Search Results (66)

Background: Infections caused by the protozoan Trichomonas vaginalis affect millions of people worldwide and are responsible for one of the most common sexually transmitted diseases. Despite the efficacy of 5-nitroimidazoles like metronidazole, concerns regarding widespread resistance and the absence of viable alternatives for specific patient populations necessitate the development of structurally diverse pharmacological agents. In this study, we investigated the antiparasitic activity of 1,3-thiazolidin-4-one derivatives against T. vaginalis. Methods: Thiazolidines were synthesized via multicomponent reaction (MCR) using one-pot methodology and tested in vitro against the parasite and mammalian cell lines. Results: Seventy percent of the compounds showed more than 80% antiparasitic activity at 100 μM, with compounds 4a, 4b, and 4f exhibiting IC₅₀ ≤ 20 µM. None of the molecules exhibited cytotoxic against Vero CCL-81 and HeLa cells. Evaluation of the structure–activity relationship (SAR) indicates that the substituent at the nitrogen position of the heterocycle may be involved in the antiparasitic effect of these compounds. In silico studies also revealed that the three compounds possess adequate oral bioavailability and do not present mutagenic, tumorigenic or irritating risks. Finally, molecular docking predicted strong interactions of compounds 4a, 4b, and 4f with T. vaginalis enzymes lactate dehydrogenase and purine nucleoside phosphorylase; compound 4f also interacted with methionine Ƴ-lyase. Conclusions: These preliminary results suggest that 1,3-thiazolidin-4-ones are promising scaffolds for developing new trichomonacidal agents. Full article

The synthesis of novel pyrazole derivatives (SPDs) and their evaluation for antibacterial potential against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Streptococcus pneumoniae (S. pneumoniae) was developed herein. These compounds were obtained via a microwave-assisted eco-friendly multicomponent reaction (MCR) and were characterized for structural confirmation using ¹H NMR, ¹³C NMR, 2D experiments, TOF-MS, and FTIR spectrometry. Antibacterial activity, as measured by minimum inhibitory concentrations (MICs) of SPDs, ranged between 0.212 and 2.50 mg/mL against S. aureus, S. pneumoniae, P. aeruginosa, and E. coli. Compound 4e was the most potent against S. pneumoniae, with an MIC value of 0.0156 mg/mL compared with Amoxicillin’s MIC value of 0.0306 mg/mL. Thus, compound 4e was observed as a potential lead candidate against S. pneumoniae. Further corroboration by molecular docking at the active site of the key penicillin-binding protein (PBP) revealed that the most potent compounds against each organism showed comparable docking scores to those of amoxicillin. In addition, a pharmacokinetics study showed that synthesized SPDs were predicted to be orally bioavailable and non-inhibitors of cytochrome 3A4 and belong to drug classes 4 and 6. Hence, they were suitable for drug development and warrant further studies such as in vitro assays, in silico modeling, DFT studies, and machine learning for drug design. Full article

The combination of multicomponent reactions with post-transformation processes is a powerful strategy for the rapid synthesis of structurally complex polyheterocycles. Herein, we describe the preparation of the novel compound 2-benzyl-6-(3-((7-chloroquinolin-4-yl)amino)propyl)-3-morpholino-7-(4-(pyridin-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one via a sequence that combines an Ugi-Zhu reaction with a cascade process (aza-Diels–Alder/N-acylation/aromatization) under microwave irradiation in chlorobenzene using ytterbium (III) triflate (Yb(OTf)₃) as the catalyst. The method provided the target polyheterocycle in 75% yield and 85% atom economy. Structural characterization was performed by 1D (¹H and ¹³C) and 2D (COSY, HSQC and HMBC) NMR spectroscopy, and the molecular mass was confirmed by high-resolution mass spectrometry (HRMS). These results illustrate the effectiveness of MCR as powerful synthetic tools for expanding chemical diversity. Full article

The imidazo[1,2-a]pyridine (IMP) scaffold has attracted considerable attention due to its photophysical properties and their applications in medicinal chemistry and material sciences. Isocyanide-based multicomponent reactions (I-MCRs), particularly the Groebke –Blackburn–Bienaymé reaction (GBBR), are considered election synthetic one-pot processes for synthesis of IMP analogs. Herein we described a novel ultrasound assisted one-pot green synthesis of IMPs via GBBR using water as solvent. The approach aligns with the principles and metrics of green chemistry and enables the efficient synthesis of highly fluorescent molecules. These compounds show potential applications in chemical sensing, optoelectronic devices, and bioimaging. Full article

The growing demand for sustainable and efficient synthetic methodologies has brought nanocatalysis to the forefront of modern organic chemistry, particularly in the construction of heterocyclic compounds through multicomponent reactions (MCRs). Among various nanocatalysts, calcium oxide nanoparticles (CaO NPs) have gained significant attention because of their strong basicity, thermal stability, low toxicity, and cost-effectiveness. This review provides a comprehensive account of the recent strategies using CaO NPs as heterogeneous catalysts for the green synthesis of nitrogen- and oxygen-containing heterocycles through MCRs. Key reactions such as Biginelli, Hantzsch, and pyran annulations are discussed in detail, with emphasis on atom economy, reaction conditions, product yields, and catalyst reusability. In many instances, CaO NPs have enabled solvent-free or aqueous protocols with high efficiency and reduced reaction times, often under mild conditions. Mechanistic aspects are analyzed to highlight the catalytic role of surface basic sites in facilitating condensation and cyclization steps. The performance of CaO NPs is also compared with other oxide nanocatalysts, showcasing their benefits from green metrics evaluation like E-factor and turnover frequency. Despite significant progress, challenges remain in areas such as asymmetric catalysis, industrial scalability, and catalytic stability under continuous use. To address these gaps, future directions involving doped CaO nanomaterials, hybrid composites, and mechanochemical approaches are proposed. This review aims to provide a focused and critical perspective on CaO NP-catalyzed MCRs, offering insights that may guide further innovations in sustainable heterocyclic synthesis. Full article

Quinazolin-4(3H)-ones are nitrogen heterocycles that have attracted considerable interest over many years due to their important biological and pharmacological properties. It has been shown that quinazolinone derivatives exhibit, e.g., analgesic, anti-inflammatory, antibacterial, anticonvulsant, antifungal, and antitumor activities. Some of these compounds have found applications in medicine; for instance, Zydelig (Idelalisib) has been approved for the treatment of several types of blood cancers. Furthermore, the quinazolinone skeleton is an important structural moiety present in many naturally occurring alkaloids, such as Febrifugine, a potent anti-malarial agent. To date, numerous synthetic methods have been developed for the synthesis of quinazolinone derivatives. Among them, multicomponent reactions (MCRs) have emerged as a powerful tool, allowing for the rapid and straightforward construction of the quinazolinone scaffold from readily available substrates. This review article presents a concise overview of selected strategies for synthesizing quinazolinone frameworks via one-pot MCRs. The reported methods are categorized into three main groups: metal-catalyzed reactions; isatoic-anhydride-based strategies, utilizing isatoic anhydride as a key starting material, and alternative approaches involving, among others, the utilization of N-(2-aminobenzoyl)benzotriazoles or aryldiazonium salts as efficient building materials. 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

A one-pot synthetic methodology that combines an Ugi-Zhu three-component reaction (UZ-3CR) with a cascade sequence (intermolecular aza Diels–Alder cycloaddition/intramolecular N-acylation/decarboxylation/dehydration) using microwave-heating conditions, ytterbium (III) triflate (Yb(OTf)₃) as the catalyst, and chlorobenzene (for the first time in a multi-component reaction (MCR)) as the solvent, was developed to synthesize twelve new fluorinated-pyrrolo[3,4-b]pyridin-5-ones containing a 4-amino-7-chloroquinoline moiety, yielding 50–77% in 95 min per product, with associated atom economies around 88%, also per product. Additionally, by in vitro tests, compounds 19d and 19i were found to effectively stop early SARS-CoV-2 replication, IC₅₀ = 6.74 µM and 5.29 µM, at 0 h and 1 h respectively, while cell viability remained above 90% relative to the control vehicle at 10 µM. Additional computer-based studies revealed that the most active compounds formed strong favorable interactions with important viral proteins (M_pro, NTDα and NTDo) of coronavirus, supporting a two-pronged approach that affects both how the virus infects the cells and how it replicates its genetic material. Finally, quantum chemistry analyses of non-covalent interactions were performed from Density-Functional Theory (DFT) to better understand how the active compounds hit the virus. Full article

Multicomponent reactions (MCRs) enable the efficient assembly of complex small molecules via multiple bond-forming events in a single step. However, individual MCRs typically yield products with similar core structures, limiting access to larger, more intricate scaffolds. Strategic selection of reactants allows the combination of distinct MCRs, thus facilitating the synthesis of advanced molecular architectures with potential biological significance. Using our previously reported method for performing the aza-Friedel Crafts multicomponent reaction under green heterogeneous conditions, we have incorporated some of the obtained products into diverse multicomponent reactions to generate, in an unprecedent approach, eight novel products, some of which were also characterized by two-dimensional NMR techniques. The biological properties of such products are under investigation. Full article

A concerted five-component reaction strategy has been developed, featuring double [3+2] cycloadditions utilizing aspartic acid. This approach provides valuable insights into mechanistic pathways, allowing for the distinction between concerted and stepwise processes based on reaction efficiency and diastereoselectivity. Both aspartic and glutamic acids have been employed for a thorough evaluation and exploration of decarboxylation-driven double annulations. This method effectively constructs pyrrolizidine frameworks through a concerted double 1,3-dipolar cycloaddition with aspartic acid, as well as tetrahydropyrrolizinones via three-component double annulations, which include decarboxylative 1,3-dipolar cycloaddition and lactamization with glutamic acid. These highly convergent, decarboxylation-driven multicomponent reactions (MCRs) efficiently produce fused polyheterocyclic systems while being environmentally friendly, generating only CO₂ and water as byproducts. Full article

A series of new quinazolin-2,4-dione derivatives incorporating amide/eight-membered nitrogen-heterocycles 2a–c, in addition, acylthiourea/amide/dithiolan-4-one and/or phenylthiazolidin-4-one 3a–d and 4a–d. The starting compound 1 was prepared by reaction of 4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-benzoyl chloride with ammonium thiocyanate and cyanoacetic acid hydrazide. The reaction of 1 with strong electrophiles, namely, o-aminophenol, o-amino thiophenol, and/or o-phenylene diamine, resulted in corresponding quinazolin-2,4-dione derivatives incorporating eight-membered nitrogen-heterocycles 2a–d. Compounds 3a–d and 4a–d were synthesized in good-to-excellent yield through a one-pot multi-component reaction (MCR) of 1 with carbon disulfide and/or phenyl isocyanate under mild alkaline conditions, followed by ethyl chloroacetate, ethyl iodide, methyl iodide, and/or concentrated HCl, respectively. The obtained products were physicochemically characterized by melting points, elemental analysis, and spectroscopic techniques, such as FT-IR, ¹H-NMR, ¹³C-NMR, and MS. The antibacterial efficacy of the obtained eleven molecules was examined in vitro against two Gram-positive bacterial strains (Staphylococcus aureus and Staphylococcus haemolyticus). Furthermore, Computer-Aided Drug Design (CADD) was performed on the synthesized derivatives, standard drug (Methotrexate), and reported antibacterial drug with the target enzymes of bacterial strains (S. aureus and S. haemolyticus) to explain their binding mode of actions. Notably, our findings highlight compounds 2b and 2c as showing both the best antibacterial activity and docking scores against the targets. Finally, according to ADMET predictions, compounds 2b and 2c possessed acceptable pharmacokinetics properties and drug-likeness properties. 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

Here, we describe some well-known multicomponent reactions and the progress made over the past decade to make these processes even more environmentally friendly. We focus on the Mannich, Hantzsch, Biginelli, Ugi, Passerini, Petasis, and Groebke–Blackburn–Bienaymé reactions. After describing the origin of the reactions and their mechanisms, we summarize some advances in terms of the eco-compatibility of these different MCRs. These are followed by examples of some reactions, considered as variants, which are less well documented but which are promising in terms of structures generated or synthetic routes. Full article

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides. A group of twenty novel diterpene hybrids was subjected to NCI in vitro assessment, and a consistent structure–activity relationship was established. Eleven of the synthesized derivatives inhibited the growth of cancer cells of 4 to 39 cell lines in one dose assay, and the most active were derivatives 3d, 9d, and 10d holding a fragment of 1a,4a-dehydroquinopimaric acid. They were selected for a five-dose analysis and demonstrated a significant antiproliferative effect towards human cancer cell lines. The outstanding cytotoxic activity was observed for the P-3CR product 3d with growth inhibitory at submicromolar and micromolar concentrations (GI₅₀ = 0.42–3 μM) against the most sensitive cell lines. The U-4CR products 9d and 10d showed selective activity against all leukemia cell lines with GI₅₀ in the range of 1–17 µM and selectivity indexes of 5.49 and 4.72, respectively. Matrix COMPARE analysis using the GI₅₀ vector showed a moderate positive correlation of compound 3d with standard anticancer agents that can influence kinase receptors and epidermal growth factor receptors (EGFRs). The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents. The obtained results indicate that these new hybrids could be useful for the further development of anticancer drugs, and 1a,4a-dehydroquinopimaric acid derivatives could be recommended for in-depth studies and the synthesis of new antitumor analogs on their basis. Full article

Carbon dioxide (CO₂) is a non-toxic, abundant and recoverable source of carbon monoxide. Despite its thermodynamically stable and kinetically inert nature, research on CO₂ utilisation is ongoing. CO₂-based aryne reactions, crucial for synthesising ortho-substituted benzoic acids and their cyclisation products, have garnered significant attention, and multi-component reactions (MCRs) involving CO₂, aryne and nucleophilic reagents have been extensively studied. This review highlights recent advancements in CO₂ capture reactions utilising phenylalkyne reactive intermediates. Mechanistic insights into these reactions are provided together with prospects for further development in this field. Full article