Search Results (107)

In this study, the design and synthesis of a novel series of cinnamic acid and 1,2,4-triazole hybrids were reported, aiming to enhance antioxidant and lipoxygenase inhibitory activities through pharmacophore combination. Cinnamic acid derivatives and 1,2,4-triazoles exhibit a broad spectrum of biological activities; therefore, by synthesizing hybrid molecules, we would like to exploit the beneficial characteristics of each scaffold. The general synthetic procedure comprises three synthetic steps, starting from the reaction of appropriate substituted cinnamic acid with hydrazine monohydrate in acetonitrile with cyclohexane and resulting in the formation of hydrazides. Consequently, the hydrazides reacted with phenylisothiocyanate under microwave irradiation conditions. Then, cyclization proceeded to the 1,2,4-triazole after the addition of NaOH solution and microwave irradiation. All the synthesized derivatives have been studied for their ability (a) to interact with the free radical DPPH, (b) inhibit lipid peroxidation induced by AAPH, and (c) inhibit soybean lipoxygenase. The synthesized derivatives have shown significant antioxidant activity and have been proved to be very good lipoxygenase inhibitors. Compounds 4b and 4g (IC₅₀ = 4.5 μM) are the most potent within the series followed by compound 6a (IC₅₀ = 5.0 μM). All the synthesized derivatives have been subjected to docking studies related to soybean lipoxygenase. Compound 4g exhibited a docking score of −9.2 kcal/mol and formed hydrophobic interactions with Val126, Tyr525, Lys526, Arg533, and Trp772, as well as a π−cation interaction with Lys526. Full article

To further extend the structure–activity relationships on previously identified anti-proliferative imidazo-pyrazoles, a novel series of compounds was designed and synthesized. In the obtained derivatives (1), the imidazo-pyrazole scaffold was formally condensed with a substituted triazole moiety, known for its biological properties. All derivatives were tested for anti-proliferative activity on a panel of 60 different cancer cell lines and compound 1h was identified as the most promising derivative, being highly effective against melanoma cells. Additional investigations demonstrated a cytotoxic and pro-oxidant action of the compound 1h on human metastatic melanoma cell lines (MeOV and MeTA) but not on healthy keratinocytes (HaCAT), confirming the selective activity of the compound. In silico calculations predicted favorable drug-like and pharmacokinetic properties and pre-formulation studies evaluated the effect of Tween 80 on 1h solubility. Overall, the collected data confirmed the pharmacological potential of the imidazo-pyrazole scaffold and indicated 1h as an interesting lead structure for the development of novel anti-melanoma agents. Full article

Background/Objectives: The search for new anticancer agents from natural sources remains a key strategy in drug discovery. This study aimed to synthesize and evaluate novel triazole derivatives of the diterpenic lactone andrographolide for their antiproliferative activity against various cancer cell lines. Methods: Twenty-two new triazole derivatives (5–26), of the triacetyl derivative (2) of the diterpenic lactone andrographolide (1), were synthesized via the azide-alkyne “click reaction”. The antiproliferative effects of compounds 1–26 were evaluated using the sulforhodamine B assay against a panel of cancer cell lines and a non-tumorigenic colon cell line. A representative compound, triazole derivative 12, was further evaluated in human pancreatic ductal adenocarcinoma (PANC-1) cells for its effects on the cell cycle, apoptosis, migration, and drug synergy with 5-fluorouracil. Results: Several compounds, specifically, 9, 14, 16, and 17, bearing a phenyl moiety, exhibited improved antiproliferative activity compared to the parental compound 1. Derivative 12, selected for further investigation, induced G2/M cell cycle arrest and apoptosis in a concentration-dependent manner. Additionally, this compound significantly reduced cell migration and demonstrated synergistic effects with 5-fluorouracil in PANC-1 cells. Conclusions: The synthesized andrographolide-based triazole derivatives, particularly compound 12, showed promising antiproliferative activity and mechanisms relevant to cancer therapy. These findings support their potential as lead compounds for further development in anticancer research. Full article

A series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, 6c1, exhibited strong BChE inhibition (IC₅₀ = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure–activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development. Full article

The synthesis of (E)-1-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-3-phenyl-2-propen-1-one derivatives was carried out in two steps, using benzylic chloride derivatives as starting material. The structural determination of intermediates and final products was performed by spectroscopic methods: infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry (IR, NMR, and MS). In vitro evaluation of cytotoxic activity on adherent and non-adherent cells showed that triazole chalcones exhibited significant activity against three of the five cell lines studied: non-Hodgkin lymphoma U937, glioblastoma multiform tumor T98G, and gallbladder cancer cells Gb-d1. In contrast, the cytotoxic activity observed for cervical cancer HeLa and gallbladder adenocarcinoma G-415 was considerably lower. Additionally, in the cell lines where activity was observed, some compounds demonstrated an In vitro inhibitory effect superior to that of the control, paclitaxel. Molecular docking studies revealed specific interactions between the synthesized ligands and therapeutic targets in various cell lines. In U937 cells, compounds 4a and 4c exhibited significant inhibition of vascular endothelial growth factor receptor (VEGFR) kinase, correlating with their biological activity. This effect was attributed to favorable interactions with key residues in the binding site. In T98G cells, compounds 4r and 4w showed affinity for transglutaminase 2 (TG2) protein, driven by their ability to form hydrophobic interactions. In Gb-d1 cells, compounds 4l and 4p exhibited favorable interactions with mitogen-activated protein kinase (MEK) protein, similar to those observed with the known inhibitor selumetinib. In HeLa cells, compounds 4h and 4g showed activity against dihydrofolate reductase (DHFR) protein, driven by hydrogen bonding interactions and favorable aromatic ring orientations. On the other hand, compounds 4b and 4t exhibited no activity, likely due to unfavorable interactions related to halogen substitutions in the aromatic rings. Full article

Despite the discovery of many chemotherapeutic drugs that prevent uncontrolled cell division processes, the development of compounds with higher anticancer efficacy and a lower level of side effects is an important task in modern pharmaceutical chemistry. Herein, a mild and convenient method for the preparation of N1-substituted 3-(1,2,3-triazolyl-methoxycarbonyl)coumarins or bis(coumarine-3-carboxylate)bis(triazole)alkandiyl by the copper(I)-catalyzed Huisgen cycloaddition reaction of readily available coumarin-3-carboxylic acid propynyl ester with azides or diazides has been presented. The synthesized compounds have been tested for their cytotoxicity on various cancer and noncancerous cell lines using the MTT assay. All new compounds were nontoxic on normal epithelial VERO cells. Two derivatives exhibited selectivity towards HPV-negative human cervical cancer cells, C33 A, with excellent activities in low concentrations (GI₅₀ 4.4–7.0 µM). In vitro mechanistic studies showed that bis(coumarine)bis(triazolylester) conjugate 3 induced time-dependent apoptosis in cervical cancer cell lines C33 A and CaSki, at the GI₅₀ concentration, as measured by Annexin V-FITC/PI staining. The most active coumarin–triazolyl ester conjugate 2g possessed anticancer activities, as indicated by its ability to induce S/G2 phase cell cycle arrest at a low concentration and early apoptosis in CaSki cells. The obtained results revealed the potential of new compounds as anticancer agents, particularly against cervical cancer. Full article

An efficient access to novel 2-substituted 1H-imidazole derivatives was developed based on acid-mediated denitrogenative transformation of 5-amino-1,2,3-triazole derivatives available through dipolar azide−nitrile cycloaddition (DCR). The proposed approach includes intramolecular cyclization of 5-amino-4-aryl-1-(2,2-diethoxyethyl) 1,2,3-triazoles followed by triazole ring opening and insertion of in situ formed carbene intermediate into the O-H bond of different alcohols under acidic conditions. Full article

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability. Full article

Background/Objectives: Fungal pathogens are increasingly developing concerning resistance against the currently available antifungal drugs, which creates a constant demand for new antifungal agents. Methods: Here, we report the synthesis of C3,N4-substituted triazole derivatives containing a N4-(2-((4-methoxybenzyl)thio)phenyl) group. By selectively removing the 4-methoxybenzyl group, we were able to access the free thiol analogs which, under oxidative conditions, undergo a cyclization reaction yielding a C5-substituted benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. We were able to show a broad functional group tolerance for the preparation of the triazole derivatives, as well as the tricyclic heteroarenes prepared thereof. Mechanistic investigations suggest that the oxidative cyclization reaction proceeds via an ionic pathway involving a disulfide intermediate. Isolation of the disulfide intermediate and resubjecting it to the reaction conditions shows that the presence of acid significantly increases its rate of conversion to the corresponding benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. Antifungal testing of both the novel triazoles and the benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles was carried out with Candida albicans (SC5314) and a clinical strain of Trichosporon asahii (OK01). Results: Most of the novel sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles showed activity against Candida albicans (SC5314) and the emerging pathogen Trichosporon asahii (OK01). Conclusions: A series of new sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles were synthesized. Antifungal testing revealed modest activity against Candida albicans (SC5314) and Trichosporon asahii (OK01). Full article

Background: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we developed and successfully implemented a strategy for the search for new hybrid molecules, namely, the not broadly known [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines. They can act as “building blocks” and allow for the introduction of certain structural motifs into the desired final products in order to enhance the antistaphylococcal effect. Methods: The “one-pot” synthesis of the latter is based on the conversion of substituted 4-hydrazinoquinazolines or substituted 2-aminobenzonitriles and carboxylic acid derivatives to the target products. The possible molecular mechanism of the synthesized compounds (DNA gyrase inhibitors) was investigated and discussed using molecular docking, and their further study for antistaphylococcal activity was substantiated. Results: A significant part of the obtained compounds showed high antibacterial activity against Staphylococcus aureus (MIC: 10.1–62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1H-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1H-1,2,4-triazol-5-yl)aniline, with MICs of 5.2 and 6.1 µM, respectively, approaching the strength of the effect of the reference drug, “Ciprofloxacin” (MIC: 4.7 µM). The conducted SAR and ADME analyses confirm the prospects of the further structural modification of these compounds. The obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antimicrobial activity and deserve further structural modification and detailed study as effective antistaphylococcal agents. The SAR analysis revealed that the presence of a cycloalkyl or electron-rich heterocyclic fragment in the third position of the triazole ring was essential for the antibacterial activity of the obtained compounds. At the same time, the introduction of a methyl group into the aniline moiety led to an enhancement of activity. The introduction of halogen into the aniline fragment has an ambiguous effect on the level of antistaphylococcal activity and depends on the nature of the substituent in the third position. Conclusions: Obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents. Full article

A series of target 4-substituted-5-(2-(pyridine-2-ylamino)ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones and their chloro analogs 7–21 were synthesized in a reaction of the selected aldehydes with the corresponding 4-amino-1,2,4-triazole-3-thiones 5 and 6, which were obtained from 3-(pyridin-2-ylamino)propanoic acid (3) or 3-((5-chloropyridin-2-yl)amino)propanoic acid (4), respectively, with thioacetohydrazide. The antibacterial and antifungal activities of the synthesized hydrazones were screened against the bacteria Escherichia coli, Staphylococcus aureus, and Mycobacterium luteum and the fungi Candida tenuis and Aspergillus niger by agar diffusion and serial dilution methods. 4-Amino-5-(2-((5-chloropyridin-2-yl)amino)ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (6) and 4-(benzylideneamino)-5-(2-(pyridin-2-ylamino)ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (7) were identified as exceptionally active (MIC 0.9 µg/mL) against the fungus C. tenuis. 5-Chloropyridine derivatives bearing 4-benzylidene 8, 2-nitrobenzylidene 10, pyridinylmethylene 16, and 4-methylthiobenzylidene 21 moieties showed very high antibacterial activity (MIC 3.9 µg/mL) against the M. luteum strain. The cell viability screening of the synthesized compounds using triple-negative breast cancer MDA-MB-231 and glioblastoma U-87 cell lines by MTT assay identified three active hydrazones, of which 5-(2-(pyridin-2-ylamino)ethyl)-4-((pyridin-3-ylmethylene)amino)-2,4-dihydro-3H-1,2,4-triazole-3-thione (15) had the highest effect on the viability of cells (IC₅₀ value 39.2 ± 1.7 μM against MDA-MD-231). The in silico molecular modeling results suggested that these three most active hydrazones might have influenced the mitogen-activated protein kinase pathway through the inhibition of BRAF and MEK serine–threonine protein kinases. 5-(2-((5-Chloropyridin-2-yl)amino)ethyl)-4-((4-(methylthio)benzylidene)amino)-2,4-dihydro-3H-1,2,4-triazole-3-thione (21) demonstrated the highest affinity among them. Full article

A novel series of substituted benzofuran-tethered triazolylcarbazoles was synthesized in good to high yields (65–89%) via S-alkylation of benzofuran-based triazoles with 2-bromo-N-(9-ethyl-9H-carbazol-3-yl)acetamide. The inhibitory potency of the synthesized compounds against SARS-CoV-2 was evaluated by enacting molecular docking against its three pivotal proteins, namely, M^pro (main protease; PDB ID: 6LU7), the spike glycoprotein (PDB ID: 6WPT), and RdRp (RNA-dependent RNA polymerase; PDB ID: 6M71). The docking results indicated strong binding affinities between SARS-CoV-2 proteins and the synthesized compounds, which were thereby expected to obstruct the function of SARS proteins. Among the synthesized derivatives, the compounds 9e, 9h, 9i, and 9j exposited the best binding scores of −8.77, −8.76, −8.87, and −8.85 Kcal/mol against M^pro, respectively, −6.69, −6.54, −6.44, and −6.56 Kcal/mol against the spike glycoprotein, respectively, and −7.61, −8.10, −8.01, and −7.54 Kcal/mol against RdRp, respectively. Furthermore, the binding scores of 9b (−8.83 Kcal/mol) and 9c (−8.92 Kcal/mol) against 6LU7 are worth mentioning. Regarding the spike glycoprotein, 9b, 9d, and 9f expressed high binding energies of −6.43, −6.38, and −6.41 Kcal/mol, accordingly. Correspondingly, the binding affinity of 9g (−7.62 Kcal/mol) against RdRp is also noteworthy. Furthermore, the potent compounds were also subjected to ADMET analysis to evaluate their pharmacokinetic properties, suggesting that the compounds 9e, 9h, 9i, and 9j exhibited comparable values. These potent compounds may be selected as inhibitory agents and provide a pertinent context for further investigations. Full article

Background: The triazole ring is an attractive structural unit in medicinal chemistry, and chemical compounds containing this type of system in their structure exhibit a wide spectrum of biological activity. They are used in the development of new pharmaceuticals. One of the basic parameters considered in the initial phase of designing potential drugs is lipophilicity, which affects the bioavailability and pharmacokinetics of drugs. Methods: The study aimed to assess the lipophilicity of fifteen new triazole derivatives of aniline using reversed phase thin layer chromatography (RP-TLC) and free web servers. Based on in silico methods, the drug similarity and pharmacokinetic profile (ADMET) of synthesized molecules were assessed. Results: A relationship was observed between the structure of the title compound, including the position of substitution in the aniline ring, and the experimental values of lipophilicity parameters (logP_TLC). Most of the algorithms used to determine theoretical logP values showed less sensitivity to structural differences of the tested molecules. All obtained derivatives satisfy the drug similarity rules formulated by Lipinski, Ghose and Veber. Moreover, in silico analysis of the ADME profile showed favorable values of parameters related to absorption. Full article

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin’s aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments. Full article

Triazole derivatives of fluorescein-containing N,N-dimethylaminopropyl fragments and their ammonium salts were synthesized with yields of 74–85%. The resulting compounds exhibit fluorescent properties in the green region of the visible spectrum. The critical aggregation concentration (CAC) was estimated using a pyrene fluorescent probe corresponding to a range of 0.28–1.43 mM, and at concentrations above the CAC, the compounds form stable aggregates ranging from 165 to 202 nm. A relative quantum yield of 5–24% has been calculated based on fluorescence and UV spectra. The best value is shown by a derivative containing a tetradecyl substituent. When studying the photocatalytic properties of synthesized compounds through the reaction between N-substituted 1,2,3,4-tetrahydroisoquinoline and malonic ester, the mono-tetradecyl derivative demonstrated the best results. According to gas chromatography–mass spectrometry (GC-MS) data, the conversion of the initial heterocycle reached 95%. Therefore, these resulting compounds have the potential to act as an effective photocatalysts. Full article