Search Results (83)

The unprecedented use of ethynyl trifluoromethyl sulfide (CF₃S–C≡CH) as a synthetically useful building block has been described for the first time. It was reacted with various aromatic and aliphatic azides under copper-catalyzed conditions to yield a novel class of 1,4-disubstituted triazoles bearing the SCF₃ group (15 examples, up to 86% yield). Full article

Despite multiple advances in treatment and prevention, cancer remains one of the leading causes of death worldwide. Chemotherapy remains the most effective method for cancer treatment. However, commercial chemotherapeutic drugs have limited efficacy, severe side effects, and acquired resistance. Therefore, the scientific community has devoted a great effort to designing new, more effective, and cheaper drugs. In this sense, copper-catalyzed azide-alkyne cycloaddition reactions (CuAAC) provide 1,4-disubstituted 1H-1,2,3-triazoles in high yields without forming by-products. This reaction allows the easy, efficient, functional, ordered, rapid, selective, and specific joining of small molecules, giving rise to more complex molecules. The CuACC reaction simplifies the synthesis processes, accelerating the discovery of new chemotherapeutic agents by allowing the joining of commercial platinum drugs, slightly altering their structure, or creating new molecules with improved properties. This work shows the importance of CuAAC reactions in the search for new metallodrugs with possible anticancer activity. Full article

Bis-triazoles separated by a symmetrical linking group are joined at C4 of each triazole or at N1 of each triazole. Preparation of a series of bis-1H-1,2,3-triazoles derived from o-bis(azidomethyl)benzene and an alkyne is reported with use of copper N-heterocyclic carbene catalysis with microwave-assisted heating in an aqueous solvent. The products were symmetrical N1–N1′-bis-1H-1,2,3-triazoles. Additional syntheses utilized dialkynes and organic azides to prepare symmetrical C4–C4′-bis-1H-1,2,3-triazoles. Pure products were often obtained directly when water was used as the solvent with microwave-assisted heating. Results are given for experiments using conventional heating or no heating. Sonication results are given for a reaction where microwave-assisted heating was unsatisfactory. Full article

Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC₅₀ in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 $\mathsf{\mu }$M; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents. Full article

In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide–alkyne cycloaddition reaction (CuAAC). 8-N-Methyl-N-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment. Full article

1,2,4-Triazole derivatives have a wide range of biological activities. The most well-known drug that contains 1,2,4-triazole as part of its structure is the nucleoside analogue ribavirin, an antiviral drug. Finding new nucleosides based on 1,2,4-triazole is a topical task. The aim of this study was to synthesize ribosides and deoxyribosides of 1,2,4-triazole-3-thione derivatives and test their antiviral activity against herpes simplex viruses. Three compounds from a series of synthesized mono- and disubstituted 1,2,4-triazole-3-thione derivatives were found to be substrates for E. coli purine nucleoside phosphorylase. Of six prepared nucleosides, the riboside and deoxyriboside of 3-phenacylthio-1,2,4-triazole were obtained at good yields. The yields of the disubstituted 1,2,4-triazol-3-thiones were low due to the effect of bulky substituents at the C3 and C5 positions on the selectivity of enzymatic glycosylation for one particular nitrogen atom in the triazole ring. The results of cytotoxic and antiviral studies on acyclovir-sensitive wild-type strain HSV-1/L2(TK+) and acyclovir-resistant strain (HSV-1/L2/R^ACV) in Vero E6 cell culture showed that the incorporation of a thiobutyl substituent into the C5 position of 3-phenyl-1,2,4-triazole results in a significant increase in the cytotoxicity of the base and antiviral activity. The highest antiviral activity was observed in the 3-phenacylthio-1-(β-D-ribofuranosyl)-1,2,4-triazole and 5-butylthio-1-(2-deoxy-β-D-ribofuranosyl)-3-phenyl-1,2,4-triazole nucleosides, with their selectivity indexes being significantly higher than that of ribavirin. It was also found that with the increasing lipophilicity of the nucleosides, the activity and toxicity of the tested compounds increased. Full article

The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes. Full article

The use of metabolically stabilized, radiolabeled somatostatin (SST) analogs ([⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-TATE/TOC/NOC) is well established in nuclear medicine. Despite the pivotal role of these radioligands in the diagnosis and therapy of neuroendocrine tumors (NETs), their inability to interact with all five somatostatin receptors (SST_1–5R) limits their clinical potential. [¹¹¹In]In-AT2S is a radiolabeled DOTA-conjugate derived from the parent peptide SST-14 that exhibits high binding affinity to all SSTR subtypes, but its poor metabolic stability represents a serious disadvantage for clinical use. In order to address this issue, we have replaced strategic trans-amide bonds of [¹¹¹In]In-AT2S with metabolically stable 1,4-disubstituted 1,2,3-triazole bioisosteres. From the five cyclic triazolo-peptidomimetics investigated, only [¹¹¹In]In-XG1 combined a preserved nanomolar affinity for the SST_1,2,3,5R subtypes in vitro and an improved stability in vivo (up to 17% of intact peptide 5 min postinjection (pi) versus 6% for [¹¹¹In]In-AT2S). The involvement of neprilysin (NEP) in the metabolism of [¹¹¹In]In-XG1 was confirmed by coadministration of Entresto^®, a registered antihypertensive drug, in vivo releasing the selective and potent NEP-inhibitor sacubitrilat. A pilot SPECT/CT imaging study conducted in mice bearing hSST₂R-positive xenografts failed to visualize the xenografts due to the pronounced kidney uptake (>200% injected activity (IA)/g at 4 h pi), likely the result of the formation of cationic metabolites. To corroborate the imaging data, the tumors and the kidneys were excised and analyzed with a γ-counter. Even if receptor-specific tumor uptake for [¹¹¹In]In-XG1 could be confirmed (1.61% IA/g), further optimization is required to improve its pharmacokinetic properties for radiotracer development. Full article

A series of novel triazole-tethered ferrocenoylamino-substituted cinchona–chalcone hybrids along with two representative benzoylamino-substituted reference compounds were prepared by three methods of CuAAC chemistry. In line with the limited success or complete failure of attempted conversions with low catalyst loadings, by means of DFT modeling studies, we demonstrated that a substantial part of the Cu(I) ions can be chelated and thus trapped in the aroylamino-substituted cinchona fragment and all of the accessible coordinating sites of the chalcone residues. Accordingly, increased amounts of catalysts were used to achieve acceptable yields; however, the cycloadditions with para-azidochalcones were accompanied by partial or complete aldehyde-forming hydrolytic fission of the enone C=C bond in a substituent-, solvent- and copper load-dependent manner. The experienced hydrolytic stability of the hybrids obtained by cycloadditions with ortho-azidochalcones was interpreted in terms of relative energetics, DFT reactivity indices and MO analysis of simplified models of two isomer copper–enone complexes. The novel hybrids were evaluated on HeLa, MDA-MB-231 and A2780 cell lines and showed substantial activity at low-to-submicromolar concentrations. An organometallic model carrying 3,4,5-trimethoxyphenyl residue in the enone part with a para-disubstituted benzene ring in the central skeletal region was identified as the most potent antiproliferative lead, characterized by submicromolar IC₅₀ values measured on the three investigated cells. The biological assays also disclosed that this ferrocenoylamino-containing lead compound displays a ca. two- to five-fold more substantial antiproliferative effect than its benzoylamino-substituted counterpart. Full article

Bioisosteres of amide bonds such as 4,5-disubstituted-1,2,3-triazoles (4,5-DS-1,2,3-Ts) and 1,5-disubstituted tetrazoles (1,5-DST) are present in compounds with important biological activities like those that are antineoplastic, antibacterial, antifungal, and antiparasitic, and antifungal, antiparasitic, antiviral, and anti-inflammatory. In the present work, we describe the synthesis of tetrazole–triazole bis-heterocycles via the Ugi–Azide strategy. The target molecules were synthesized with moderate yields, under mild conditions, employing 2H-1,2,3-triazole aldehyde as an input. Full article

A biologically effective study regarding the synthesis of a library of hybrids based on a triazole ring, propanamide and azinane was performed in this study. The targeted hybrids, 9a–9l, were synthesized through a multistep protocol followed by two methodologies, that is, conventional and microwave-assisted ones. Initially, compound 3 was synthesized via the room-temperature stirring of 4-methoxybenzenesulfonyl chloride (1) and ethyl ester (2). Resulting carboxylate was converted into carbohydrazide 4, which was refluxed with phenyl isothiocyanate and KOH to synthesize product 5. A library of amides, 8a–8l, was stirred at room temperature with compound 5 to avail the targeted library of hybrids 9a–9l. The designed hybrids were screened for their antioxidant, urease, AChE and BChE inhibition potential. All the compounds were found to be active with variable potential. The best antioxidant agent was compound 9c with an IC₅₀ value of 45.2 ± 0.15. The compound 9e (63.27 ± 1.21) was the best AChE inhibitor; 9g (20.2 ± 0.21) and 9k (19.2 ± 0.09) were the best anti-urease agents; and 9d (15.5 ± 0.39) and 9e (15.9 ± 0.67) were the best BChE inhibitors. The computational and BSA binding studies of the selected synthesized compounds against urease, BChE and AChE enzymes were carried out to elaborate the strong and weak enzyme-inhibition potential through the binding forces of the synthesized compounds with the different enzymatic sites that are responsible for their activity. Full article

The anticarcinogenic potential of a series of 1,5-disubstituted tetrazole-1,2,3-triazole hybrids (T-THs) was evaluated in the breast cancer (BC)-derived cell lines MCF-7 (ER+, PR+, and HER2−), CAMA-1 (ER+, PR+/−, and HER2−), SKBR-3 (ER+, PR+, and HER2+), and HCC1954 (ER+, PR+, and HER2+). The T-THs 7f, 7l, and 7g inhibited the proliferation of MCF-7 and CAMA-1, HCC1954, and SKBR-3 cells, respectively. The compounds with stronger effect in terms of migration and invasion inhibition were 7o, 7b, 7n, and 7k for the CAMA-1, MCF-7, HCC1954, and SKBR-3 cells respectively. Interestingly, these T-THs were the compounds with a fluorine present in their structures. To discover a possible target protein, a molecular docking analysis was performed for p53, p38, p58, and JNK1. The T-THs presented a higher affinity for p53, followed by JNK1, p58, and lastly p38. The best-predicted affinity for p53 showed interactions between the T-THs and both the DNA fragment and the protein. These results provide an opportunity for these compounds to be studied as potential drug candidates for breast cancer treatment. Full article

1,2,3-triazole pharmacophore is a widely recognized motif used for a variety of applications, including drug discovery, chemical biology, and materials science. We herein report the synthesis of a derivative of azidothymidine (AZT), which was combined with the 7-chloro quinoline scaffold through a 1,4-disubstituted 1,2,3-triazole. The chemical structure of the new molecule was fully characterized by Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (¹H-NMR), carbon-13 nuclear magnetic resonance (¹³C-NMR), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC) distortionless enhancement by polarization transfer (DEPT), correlation spectroscopy (¹H-¹H-COSY), ultraviolet (UV) spectroscopy, and high-resolution mass spectrometry (HRMS). Computational studies were used to predict the interaction of the synthesized compound with HIV reverse transcriptase, a target of relevance for developing new therapeutics against AIDS. The drug-likeness of the compound was also investigated by computing the physico-chemical properties that are important for the pharmacokinetic profile. Full article

We hereby describe an efficient method for the preparation of a series of new 1-substituted 1,2,3-triazole-based acetaminophen derivatives through a clean, good-yielding, simple, and expeditious procedure based on the O-propargylation reaction of the acetaminophen (APAP) obtained from expired commercial tablets and the CuBr(PPh₃)₃-catalyzed Huisgen reaction between O-propargylated APAP and diverse organoazides prepared from commercially available anilines as available starting reagents. An interesting nitric oxide-releasing 1,2,3-triazole hybrid of APAP was also obtained easily using the developed method. The structures of the designed hybrid compounds, which are expected to be pharmacologically active, were characterized by FT-IR, ¹H-, and ¹³C-NMR and are reported for the first time. According to the in-silico ADMET prediction studies performed in this work and literature analysis, these hybrids are interesting models in search of new pharmacological nontoxic agents endowed with anti-inflammatory and anticancer properties. Full article

Ruthenium(II)-catalyzed azide–alkyne cycloaddition (RuAAC) polymerization of t-butyl 4-azido-5-hexynoate (tBuAH), i.e., a heterobifunctional monomer carrying azide and alkyne moieties, was investigated in this study. RuAAC of the monofunctional precursors of tBuAH yielded a dimer possessing a 1,5-disubstituted 1,2,3-triazole moiety. ¹H NMR data showed that the dimer was a mixture of diastereomers. Polymerization of tBuAH using ruthenium(II) (Ru(II)) catalysts produced oligomers of M_w ≈ (2.7–3.6) × 10³ consisting of 1,5-disubstituted 1,2,3-triazole units (1,5-units) as well as 1,4-disubstituted 1,2,3-triazole units (1,4-units). The fractions of 1,5-unit (f_1,5) were roughly estimated to be ca. 0.8 by comparison of signals of the methine and triazole protons in ¹H NMR spectra, indicating that RuAAC proceeded preferentially and thermal Huisgen cycloaddition (HC) somehow took place during the polymerization. The oligomer samples obtained were also characterized by solubility test, size exclusion chromatography (SEC), ultraviolet-visible (UV-Vis) absorption spectroscopy, and thermogravimetric analysis (TGA). The UV-Vis and TGA data indicated that the oligomer samples contained a substantial amount of Ru(II) catalysts. To the best of our knowledge, this is the first report on dense 1,2,3-triazole oligomers consisting of 1,5-units linked via a carbon atom. Full article