respectively), indicating apoptosis-inducing effects. Conclusions: The synthesized indolyl-based hybrid heterocycles represent a promising chemotype with in vitro cytotoxic activity and VEGFR-2 inhibitory effects, supporting further investigation, optimization, and mechanistic studies to evaluate their potential lead for anticancer drug development. Full article

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR), with rarer forms occurring less frequently. AL amyloidosis arises from plasma cell-derived light chains and typically follows an aggressive clinical course, whereas ATTR amyloidosis results from misfolded wild-type or variant transthyretin and progresses more indolently. Extracellular vesicles (EVs) have recently been recognized as mediators of amyloid propagation, inflammation, and myocardial remodeling, particularly at later stages of disease. Despite growing evidence, no comprehensive reviews have focused on this relationship. We conducted a structured narrative review (PubMed and Scopus, 2020–2025) following Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines to synthesize emerging data. EVs act as scaffolds for transthyretin and serum amyloid A aggregation and carry disease-specific protein and RNA cargo detectable in blood and urine. Experimental models also demonstrate EV-mediated transport of serum amyloid A under conditions of cardiac stress, representing a reactive amyloidogenic pathway rather than a common cause of human cardiac amyloidosis. Preclinical studies show regenerative and anti-fibrotic effects of stem-cell-derived EVs, and early clinical trials demonstrate the feasibility of EV-based cardiac therapy. While methodological and translational challenges persist, EVs represent promising diagnostic and therapeutic tools that could transform the precision management of cardiac amyloidosis. Full article

Giardiasis, caused by the protozoan parasite Giardia lamblia, remains a prevalent intestinal infection worldwide and a growing concern due to increasing resistance to nitroimidazole drugs. This study proposes an alternative therapeutic strategy by targeting fructose-1,6-bisphosphate aldolase (FBPA), a key glycolytic enzyme of the parasite, through structure-based virtual screening. A curated library of microbiome-derived metabolites was computationally evaluated and compared with clinically used antigiardial drugs. Several indole-based compounds exhibited favorable binding affinities and stable interactions within the catalytic pocket of FBPA. These findings suggest that microbiome metabolites could serve as promising scaffolds for the rational design of new antiparasitic agents. Overall, the study highlights the potential of integrating metabolic and computational approaches to identify next-generation therapeutics against giardiasis. Full article

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

Type 2 diabetes mellitus (T2DM) remains a global health challenge, prompting the development of novel α-glucosidase inhibitors (AGIs) to regulate postprandial hyperglycemia. This study reports the design, synthesis, and evaluation of indole-based Schiff base derivatives (4a–j) bearing a fixed methoxy group at the C₅ position. This substitution was strategically introduced to enhance lipophilicity, electronic delocalization, and π-stacking within the enzyme active site. Among the series, compound 4g (3-bromophenyl) exhibited the highest inhibitory activity (IC₅₀ = 10.89 µM), outperforming the clinical reference acarbose (IC₅₀ = 48.95 µM). The mechanism was supported by in silico analyses, such as the Density Functional Theory (DFT), molecular electrostatic potential (MEP) mapping, and molecular dynamics simulations, and CNN-based docking revealed that 4g engages in stable hydrogen bonding and π–π interactions with key residues (Asp327, Asp542, and Phe649), suggesting a potent and selective mode of inhibition. In silico ADMET predictions indicated favorable pharmacokinetic properties. Together, these results establish C₅–methoxy substitution as a viable strategy to enhance α-glucosidase inhibition in indole-based scaffolds. Full article

The synthesis of heterocyclic compounds has gained significant attention in organic chemistry due to their diverse pharmacological properties. However, traditional synthetic approaches often involve hazardous chemicals, high energy consumption, and tedious workup procedures, leading to environmental concerns and low yields. In response, green chemistry strategies have emerged, emphasizing safer and more sustainable alternatives. Among these, magnetic nanoparticle (MNP)-based catalysts have shown remarkable promise in facilitating one-pot multicomponent reactions (MCRs), offering enhanced catalytic efficiency, ease of recovery, and reusability. This article provides a comprehensive overview of multicomponent reactions (MCRs) for the construction of a wide range of heterocyclic scaffolds—including chromenes, pyrazoles, phenazines, triazoles, tetrazoles, xanthenes, furans, indoles, imidazoles, pyridines, pyrimidines, oxazoles, and acridine derivatives—catalyzed by magnetic nanoparticles under sustainable and environmentally benign conditions. This review highlights recent advances (2018–2024) in the development and application of modified magnetic nanoparticles for green multicomponent synthesis. Emphasis is placed on their structural features, catalytic roles, and benefits in eco-friendly organic transformations. Full article

Background/Objectives: Diabetes mellitus is a group of chronic metabolic disorders characterized by persistent hyperglycemia. Aldose reductase, the first enzyme in the polyol pathway, plays a key role in the onset of long-term diabetic complications. Aldose reductase inhibition has been widely established as a potential pharmacotherapeutic approach to prevent and treat diabetes mellitus-related comorbidities. Although several promising aldose reductase inhibitors have been developed over the past few decades, they have failed in clinical trials due to unacceptable pharmacokinetic properties and severe side effects. This paper describes the design, synthesis, and pharmacological evaluation of four novel 5-halogenated N-indolylsulfonyl-2-fluorophenol derivatives (3a-d) as aldose reductase inhibitors. Methods: The design of compounds was based on a previously published lead compound (IIc) developed by our research group to enhance its inhibitory capacity. Compounds 3a-d were screened for their ability to inhibit in vitro partially purified aldose reductase from rat lenses, and their binding modes were investigated through molecular docking. Results: The presence of a sulfonyl linker between indole and o-fluorophenol aromatic rings is mandatory for potent aldose reductase inhibition. The 5-substitution of the indole core with halogens resulted in a slight decrease in the inhibitory power of 3a-c compared to IIc. Among halogens, bromine was the most capable of filling the selectivity pocket through hydrophobic interactions with Thr113 and Phe115 residues. Conclusions: Although our strategy to optimize the inhibitory potency of IIc via inserting halogen atoms in the indole scaffold was not fruitful, aromatic ring halogenation can be still utilized as a promising approach for designing more potent aldose reductase inhibitors. Full article

Daldinia carpinicola is a newly identified species of wood-rotting fungi, with substantial aspects of its biology and ecological function yet to be clarified. A Nanopore third-generation sequencer was employed for de novo genome assembly to examine the genetic characteristics. The genome consisted of 35.93 Mb in 46 contigs with a scaffold N50 of 4.384 Mb. Glycoside hydrolases and activities enzymes accounted for a large proportion of the 522 identified carbohydrate-active enzymes (CAZymes), suggesting a strong wood degradation ability. Phylogenetic and comparative analysis revealed a close evolutionary relationship between D. carpinicola and D. bambusicola. D. carpinicola and Hypoxylon fragiforme exhibited significant collinear inter-species genome alignment. Based on transcriptome and metabolomic analyses, D. carpinicola showed a greater ability to utilize sucrose over sawdust as a carbon source, enhancing its growth by activating glycolysis/gluconeogenesis and the citrate cycle. However, compared with sucrose, sawdust as a carbon source activated D. carpinicola amino acid biosynthesis and the production of various secondary metabolites, including diterpenoid, indole alkaloid, folate, porphyrin, and biotin metabolism. The study establishes a theoretical basis for research and applications in biological processes, demonstrating a strategy to modulate the production of secondary metabolites by altering its carbon sources in D. carpinicola. Full article

Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview of recent advances in the evaluation of indole-based compounds in the last five years, highlighting their roles in cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, and neurodegenerative disease management. Indole derivatives have shown significant efficacy in targeting diverse biological pathways, making them valuable scaffolds in designing new drugs. Notably, these compounds have demonstrated the ability to combat drug-resistant cancer cells and pathogens, a significant breakthrough in the field, and offer promising therapeutic options for chronic diseases such as diabetes and hypertension. By summarizing recent key findings and exploring the underlying biological mechanisms, this review underscores the potential of indole derivatives in addressing major healthcare challenges, thereby instilling hope and optimism in the field of modern medicine. Full article

The reaction between glycine-type aminonaphthol derivatives substituted with 2- or 1-naphthol and indole or 7-azaindole has been tested. Starting from 2-naphthol as a precursor, the reaction led to the formation of ring-closed products, while in the case of a 1-naphthol-type precursor, the desired biaryl ester was isolated. The synthesis of a bifunctional precursor starting from 5-chloro-8-hydroxyquinoline, morpholine, and ethyl glyoxylate via modified Mannich reaction is reported. The formed Mannich base 10 was subjected to give bioconjugates with indole and 7-azaindole. The effect of the aldehyde component and the amine part of the Mannich base on the synthetic pathway was also investigated. In favor of having a preliminary overview of the structure-activity relationships, the derivatives have been tested on cancer and normal cell lines. In the case of bioconjugate 16, as the most powerful scaffold in the series bearing indole and a 5-chloro-8-hydroxyquinoline skeleton, a potent toxic activity against the resistant Colo320 colon adenocarcinoma cell line was observed. Furthermore, this derivative was selective towards cancer cell lines showing no toxicity on non-tumor fibroblast cells. Full article

Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research. Full article

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A (1) and echinosulfonic acids A–D (2–5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3′-indolyl) alkaloid (17), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3′-indolyl) acids and acetates (11–16) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3′-indolyl) and α-methine bis(3′-indolyl) analogues (11, 14, and 17) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3′-indolyl) alkaloids (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3′-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3′-indolyl) alkaloids. Full article

Alkaloids are natural compounds useful as scaffolds for discovering new bioactive molecules. This study utilized alkaloid gramine to synthesize two groups of C3-substituted indole derivatives, which were either functionalized at N1 or not. The compounds were characterized by spectroscopic methods. The protective effects of the new compounds against in vitro oxidative hemolysis induced by standard oxidant 2,2′-azobis(2-amidinopropane dihydro chloride (AAPH) on human erythrocytes as a cell model were investigated. Additionally, the compounds were screened for antimicrobial activity. The results indicated that most of the indole derivatives devoid of the N1 substitution exhibited strong cytoprotective properties. The docking studies supported the affinities of selected indole-based ligands as potential antioxidants. Furthermore, the derivatives obtained exhibited potent fungicidal properties. The structures of the eight derivatives possessing indole moiety bridged to the imidazole-, benzimidazole-, thiazole-, benzothiazole-, and 5-methylbenzothiazoline-2-thiones were determined by X-ray diffraction. The C=S bond lengths in the thioamide fragment pointed to the involvement of zwitterionic structures of varying contribution. The predominance of zwitterionic mesomers may explain the lack of cytoprotective properties, while steric effects, which limit multiple the hydrogen-bond acceptor properties of a thione sulfur, seem to be responsible for the high hemolytic activity. Full article

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023. Full article

The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran–indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran–indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations. Full article