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26 pages, 1651 KB

Open AccessArticle

Synthesis of Bioconjugation Reagents for Use in Covalent Cross-Linking of Proteins by Azide-Alkyne Cycloaddition

by Nadja Suhorepec, Luka Ciber, Uroš Grošelj, Nejc Petek, Bogdan Štefane, Marko Novinec and Jurij Svete

Molecules 2025, 30(23), 4623; https://doi.org/10.3390/molecules30234623 - 2 Dec 2025

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Abstract

A series of azide- and cyclooctyne-functionalized N-hydroxysuccinimidyl esters (NHS esters) and benzotriazolides were prepared and used as N-acylation reagents to obtain azide-(BSA-1) and cyclooctyne-functionalized bovine serum albumin proteins (BSA-2), fluorescein derivatives 5 and 6, and homobifunctional linkers [...] Read more.

A series of azide- and cyclooctyne-functionalized N-hydroxysuccinimidyl esters (NHS esters) and benzotriazolides were prepared and used as N-acylation reagents to obtain azide-(BSA-1) and cyclooctyne-functionalized bovine serum albumin proteins (BSA-2), fluorescein derivatives 5 and 6, and homobifunctional linkers 3 and 4. Strain-promoted azide-alkyne cycloaddition (SPAAC) and copper-catalyzed azide-alkyne cycloaddition (CuAAC) of azide-functionalized fluorescent probe 5 and alkyne-functionalized fluorescent probe 6 with complementary functionalized proteins BSA-2 and BSA-1 yielded fluorescent cycloadducts BSA-2-5 and BSA-1-6. These cycloadducts were used to determine the loading of BSA-1 and BSA-2 with the respective azido and cyclooctyne groups based on their molar absorbances and fluorescence intensities. Dimerization through covalent cross-linking of BSA was then performed by SPAAC between azide-functionalized BSA-1 and cyclooctyne-functionalized BSA-2, and by treating BSA-1 and BSA-2 with 0.5 equiv. of complementary bis-cyclooctyne linker 4 and bis-azide linker 3. Although the formation of covalent dimers BSA-1-2-BSA, BSA-1-6-1-BSA, and BSA-2-5-2-BSA was detected by SDS-PAGE analysis, this was a minor process, and most of the functionalized BSA did not form covalent dimers. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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28 pages, 3749 KB

Open AccessArticle

Novel 5-Aryl-[1,2,4]triazoloquinazoline Fluorophores: Synthesis, Comparative Studies of the Optical Properties and ICT-Based Sensing Application

by Alexandra E. Kopotilova, Julia V. Permyakova, Ekaterina S. Starnovskaya, Tatyana N. Moshkina, Alexander S. Novikov, Pavel A. Slepukhin and Emiliya V. Nosova

Molecules 2025, 30(22), 4420; https://doi.org/10.3390/molecules30224420 - 15 Nov 2025

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Abstract

Novel tricyclic fluorophores were obtained from 2-aryl-[1,2,4]triazolo[1,5-c]quinazoline-5(6H)-ones through chlorodesoxygenation and subsequent Suzuki–Imamura cross-coupling reactions. Their π-extended analogues were synthesized from 5-(4-bromophenyl)-[1,2,4]triazoloquinazolines. The structure of target fluorophores was confirmed by X-ray single crystal diffraction. Photophysical properties in solutions and solid state were [...] Read more.

Novel tricyclic fluorophores were obtained from 2-aryl-[1,2,4]triazolo[1,5-c]quinazoline-5(6H)-ones through chlorodesoxygenation and subsequent Suzuki–Imamura cross-coupling reactions. Their π-extended analogues were synthesized from 5-(4-bromophenyl)-[1,2,4]triazoloquinazolines. The structure of target fluorophores was confirmed by X-ray single crystal diffraction. Photophysical properties in solutions and solid state were studied. 5-Aminoaryl-substituted [1,2,4]triazolo[1,5-c]quinazolines revealed bright blue fluorescence in toluene (Φ_F > 95%), which can be tuned by solvent polarity, the electronic nature and rigidity of the donor fragment, the π-spacer length, and the annelation pattern. Intramolecular charge transfer (ICT) behaviour was demonstrated using both experimental and theoretical data. Distinct acid-induced spectral and fluorescence changes upon protonation were observed for diethylamino-containing derivatives, indicating their potential applicability as dual-mode (polarity and pH) molecular sensors. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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17 pages, 4225 KB

Open AccessArticle

Comparative Nitrene-Transfer Chemistry to Olefins Mediated by First-Row Transition Metal Catalysts Supported by a Pyridinophane Macrocycle with N4 Ligation

by Himanshu Bhatia, Lillian P. Adams, Ingrid Cordsiemon, Suraj Kumar Sahoo, Amitava Choudhury, Thomas R. Cundari and Pericles Stavropoulos

Molecules 2025, 30(15), 3097; https://doi.org/10.3390/molecules30153097 - 24 Jul 2025

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Abstract

A 12-membered pyridinophane scaffold containing two pyridine and two tertiary amine residues is examined as a prototype ligand (^tBuN4) for supporting nitrene transfer to olefins. The known [(^tBuN4)M^II(MeCN)₂]²⁺ (M = Mn, Fe, Co, and [...] Read more.

A 12-membered pyridinophane scaffold containing two pyridine and two tertiary amine residues is examined as a prototype ligand (^tBuN4) for supporting nitrene transfer to olefins. The known [(^tBuN4)M^II(MeCN)₂]²⁺ (M = Mn, Fe, Co, and Ni) and [(^tBuN4)Cu^I(MeCN)]⁺ cations are synthesized with the hexafluorophosphate counteranion. The aziridination of para-substituted styrenes with PhI=NTs (Ts = tosyl) in various solvents proved to be high yielding for the Cu(I) and Cu(II) reagents, in contrast to the modest efficacy of all other metals. For α-substituted styrenes, aziridination is accompanied by products of aziridine ring opening, especially in chlorinated solvents. Bulkier β-substituted styrenes reduce product yields, largely for the Cu(II) reagent. Aromatic olefins are more reactive than aliphatic congeners by a significant margin. Mechanistic studies (Hammett plots, KIE, and stereochemical scrambling) suggest that both copper reagents operate via sequential formation of two N–C bonds during the aziridination of styrene, but with differential mechanistic parameters, pointing towards two distinct catalytic manifolds. Computational studies indicate that the putative copper nitrenes derived from Cu(I) and Cu(II) are each associated with closely spaced dual spin states, featuring high spin densities on the nitrene N atom. The computed electrophilicity of the Cu(I)-derived nitrene reflects the faster operation of the Cu(I) manifold. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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27 pages, 4199 KB

Open AccessArticle

Synthesis of 1-(2-Hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as a Promising Scaffold Against Disease-Causing Bacteria Relevant to Public Health

by Karolis Krikštaponis, Jūratė Šiugždaitė, Rita Vaickelionienė, Vytautas Mickevičius and Birutė Grybaitė

Molecules 2025, 30(12), 2639; https://doi.org/10.3390/molecules30122639 - 18 Jun 2025

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Abstract

The increasing number of antibiotic-resistant pathogens forces us to accelerate the search for new antimicrobial agents. Based on this, we chose to synthesize a library of 1-(2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives and evaluate their antibacterial activity against various pathogens. A series of (2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid and [...] Read more.

The increasing number of antibiotic-resistant pathogens forces us to accelerate the search for new antimicrobial agents. Based on this, we chose to synthesize a library of 1-(2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives and evaluate their antibacterial activity against various pathogens. A series of (2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid and its hydrazide derivatives were prepared and identified by the methods of IR, ¹H, and ¹³C NMR spectroscopy and a microanalysis technique. The resulting compounds were evaluated in vitro for their efficacy against the Gram-positive Staphylococcus aureus (ATCC 9144), Listeria monocytogenes (ATCC 7644), and Bacillus cereus (ATCC 11778) bacterial strains as well as the Gram-negative Escherichia coli (ATCC 8739) bacteria. Oxacillin, ampicillin, and cefuroxime were used as control antibiotics. Among the obtained compounds, hydrazone with a 5-nitrothien-2-yl fragment surpassed the control cefuroxime (7.8 μg/mL) against almost all strains tested. Hydrazone with a 5-nitrofuran-2-yl moiety showed a slightly lower but also potent effect on all bacterial strains. Moreover, hydrazone with a benzylidene moiety demonstrated very strong inhibition of S. aureus (3.9 μg/mL) in comparison with the antibacterial drug cefuroxime (7.8 μg/mL). In addition, some of these compounds exhibited remarkable bactericidal properties. In a complete biofilm disruption study, 5-nitrothienylhydrazone showed excellent results in disrupting S. aureus and E. coli biofilms. The test results show the potential of the newly obtained derivatives as a source of antibacterial agents. Therefore, further studies on the molecular optimization of these compounds are necessary for the development of new antibacterial drugs. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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17 pages, 927 KB

Open AccessArticle

Multi-Targeting Valproic Acid Conjugates as Potent Agents Against Inflammation and Hyperlipidemia

by Panagiotis Theodosis-Nobelos and Eleni A. Rekka

Molecules 2025, 30(11), 2339; https://doi.org/10.3390/molecules30112339 - 27 May 2025

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Abstract

Novel derivatives of valproic acid with biologically active moieties, such as thiomorpholine, 4-aminopyridine, serine methyl ester, trolox and the cinnamic acid derivative [(E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid], were synthesized at satisfactory yields. The conjugation of these moieties was based on the rationale [...] Read more.

Novel derivatives of valproic acid with biologically active moieties, such as thiomorpholine, 4-aminopyridine, serine methyl ester, trolox and the cinnamic acid derivative [(E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid], were synthesized at satisfactory yields. The conjugation of these moieties was based on the rationale of design and evaluation of compounds with selected structural characteristics, aiming at derivatives with multiple targets. These compounds reduced acute inflammation considerably and, in most cases, more than several highly used, well-known, non-steroidal anti-inflammatory drugs. They also offered the inhibition of soybean lipoxygenase, and some of them (compounds 5 and 6) possessed radical scavenging and lipid peroxidation attenuating effects. Their antioxidant capacity was several times higher than that of the established antioxidant trolox. All the tested compounds decreased plasma lipid markers in tyloxapol-induced hyperlipidemia in rats. Compound 2 resulted in 71.1%, 52.8% and 79.1% decrease in total cholesterol, triglycerides and LDL-cholesterol, respectively, at 150 μmol/kg (i.p.). The effect on total and LDL cholesterol is comparable or equal to that of simvastatin, a hypocholesterolemic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor, however, with additionally great triglyceride-decreasing effect compared to simvastatin. Thus, the synthesized compounds may be a valuable addition to multi-functional agents acting against various degenerative disorders that implicate inflammation and lipid derangement. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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21 pages, 2130 KB

Open AccessArticle

A Straightforward Approach Towards Phosphadecalones by Microwave-Assisted Diels–Alder Reaction

by Elżbieta Łastawiecka, Anna E. Kozioł and K. Michał Pietrusiewicz

Molecules 2025, 30(11), 2338; https://doi.org/10.3390/molecules30112338 - 27 May 2025

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Abstract

A stereoselective and scalable strategy for the synthesis of phosphorus-containing bicyclic and tricyclic compounds from 1-phenylphosphin-2-en-4-one 1-oxide is presented. This activated dienophile, available in both racemic and enantiopure forms, undergoes smooth [4+2] cycloadditions with acyclic and cyclic dienes, affording products with excellent yields [...] Read more.

A stereoselective and scalable strategy for the synthesis of phosphorus-containing bicyclic and tricyclic compounds from 1-phenylphosphin-2-en-4-one 1-oxide is presented. This activated dienophile, available in both racemic and enantiopure forms, undergoes smooth [4+2] cycloadditions with acyclic and cyclic dienes, affording products with excellent yields and controlled stereochemistry. Notably, the cis/trans-fusion of the cycloadducts (phosphadecalones and phosphahexahydrochrysene) can be selectively controlled by fine-tuning the conditions of microwave-assisted cycloaddition reaction. The influence of temperature, time, and steric effects on cis/trans and endo/exo selectivity was examined in detail. The molecular structure, including the absolute configuration, of eight products has been determined by X-ray crystallography. These analyses further established the endo-selective nature of the cycloaddition, favoring the P=O face of the dienophile. Post-cycloaddition transformations of selected P-stereogenic phosphadecalone, such as isomerization, reduction and deoxygenation, demonstrate the synthetic versatility of the resulting products. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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13 pages, 2289 KB

Open AccessArticle

A Practical Application of Machine Learning for the Development of Metallole-Based Fluorescent Materials

by Yusuke Kanematsu, Akiyoshi Ohta, Shunya Nagai, Yohei Adachi, Hiromasa Kaneko, Takayoshi Ishimoto, Takio Kurita and Joji Ohshita

Molecules 2025, 30(8), 1686; https://doi.org/10.3390/molecules30081686 - 10 Apr 2025

Cited by 1 | Viewed by 1099

Abstract

We have built a prediction model of the fluorescence quantum yields of metalloles. Based on the suggestion by the prediction model, we synthesized 10 fluorescent molecules to confirm the prediction accuracy. By measuring the fluorescence quantum yields of the synthesized molecules, it was [...] Read more.

We have built a prediction model of the fluorescence quantum yields of metalloles. Based on the suggestion by the prediction model, we synthesized 10 fluorescent molecules to confirm the prediction accuracy. By measuring the fluorescence quantum yields of the synthesized molecules, it was demonstrated that our prediction model reasonably classified the quantum yields with an accuracy of 0.7. In particular, the low quantum yields were perfectly predicted for the synthesized molecules, demonstrating the usefulness of our prediction model to screen out weakly fluorescent molecules from the candidates. On the other hand, the low precision of 0.5 was attributed to the bias in the training dataset containing many fluorine-containing molecules with high quantum yields. Our prediction model was then revised with the generator of candidate molecular structures for more efficient development of fluorescent materials with taking the applicability domain into account, and the improvement of the applicability was confirmed owing to the increment of the dataset. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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Review

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24 pages, 1206 KB

Open AccessReview

Recent Advances in the Synthesis and Applications of 1,2,3/1,2,5-Thiadiazole- and Benzo[c][1,2,5/1,2,3]thiadiazole-Type Compounds

by Diego Quiroga, Daniel Rodríguez and Ericsson Coy-Barrera

Molecules 2025, 30(22), 4373; https://doi.org/10.3390/molecules30224373 - 12 Nov 2025

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Abstract

Thiadiazole derivatives, such as 1,2,3-thiadiazole, 1,2,5-thiadiazole, benzo[c][1,2,5]thiadiazole, and benzo[d][1,2,3]thiadiazole, have garnered significant attention due to their exceptional chemical and physical properties. These molecules, which contain sulfur and nitrogen atoms in their heterocyclic structure, have a variety of applications in [...] Read more.

Thiadiazole derivatives, such as 1,2,3-thiadiazole, 1,2,5-thiadiazole, benzo[c][1,2,5]thiadiazole, and benzo[d][1,2,3]thiadiazole, have garnered significant attention due to their exceptional chemical and physical properties. These molecules, which contain sulfur and nitrogen atoms in their heterocyclic structure, have a variety of applications in agriculture, materials, and pharmaceuticals. In this review, we examine the most commonly used synthetic methods for these compounds, with a focus on the most recent techniques, including green synthesis, solid-phase chemistry, and catalytic processes, which enable greater efficiency, improved selectivity, and reduced environmental impact. Advances in the structural modification of these molecules to improve their photophysical properties and biocompatibility are also discussed. Finally, we highlight future research directions and emerging applications of thiadiazole derivatives across molecular medicine, nanotechnology, and agriculture, underscoring their potential to revolutionize multiple scientific and technological fields. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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19 pages, 3577 KB

Open AccessReview

Enantioselective Preparation of (N,O)-, (N,N)- and (N,S)-Spiroketal Moieties

by Mata Sow, Edouard Fauran and Laurent Commeiras

Molecules 2025, 30(20), 4100; https://doi.org/10.3390/molecules30204100 - 15 Oct 2025

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Abstract

This review highlights enantioselective strategies for preparing (N,O)- (N,N)- and (N,S)-spiroketal skeleton, which are key structural units found in many natural products and pharmacologically active substances. The strategies are mainly based on metallo-, organo- or Lewis acid-catalyzed cycloaddition or annulation reactions. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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