Search Results (64)

Background: Invasive and mucosal infections caused by Candida species continue to pose a significant global health burden, particularly due to the species’ increasing resistance to conventional antifungal agents. This systematic review evaluates the antifungal potential of pyrrolidine-based derivatives, focusing on structure–activity relationships, mechanisms of action, and activity against Candida species. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 2015 and January 2026, following PRISMA guidelines and registered in PROSPERO (CRD420261279035). Studies reporting in vitro, in vivo, or in silico evaluation of pyrrolidine derivatives against Candida species were included. Data extraction and risk-of-bias assessment were performed using predefined criteria. Results: Twelve studies met the inclusion criteria, describing diverse pyrrolidine-based scaffolds, including spirooxindole, dispiro, triazole-linked, tetrazole, and quinoline-fused derivatives. The compounds demonstrated antifungal activity against multiple Candida species, including resistant isolates with minimum inhibitory concentrations ranging from approximately 0.5 to 16 µg/mL. Several derivatives showed comparable activity to standard antifungal agents under the reported experimental conditions. Mechanistic investigations indicated inhibition of biofilm formation, disruption of fungal cell wall and membrane integrity, suppression of hyphal transition, and modulation of virulence-associated pathways. Multi-mechanism antifungal effects were reported across different structural classes. Conclusions: Pyrrolidine-based derivatives represent promising antifungal scaffolds with potent activity against Candida species and associated virulence factors. However, limited in vivo validation and insufficient pharmacokinetic and toxicity data remain major barriers to clinical translation. Further optimization of structure–activity relationships and comprehensive preclinical evaluation are required to advance these scaffolds toward therapeutic development. Full article

Multicomponent reactions with isocyanides (IMCRs) enable the one-step assembly of complex molecules and remain a powerful strategy for accessing bioactive scaffolds. Here, we report the first synthesis of an abietane diterpene isocyanide derived from aminoimide methyl maleopimarate 1, a levopimaric acid-maleic anhydride adduct. This isocyanide was further engaged in Passerini, Ugi, and azido-Ugi reactions to provide a series of α-acyloxy- and α-acylaminocarboxamides, as well as tetrazoles, in high yields under optimized conditions. The structures of all products were confirmed by comprehensive physicochemical analysis. In silico ADME, drug-likeness, target prediction, and toxicity studies (SwissADME, ProTox-III) revealed moderate lipophilicity with favorable membrane permeability and solubility, high gastrointestinal absorption, and selective CYP3A4 inhibition with no significant effects on other CYP450 isoforms. The compounds fulfill major drug-likeness criteria, lacking undesirable reactive fragments, with only acceptable deviations in molecular weight and flexibility typical for MCR-derived products. The modifications broaden the spectrum of predicted biological targets while maintaining low overall toxicity and absence of predicted hepato- or carcinogenicity. These results demonstrate that diterpene isocyanide is a valuable building block for chemical libraries of structurally diverse abietane derivatives with peptide-like termini and highlight its potential as a source of cytotoxic, antiviral, and anti-inflammatory candidates. Full article

The development of new anti-inflammatory agents with improved safety and efficacy remains a major therapeutic challenge, particularly in light of the adverse effects associated with conventional nonsteroidal anti-inflammatory drugs. In this study, a series of new flavone derivatives were synthesized and evaluated for their inhibitory activities against Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), and 5-Lipooxygenase (5-LOX) through combined in vitro and in silico approaches. Biological screening demonstrated that several derivatives exhibited moderate to strong inhibitory activity across the three enzymes, with IC₅₀ values ranging from 35.67 ± 2.92 to 1137.44 ± 371.05µM. Among these, compounds 5a and 5b emerged as the most promising dual COX-2/5-LOX inhibitors, displaying potent activity toward both targets while maintaining limited COX-1 inhibition, as reflected by their favorable selectivity indices (SI = 2.09 and 5.21, respectively). Molecular docking studies supported the experimental findings, revealing favorable binding affinities of compounds 5a and 5b within the COX-2 active site (PDB: 1CX2), while the flavone–tetrazole hybrid 6b exhibited the highest binding affinity toward the 5-LOX active site (PDB: 6N2W), consistent with its notable inhibitory activity. In silico ADME and toxicity predictions further suggested that the selected derivatives (4a-b, 5a-b, and 6a-b) possess acceptable physiochemical properties, low predicted toxicity, and favorable drug-likeness. Overall, this study identifies flavone-based scaffolds as a promising early-stage lead for the development of dual COX-2/5-LOX inhibitors and provides a rational basis for the design of safer anti-inflammatory agents. 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

The development of molecules that interact with G-quadruplex (G4) sequences requires effective evaluation methods. Several techniques are currently available, including nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS), fluorescence using FRET-melting, G4-fluorescent intercalator displacement assay (G4-FID) and affinity chromatography. Among these, CD spectroscopy is gaining prominence due to its lower material requirements, faster experimentation and quicker data processing. However, conventional CD methods have limitations, such as higher sample volume required and the inability to handle high-throughput analysis efficiently. The use of synchrotron radiation in high-throughput analysis methods (HT-SRCD) has further advanced the investigation of small-molecule interactions with DNA G4 structures in the presence of various monovalent cations. HT-SRCD offers the capability to analyze multiple samples simultaneously, overcoming the limitations of conventional CD methods. To validate this approach, three biologically relevant G4 sequences—HTelo1, G3T3 and T95-2T—were investigated. Their interactions with a library of small tetrazole-based molecules, synthesized via a four-component Ugi reaction, and with a peptide sequence deriving from RHAU helicases (Rhau25), were evaluated. The results demonstrate that this method not only effectively discriminates between different ligands but also provides valuable insights into the selectivity and the modes of interaction of these ligands with the G4 sequences. Full article

Chitosan is a natural, biocompatible, biodegradable, and non-toxic polymer that has consistently garnered the attention of researchers in the development of new materials across various applications. Typically, to impart the desired properties to chitosan, chemical modification is necessary. Therefore, the development of simple and convenient methods for the chemical modification of chitosan is crucial in polymer chemistry. In this work, the approaches of Click chemistry and the necessary electrochemistry, which have recently illuminated the chemistry of chitosan, were combined to achieve a straightforward and efficient synthesis of new tetrazole chitosan derivatives. This was accomplished through electrochemical coupling. The proposed synthesis method is simple, convenient, and fast, hence allowing for the easy production of low- (10%), moderate- (30%), and highly substituted (65%) tetrazole chitosan derivatives. The highly substituted chitosan derivatives exhibit high activity as catalysts for the aldol reaction, achieving almost 100% conversion in just 15 min. Notably, these derivatives enable the aldol reaction to be catalyzed in water, aligning with one of the key principles of green chemistry. Furthermore, the new tetrazole chitosan derivatives demonstrate significant in vivo antibacterial effects in the treatment of peritonitis in rats. The primary mechanism of their antibacterial action is the disruption of the bacterial cell membrane integrity. Full article

This study presents a sustainable, environmentally friendly synthetic route for the production of key intermediates in losartan using palladium nanoparticles (PdNPs) derived from a brown seaweed, Sargassum incisifolium, as a recyclable nanocatalyst. A key intermediate, biaryl, was synthesized with an excellent yield (98%) via Suzuki–Miyaura coupling between 2-bromobenzonitrile and 4-methylphenylboronic acid, catalyzed using bio-derived PdNPs under mild conditions. Subsequent bromination using N-bromosuccinimide (NBS) under LED light, followed by imidazole coupling and tetrazole ring formation, allowed for the production of losartan with an overall yield of 27%. The PdNP catalyst exhibited high stability and recyclability, as well as strong catalytic activity, even at lower loadings, and nitrosamine formation was not detected. While the overall yield was lower than that of traditional industrial methods, this was due to the deliberate avoidance of the use of toxic reagents, hazardous solvents, and protection/deprotection steps commonly used in conventional routes. This trade-off marks a shift in pharmaceutical process development, where environmental and safety considerations are increasingly prioritized in line with green chemistry and regulatory frameworks. This study provides a foundation for green scaling up strategies, incorporating sustainability principles into drug synthesis. Full article

The tetrameric protein transthyretin (TTR) transports the hormone thyroxine in plasma and cerebrospinal fluid. Certain point mutations of TTR, including the Val122Ile mutation investigated here, destabilize the tetramer leading to its dissociation, misfolding, aggregation, and the eventual buildup of amyloid fibrils in the myocardium. Cioffi et al. reported the design and synthesis of a novel TTR kinetic stabilizing ligand, referred to here as TKS14, that inhibited TTR dissociation and amyloid fibril formation. In this study, molecular dynamics simulations were used to investigate the binding of TKS14 and eight TSK14 derivatives to the Val122Ile TTR mutant. For each complex, the ligand’s solvent accessible surface area (SASA), ligand–receptor hydrogen-bonding interactions, and the free energy of ligand-binding to TTR were investigated. The goal of this study was to identify the TSK14 functional groups that contributed to TTR stabilization. TKS14 was found to form a stable, two-point interaction with TTR by hydrogen bonding to Ser-117 residues in the inner receptor binding pocket and interacting through hydrogen bonds and electrostatically with Lys-15 residues near the receptor’s surface. The free energy of TKS14-TTR binding was −18.0 kcal mol⁻¹ and the ligand’s average SASA value decreased by over 80% upon binding to the receptor. The thermodynamic favorability of TTR binding decreased when TKS14 derivatives contained either methyl ester, amide, tetrazole, or N-methyl functional groups that disrupted the above two-point interaction. One derivative in which a tetrazole ring was added to TKS14 was found to form hydrogen bonds with Thr-106, Thr-119, Ser-117, and Lys-15 residues. This derivative had a free energy of TTR binding of −21.4 kcal mol⁻¹. Overall, the molecular dynamics simulations showed that the functional groups within the TKS14 structural template can be tuned to optimize the thermodynamic favorability of ligand binding. Full article

Phenothiazine-based photosensitizers bear the intrinsic potential to substitute various expensive organometallic dyes owing to the strong electron-donating nature of the former. If coupled with a strong acceptor unit and the length of N-alkyl chain is appropriately chosen, they can easily produce high efficiency levels in dye-sensitized solar cells. Here, three novel D-A dyes containing 1H-tetrazole-5-acrylic acid as an acceptor were synthesized by varying the N-alkyl chain length at its phenothiazine core and were exploited in dye-sensitized solar cells. Differential scanning calorimetry showed that the synthesized phenothiazine derivatives exhibited behavior characteristic of molecular glasses, with glass transition and melting temperatures in the range of 42–91 and 165–198 °C, respectively. Based on cyclic and differential pulse voltammetry measurements, it was evident that their lowest unoccupied molecular orbital (LUMO) (−3.01–−3.14 eV) and highest occupied molecular orbital (HOMO) (−5.28–−5.33 eV) values were fitted to the TiO₂ conduction band and the redox energy of I⁻/I₃⁻ in electrolyte, respectively. The experimental results were supported by density functional theory, which was also utilized for estimation of the adsorption energy of the dyes on the TiO₂ and its size. Finally, the compounds were tested in dye-sensitized solar cells, which were characterized based on current–voltage measurements. Additionally, for the compound giving the best photovoltaic response, the efficiency of the DSSCs was optimized by a photoanode modification involving the use of cosensitization and coadsorption approaches and the introduction of a blocking layer. Subsequently, two types of tandem dye-sensitized solar cells were constructed, which resulted in an increase in photovoltaic efficiency to 6.37%, as compared to DSSCs before modifications, with a power conversion value of 2.50%. Full article

Pyrazole and tetrazole are among the most important heterocyclic members of the azole family. Over the past decade, these N-heterocycles and their derivatives have demonstrated specific properties that give them potent applications in several fields such as pharmacology, technology, and agriculture. Combining these two azoles in single hybrid architecture has given rise to highly potent molecules in terms of efficacy and specificity, with enhanced and scalable properties. In this context, the present paper deals with the literature of the last 10 years describing the synthesis protocols for pyrazole-tetrazole-based molecules. Their biological activities as well as their energetic properties are also reported. Full article

Angiotensin II receptor antagonists are tetrazole derivatives used in the treatment of high blood pressure, and are also indicated for the treatment of heart failure (NYHA class II-IV). They are used alone or in combination with other classes of antihypertensives or diuretics for the effective management of high blood pressure. In this study, we aim to evaluate the thermal stability and degradation kinetics for the principal compounds used in therapy from this class, namely telmisartan, valsartan, olmesartan medoxomil, and losartan potassium. To obtain the thermoanalytical data for the kinetic investigations, the TG and DTG curves were registered at five different heating rates (β = 2, 4, 6, 8, and 10 °C min⁻¹). The kinetic methods used were a preliminary ASTM E698 method and two isoconversional methods: Flynn–Wall–Ozawa and Friedman. For each molecule, the results showed complex decomposition processes consisting of complex reaction sequences. Full article

In this work, we present new methods of synthesis of different molecules including a 2-pyridone nucleus. First, we prepared a series of 1H-free 2-pyridones and N-alkyl 2-pyridones from ethyl cyanoacetate, aromatic aldehydes, various acetophenone derivatives and ammonium acetate or diamino-alkane. These molecules have served as building blocks that, in conjunction with acyl chloride derivatives, glycoside derivatives, etc. have resulted in various heterocyclic hybrid structures carrying a 2-pyridone ring. Moreover, based on the cyano group reactivity of the 2-pyridone ring, we synthesized 5-pyridone 1H-tetrazole in a single step by a cycloaddition reaction [3 + 2] between 3-cyano-2-pyridone nitriles and sodium azide in the presence of metal-free L-proline. Full article

In this paper, a novel, cost-effective, and green methodology has been investigated for the preparation of cobalt (II) nanoparticles supported on a nanodiamond-carbon-structure grafted polyethyleneimine@folic acid (ND-g-PEI@FA@Co(II)) nanocomposite. Some of the physicochemical characteristics of the synthesized efficient heterogeneous nanocatalyst, including bond formation and functional groups, percentage of elements, crystalline phase, and surface morphology were studied using techniques such as Fourier transform infrared spectroscopy (FT-IR), Energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and field emission scanning electron microscopy (FE-SEM). Following the principles of green chemistry, this nanocatalyst has been used in the production of 5-substituted 1H-tetrazole derivatives using different benzaldehyde derivatives, sodium azide, and malononitrile agents in ethanol eco-friendly solvent with high efficiency. The mechanism of tetrazole synthesis is carried out through cascade condensations, such as Knoevenagel condensation, 1,3-dipolar cycloaddition, and tautomerization reactions. The main advantages of the ND-g-PEI@FA@Co(II) nanocatalyst include facile preparation, easy separation, minimal consumption of catalyst for a multicomponent reaction (MCR), the use of cheap and recyclable materials, excellent product yield, and reusability up to four times with good efficiency. The substrate used in this heterogeneous catalyst (ND) with appropriate thermal stability, abundant availability in large quantities, and non-toxicity are prominent features of the synthesized nanocomposite. Full article

2-Chloropyridine-3-carbonitrile derivative 1 was utilized as a key precursor to build a series of linear and angular annulated pyridines linked to a 6-hydroxy-4,7-dimethoxybenzofuran moiety. Reaction of substrate 1 with various hydrazines afforded pyrazolo[3,4-b]pyridines. Treatment of substrate 1 with 1,3-N,N-binucleophiles including 3-amino-1,2,4-triazole, 5-amino-1H-tetrazole, 3-amino-6-methyl-1,2,4-triazin-5(4H)-one and 2-aminobenzimidazole produced the novel angular pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine, pyrido[3,2-e][1,2,4]tetrazolo[1,5-a]pyrimidine, pyrido[3′,2′:5,6] pyrimido[2,1-c][1,2,4]triazine and benzo[4,5]imidazo[1,2-a]pyrido[3,2-e]pyrimidine, respectively. Reaction of substrate 1 with 1,3-C,N-binucleophiles including cyanoacetamides and 1H-benzimidazol-2-ylacetonitrile furnished 1,8-naphthyridines and benzoimidazonaphthyridine. Moreover, reacting substrate 1 with 5-aminopyrazoles gave pyrazolo[3,4-b][1,8]naphthyridines. Finally, reaction of compound 1 with 6-aminouracils as cyclic enamines yielded pyrimido[4,5-b][1,8]naphthyridines. Some of the synthesized products showed noteworthy antimicrobial efficiency against all types of microbial strains. Structures of the produced compounds were established using analytical and spectroscopic tools. Full article

Breast cancer (BC) is the most common cancer in women, and is characterized by its histological and molecular heterogeneity. Luminal BC is an estrogen receptor-positive subtype, with varied clinical courses. Although BC patients are eligible for hormone therapy, both early and late relapses still occur, and thus there is a demand for new cytotoxic and selective treatment strategies for these patients. In the present study, inspired by the structure of phenylsulfonylpiperazine, a series of 20 derivatives were tested in bioassays against MCF7, MDA-MB-231 and MDA-MB-453 BC cells to discover new hit compounds. After 48 h of treatment, 12 derivatives impaired cell viability and presented significant IC₅₀ values against at least one of the tumor lineages. Overall, the luminal BC cell line MCF7 was more sensitive to treatments. Compound 3, (4-(1H-tetrazol-1-yl)phenyl)(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)methanone, was the most promising, with IC₅₀ = 4.48 μM and selective index (SI) = 35.6 in MCF7 cells. Compound 3 also presented significant antimigratory and antiproliferative activities against luminal BC cells, possibly by affecting the expression of genes involved in the epithelial–mesenchymal transition mechanism, upregulating E-Cadherin transcripts (CDH1). Our findings suggest that phenylsulfonylpiperazine derivatives are potential candidates for the development of new therapies, especially those targeting luminal BC. Full article