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A copper-catalyzed three-component reaction of diazo compounds, nitriles, and azodicarboxylates to construct 2,3-dihydro-1,2,4-triazoles is reported. Key to the success is the utilization of azodicarboxylates to trap the in-situ formed nitrile ylides from diazo compounds by [3 ​+ ​2]-cycloaddition. Both the acceptor-only and donor-acceptor diazo compounds are all tolerated to the strategy. The synthetic value of this protocol is illustrated by gram-scale synthesis and valuable transformation of the obtained 2,3-dihydro-1,2,4-triazoles.

Hydrogen‐bonding and halogen‐bonding interactions are important noncovalent interactions that play a significant role in the crystal structure of organic molecules. An in‐depth analysis is given of the crystal packing of two previously reported crystal structures of dihalogenated 1,2,4‐triazole derivatives, namely 3,5‐dichloro‐1H‐1,2,4‐triazole and 3,5‐dibromo‐1H‐1,2,4‐triazole. This work provides insights into the complex interplay of hydrogen‐bonding and halogen‐bonding interactions resulting in the formation of multiple trimeric motifs in the crystal structure of 1,2,4‐triazole derivatives. Analysis of the crystal packing of these isostructural crystal structures revealed that the molecular arrangement in these molecules is primarily stabilized by the formation of different trimeric motifs stabilized by N—H...N hydrogen bonds, N—H...X (X = Cl/Br) halogen bonds and C—X...X halogen‐bonding interactions. Computational studies further revealed that all these trimers are energetically stable. A crystallographic database search further reveals that while the cyclic trimers reported in this study are present in other molecules, structures analyzed in this study are the sole instances where all are present simultaneously. [ABSTRACT FROM AUTHOR]

Compounds with a 1,2,4–triazole scaffold serve an essential role in organic synthesis, particularly in the synthesis of bioactive organic compounds; thus, the development of new approaches for modifying this scaffold is a very interesting framework of this study. To contribute to the development of an efficient method for the conversion of anticancer triazoles, a novel series of benzimidazole based 1,2,4‐triazoles was designed and synthesized. All the newly synthesized derivatives were characterized by NMR (1H &13C), FT–IR and mass spectrometry. Among the tested compounds, hybrids 5 b, 5 g exhibited exceptional anticancer susceptibilities with IC50=8.8±0.9, 9.2±1.5 μM against the tested HCA‐7cancer cell line. Anticancer profiles showed that compounds 5 d, 5 i had better anticancer inhibitory potency against a breast cancer cell line MCF‐7with IC50values 8.3±2.1, 10.6±1.2 μM, whereas 5 d, and 5 g showed potent anticancer activity against colorectal cancer cell line HT29 with IC50 values 7.1±±0.9, 7.7±1.2 μM respectively. From docking results, 5 d demonstrated highly stable binding amino acids LeuA : 2247, GlyA : 2449, SerA : 2409, HisA : 2379, AspA : 2373, LysA : 2318, IleA : 2317, IleA : 2246, IleA : 2412, AlaA : 2410, GlnA : 2452, AsnA : 2245, TyrA : 2243, and HisA : 2448, which play a crucial role enabling optimal ligand binding in a crystal structure tyrosine phosphatase mutated in colorectal cancer (PDB: 1WCH). Furthermore, the physicochemical and absorption, distribution, metabolism, and excretion (ADME) filtration molecular properties, estimation of bioactivity, and toxicity scores of these scaffolds were evaluated. [ABSTRACT FROM AUTHOR]

A series of novel amide compounds with 1,2,4-triazine, 1,2,4-triazole and 1,3,4-oxadiazole moieties were synthesized by multistep procedure from 1,2,4-triazine-containing hydrazine-carbothioamides. Numerous synthetic compounds were tested for their ability to inhibit the growth of both gram-positive (Bacillus subtitis and Staphylococcus aureus) and gram-negative (E. coli) bacteria. All the tested compounds had no effects on fungi (Candida tropicalis). The toxicity of the synthesized chemicals was checked to guarantee their safety. The enzymic activity was studied, the enzymatic activity was not affected by the compounds under examined, and the levels of uric acid and creatine did not exceed normal limits. [ABSTRACT FROM AUTHOR]

Nowadays, the need to replace the existing drugs is felt more than ever by increasing drug resistance. Quinazoline is one of the major heterocyclic compounds in biological activity. This research was done to synthesize new derivatives of quinazolin-4(3H)-one and evaluation of their antibacterial and antifungal properties. Ten new quinazolin-4(3H)-one derivatives (5(a–d), 6(a–d), and 7(a,b)) were synthesized by using the nucleophilic substitution reaction of 2-(chloromethyl)-3-(4-chlorophenyl) quinazolin-4(3H)-one (4) and the heterocyclic moieties of 1,3,4-oxadiazole I(a–d) or 1,2,4-triazole (II(a–d), III(a,b)) in the presence of potassium carbonate as base and in acetone as solvent. The chemical structures of the products were approved using 1H-NMR, 13 C-NMR, IR, and Mass spectroscopy. The antimicrobial activity of the compounds was assessed against a panel of Gram-positive and Gram-negative bacteria and species of Candida and Aspergillus fungal. Minimum inhibitory concentration (MIC), minimum bactericidal/fungicidal concentration (MBC/MFC), and inhibition zone (IZ) of these compounds were determined. As results shown, 7a showed better effects against Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa than the other compounds. However, 5d showed better effects against Proteus vulgaris. Compound 6b showed better effects against Candida albicans, Aspergillus fumigatus, and Aspergillus niger, also compound 5a showed better effects against Candida glabrata. [ABSTRACT FROM AUTHOR]

1-[3-Methyl-3-(2,4,6-trimethylphenyl)cyclobutyl]-2-{[4-benzyl(4-methylphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethanones were synthesized by the condensation of 2-chloro-1-[3-methyl-3-(2,4,6-trimethylphenyl)cyclobutyl]ethanone with 4-benzyl- and 4-(4-methylphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiols. The new compounds were characterized by FT-IR and 1H and 13C NMR spectra. The molecular geometry, vibrational frequencies, and gauge-independent atomic orbital (GIAO) 1H and 13C NMR chemical shifts of the title compounds in the ground state were calculated using the density functional method (B3LYP) with the 6–311G(d,p) basis set. The calculated results showed that the optimized geometry well reproduces the theoretical vibrational frequencies, and the calculated chemical shifts were in good agreement with the experimental values. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of highly substituted 1,2,4-triazole-based 3-nitrochromanes through the aza-Michael addition reaction. The authors provide experimental details and optimization parameters for the reaction, including solvents, temperature, and reaction time. They demonstrate the synthetic utility of the method by obtaining various products with good yields and performing derivatizations of the addition products. The article also discusses the potential applications of the synthesized compounds in medicinal chemistry research and provides detailed information on their chemical properties and physical properties. Supporting information for the article is available online. [Extracted from the article]

New Eu(III) and Tb(III) hybrid materials based on N-((1-methyl-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)methyl)methacrylamide were synthesized and characterized as potential fluorescent emitters. Complexes of Eu(III) and Tb(III) demonstrate red and green luminescence in the visible region, respectively. The intense broad bands in the region of 270-290nm are related to electronic transitions within pyridine-triazole-containing fragment coordinated to Ln(III) ion. [ABSTRACT FROM AUTHOR]

A series of (E)-5-{[(1H-1,2,3-triazol-5-yl)sulfanyl]methyl}-4-(benzylideneamino)-4H-1,2,4-tri-azole-3-thiols were synthesized using 4-amino-5-{[(1H-1,2,3-triazol-5-yl)sulfanyl]methyl}-4H-1,2,4-triazole-3-thiol as an intermediate compound. The structure of the newly synthesized compounds was confirmed by 1H and 13C NMR, IR, and electrospray ionization mass spectra. Six compounds showed promising insecticidal activity against Plodia interpunctella. [ABSTRACT FROM AUTHOR]

Triazoles are an important class of compounds with widespread applications. Functionalization of the triazole backbone is thus of significant interest. In comparison to 1,2,3‐triazoles, C−H activation‐functionalization of the congeners 1,2,4‐triazoles is surprisingly underdeveloped. Indeed, no such C−H activation‐functionalization has been reported for 4‐substituted 1,2,4‐triazole cores. Furthermore, although denitrogenative ring‐opening of 1,2,3‐triazoles is well‐explored, 1,2,4‐triazole/triazolium substrates have not been known to exhibit N−N bond‐cleaving ring‐opening reactivity so far. In this work, we unveiled an unusual hidden reactivity of the 1,2,4‐triazole backbone involving the elusive N−N bond‐cleaving ring‐opening reaction. This new reactivity was induced by a Satoh‐Miura‐type C−H activation‐annulation at the 1,2,4‐triazole motif appended with a pyridine directing group. This unique reaction allowed ready access to a novel class of unsymmetrically substituted 2,2′‐dipyridylamines, with one pyridine ring fully‐substituted with alkyl groups. The unsymmetrical 2,2′‐dipyridylamines were utilized to access unsymmetrical boron‐aza‐dipyridylmethene fluorescent dyes. Empowered with desirable optical/physical properties such as large Stokes shifts and suitable hydrophobicity arising from optimal alkyl chain length at the fully‐substituted pyridine‐ring, these dyes were used for intracellular lipid droplet‐selective imaging studies, which provided useful information toward designing suitable lipid droplet‐selective imaging probes for biomedical applications. [ABSTRACT FROM AUTHOR]

In this study, we synthesized a number of new intriguing azoles bearing nicotinoyl moiety, their antimicrobial and antitumor activities were investigated as well. We succeeded to prepare sequence of hydrazones 2,4, 1,3,4-oxadiazoles 5, 6, 11, 12, 1,2,4-triazole 8, pyrazoles 9, 10, 13, 14, 16, 18, 20, 22, 25 and pyrazolo[3,4-d]pyrimidines 15, 23, and 24. Most of the synthesized compounds were tested against strains of fungus and bacteria. Some compounds that demonstrated significant biological activity were selected to test for their activity against cancer cells. It is interesting to note that, some of the tested compounds showed moderate to potent antibacterial activity. Strong antibacterial activity was demonstrated by compounds 16 and 23 (MIC = 2.5–5 µg/mL) against most of the microorganisms. Compounds 24 and 4a demonstrated a reasonable response to the microorganisms. Compound 2 explained a weak activity towards one of the tested microorganisms. Also, it was found that at a given concentration (3.16 µg/mL) the amino nitrile 9 exhibited strong cell-growth inhibiting action (>50 %). Based on these findings, compound 9 and 23 seems like good lead candidates to investigate further as potential anticancer and antibacterial agent respectively.

Candida species have long been attributed to various diseases like candidiasis and systemic diseases and exacerbate the symptoms of immunocompromised patients. Candida species have enzymes that could function as drug targets to decrease their pathogenicity and eradicate the fungi. This research aimed to investigate the potency of new bis-triazolothiadiazine derivatives contained in inhibiting important enzymes of C. albicans as an example, through molecular docking simulation. Thus, a novel series of bis-triazolo[3,4-b][1,3,4]thiadiazines were designed and prepared via the reaction of the most versatile, hitherto unreported 5,5′-(1,2,2-trimethylcyclopentane-1,3-diyl)bis(4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thione) with the appropriate hydrazonoyl halides and phenacyl bromides. Various spectroscopic techniques were used to identify the structures of the synthesized derivatives. The synthesized derivatives were tested against different species of Candida spp. The most effective compound was 6f followed by 6b, 6d, and 6e, where the inhibition zone ranged from 45 mm to 38 mm. By using molecular docking, which highlighted the important interactions with the amino acid residues Lys57, Leu77, Glu116, Gly114, Phe36, Thr58, and Glu32 at the point of binding, it was possible to determine the binding interactions of the produced derivatives to the fluconazole target fungi. The binding interaction energy was discovered to be −6.494 kcal/mol for the fungi candida albicans (PDB ID: 1IA2). The derivatives 6f and 6d, which demonstrated the highest efficacy, displayed significant conserved interactions with the amino acid residues at the binding site of the fluconazole fungi, in conjunction with the PDB co-crystal ligand 1IA2. The study’s results also revealed that the dG scores of the novel bis-triazolo-thiadiazines 6b-f. The study shows good docking scores with acceptable binding interactions. Finally, molecular docking studies revealed the lowest binding activity of derivatives 6e and 6c with the target fungi.

Background: Famous synthetic pharmacophores like Filgotinib, Dapiprazole, and Trazodone have Triazolopyridine as their primary building element. It has become more well-known in medicinal chemistry, to which its broad-spectrum impact may be attributed. Objective: The derivatization of the triazolopyridine molecule has been widely discussed in several scientific articles, focusing on its biological and pharmacological properties. As lead compounds for developing new drugs, many analogues of Triazolopyridine have been found. This article summarizes and discusses the literature surrounding the synthesis and biological evaluation of the triazolopyridine framework. Methods: Relevant keywords were used to identify relevant published literature from all relevant databases, including SciFinder, PubMed, and Google Scholar. Supplementary relevant literature bibliographies were also searched to locate linked reports. Results: Step-by-step explanations of the synthetic approaches to Triazolopyridine-based ring systems were found in the literature. All Triazolopyridine derivative's pharmacological activities were enumerated according to their targets, and a detailed structure–activity link was created. Conclusion: The current review highlights various synthetic techniques for fabricating the triazolopyridine framework and its uses across several medical chemistry fields. The wide range of biological effects of compounds with the triazolopyridine skeleton, including those that are antibacterial, antifungal, anticancer, anti-inflammatory, antitubercular, analgesic, anticancer, and antidepressant, make them crucial in the process of developing new drugs and so on. Despite extensive research, the structure-based drug design technique can create new, effective pharmacophores.

An entirely new family of 5-benzylidene-2-(furan-2-yl)-3-(4H-1,2,4-triazol-4-yl)thiazolidin-4-ones was synthesized. Their antibacterial and antifungal activity was evaluated towards gram-positive and gram-negative strains of bacteria and fungi. Against bacterial strains, products with nitro, methyl, and bromo substituents in the p-position of the benzene ring, as well as products with the nitro group at the m-position, showed very excellent activities against bacterial strains, while compounds with chloro substituent at p-position and m-position demonstrated good activity against the fungal strains Aspergillus niger and Fusarium javanicum. [ABSTRACT FROM AUTHOR]

The results of synthesis and study of magnetically-active iron(II) complexes with polynitrogen heterocyclic ligands and outer-sphere boron cluster anions have been considered. Derivatives of 1,2,4-triazole, tris(pyrazol-1-yl)methane, and 2,6-bis(imidazol-2-yl)pyridine have been used as ligands, decahydro-closo-decaborate, dodecahydro-closo-dodecaborate, decachloro-closo-decaborate, and 1,5,6,10-tetra(R)-7,8-dicarba-nido-undecaborates (R = H, Cl, Br) have been studied as outer-sphere anions. A number of iron(II) complexes showing spin crossover accompanied by thermochromism in the majority of cases has been obtained. Effect of ligand nature and cluster anion on temperature (Tc) and spin transition character has been considered. In particular, it has been shown that introduction of substituent increasing electron density over the system of conjugated three-centered two-electron bonds in cluster anion leads to increase in the field strength of ligand bound to anion via network of hydrogen bonds. [ABSTRACT FROM AUTHOR]

The present work documents an organophotoredox‐mediated formal [3+2]‐cycloaddition of 2H‐azirines with aryl diazonium tetrafluoroborate salts to furnish 1,3,5‐trisubstituted 1,2,4‐triazoles. The reaction furnishes a regioisomeric mixture of 1,2,4‐triazoles in case of unsymmetrically substituted azirines. It is noteworthy that aryl radical generation from diazonium salt under visible light photoredox conditions could be successfully avoided by carefully selecting the reaction conditions. [ABSTRACT FROM AUTHOR]

Herein; we report protocols for the synthesis of 1,2,4‐triazoles and 1,3,4‐ thiadiazinones by [3+2] and [3+3] domino annulation reactions of nitrile imines with succinimide and thiazolidine‐2,4‐dione, respectively, using a base (1.5 equivalents) and alcohol as a solvent. In these reactions, notably, alcohol serves not only as a solvent but also as a reactant participating in the formation of ester functionality in products. These methodologies provide metal‐free and direct approaches to the synthesis of 1,2,4‐triazoles and 1,3,4‐thiadiazinones under mild conditions with a wide substrate scope and high yields. [ABSTRACT FROM AUTHOR]

A novel, efficient, and solvent-free approach for the synthesis of aryl-3,5-bis(trifluoromethyl)-4 H -1,2,4-triazoles is disclosed via the nucleophilic intramolecular cyclization reaction of trifluoromethylated amidrazone and 2,2,2-trifluoroacetic anhydride. The trifluoromethylated amidrazone intermediates used in this project are synthesized from the reaction of N -aryl-2,2,2-trifluoroacetimidoyl chloride derivatives and hydrazine hydrate at ambient temperature in excellent yields. [ABSTRACT FROM AUTHOR]

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin. However, the spectrum of antibacterial activity was quite different, as the new compounds showed no activity against Pseudomonas aeruginosa. Among the prepared and tested compounds, the broadest range of activity (five pathogens of the six in the ESKAPE panel) and the highest level of activity were demonstrated by 1-yclopropyl-7-[8-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-azaspiro[3.4]oct-6-yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the lead compound nominated for further characterization and development. [ABSTRACT FROM AUTHOR]

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An efficient synthesis of densely 1,2,4‐triazoles has been achieved by [3+2] cycloaddition of nitrileimides with amidine hydrochlorides under transition metal‐free conditions. This method features mild reaction conditions, wide substrate scope and good functional group tolerance. A series of aryl, heterocyclic and alkyl substituted 3‐CF3‐1,2,4‐triazoles were synthesized smoothly under the promotion of NaHCO3 and yield up to 96%. In addition, both gram‐scale reaction and synthetic transformations are smoothly elaborated to indicate the utility of this reaction. [ABSTRACT FROM AUTHOR]

Complexes [Сu(NCS)2L3], [Сu(NO3)2L4] and [Cu(NCS)2L4]·L have been prepared by direct synthesis involving the interaction of metallic copper, ammonium salts NH4X (Х = NCS, NO3) and 1-tert-butyl-1H-1,2,4-triazole (L). Their composition and structure were determined by elemental analysis, single crystal X-ray analysis, and IR spectroscopy (range of 4000–500 cm–1). All the complexes showed mononuclear structure. In them triazole acts as a monodentate ligand, being coordinated by the N4 atom of the heterocycle. The NCS– and NO–3 anions display monodentate N- and O-coordination, accordingly. In [Сu(NCS)2L3], copper(II) cation has square-pyramidal environment of nitrogen atoms of two ligands L and two thiocyanate anions in the basal sites, and one nitrogen atom of ligand L in the apical position. In complexes [Сu(NO3)2L4] and [Cu(NCS)2L4]·L, copper(II) cations are octahedrally surrounded by nitrogen atoms of ligand L in the equatorial sites and by O or N atoms of corresponding anions in the axial positions.

A series of 5‐(4‐pyridyl)‐1,2,4‐triazoles hybrids with acetophenones and their oxime derivatives was rationally designed and synthesized as epidermal growth factor receptor (EGFR) kinase inhibitors. Initially, drug Likeness and pharmacokinetics properties of the prepared compounds were evaluated. Afterward, the prepared compounds were in vitro screened for their ability to inhibit the growth of the NCI‐60 human cancer cell lines where certain compounds showed moderate activity. Compounds 4e and 5b emerged as the most potent compounds in this series were further tested for their EGFR enzyme inhibition activity. They showed IC50 values of 0.14 and 0.18 µM, respectively, in comparison with Gefitinib as a reference with an IC50 value of 0.06 µM. Docking of compounds 4e and 5b into the binding site of EGFR tyrosine kinase was performed to explains their possible binding mode and to compare it with known inhibitors. Moreover, molecular dynamic simulations were estimated for deeper understanding of the binding mode of compounds 4e and 5b at the binding site of EGFR tyrosine kinase. The findings indicated that the novel ligands 4e and 5b were stable in the EGFR tyrosine kinase active site. [ABSTRACT FROM AUTHOR]

Derivatives of 1,2,4-triazole exhibit antimicrobial, anticonvulsant, anti-inflammatory, immunomodulatory, and other types of activity, which makes it possible to create effective drugs on their basis. Understanding the reaction mechanism for the formation of triazoles helps to control the chemical process and conduct targeted synthesis. Quantum-chemical modeling of the mechanism of interaction of diformylhydrazine with o- and p-aminophenols was carried out using the combined approach CCSD (T)/6–31+G*//B3LYP/6–311++G**. The elementary stages of the reaction, possible intermediate compounds, and transition states have been established. The obtained results have been compared with the data from NMR spectroscopy. [ABSTRACT FROM AUTHOR]

N‐heterocyclic carbene (NHC) complexes of gold(I/III) attained immense interest in catalytic organic transformations and as anticancer agents against several types of human cancers; however, their potential as electrocatalysts is scarce. The electrocatalytic oxygen evolution reaction was performed for the first time using pyridine‐functionalized NHC gold(I) binuclear metallacycles (8 and 9) possessing aptly designed ligand field. Complexes were prepared by the transmetallation of corresponding silver(I) NHC complexes, which were prepared by in situ deprotonation of pyridine and aryl substituted 1,2,4‐triazolium hexafluorophosphate salts (6 and 7) with Ag2O under dark. Both triazolium salts and binuclear gold(I) metallacycles were thoroughly characterised by NMR and ATR‐IR spectral and elemental analyses. A bromide salt 4 and a binuclear gold complex 9 were elucidated for structure by single crystal X‐ray diffraction analysis. Complex 9 possesses distorted linear coordination geometry around the gold atoms by the coordination of carbene carbon and pyridine nitrogen atoms bearing close Au–Au interaction (3.251 Å). The binuclear gold complexes 8 and 9 (along with 10 wt% conductive mesoporous carbon) were investigated as molecular electrocatalysts in oxygen evolution reaction (OER), which evidenced an oxygen evolution overpotential of 2.422 and 2.370 V versus reversible hydrogen electrode (RHE), respectively, to attain a current density of 10 mA.cm−2. The Tafel slope values of 40.9 and 30.4 mV dec−1 for 8 and 9, respectively, indicate the reaction mechanism involved and the suitability of these complexes as apt electrocatalysts for OER. The stability of the prepared molecular electrocatalysts was investigated by cyclic voltammetry and chronoamperometry techniques. [ABSTRACT FROM AUTHOR]

Some novel triazole-bearing acetamide derivatives 9-26 were synthesized starting from carvacrol. All synthesized compounds were characterized by FTIR, ¹H-NMR, 13C-NMR and MS data. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human chronic myelogenous leukemia K562, human neuroblastoma SH-SY5Y cell lines) were evaluated by MTT assay. Compounds were also tested on mouse embryonic fibroblast cells (NIH/3T3) to determine selectivity. Eighteen target compounds 9-26 were screened for their mPGES-1 and COX-1/2 inhibitory activities. Of these compounds, 26 (KUC16D425) showed the highest mPGES-1 inhibition at 10 µM. This compound has also been observed to induce apoptosis and inhibit cell migration in MCF-7 cells. In silico molecular docking calculations were performed to understand the binding interactions of compounds with target proteins. ADMET predictions were also done to evaluate drug-like properties of the novel compounds. [ABSTRACT FROM AUTHOR]

• A variety of pyrimidinyl oxa/thia/triazoles are prepared using trimethylsilyl isothiocyanate. • Docking results indicated that the compounds 3e, 5e, 7a have better docking scores than Chloramphenicol. • The compounds 3e, 5a, 5e have better docking scores than Fluconazole. • The unsubstituted, methyl and nitro substituted molecules showed greater antimicrobial activity. Organosilicon reagent-trimethylsilyl isothiocyanate, a common reagent for the development of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles was reported by the reaction with heteroaromatic acid hydrazides under conventional and ultrasonication methodologies in a polar protic solvent, ethanol under appropriate conditions. Molecular docking studies were performed with the X-ray crystal structures of the target molecules (PDB ID: 2w9s and PDB ID: 6f0e). The docking results indicated that H-bond interactions and hydrophobic interactions were responsible for the inhibition of protein. All 15 synthesized molecules showed excellent binding energy than the standard drugs. The compounds 3a, 3b, 3e, 5a, 5b, 5e and 7a exhibited low MIC values against S. aureus whereas 3a, 3b, 5a, 5b and 7a against B. subtilis. The compounds 5a, and 5b also displayed low MIC values against P. aeruginosa. The MBC of these compounds is 2×MIC, and is equal to standard drug, Chloramphenicol. The compounds 3a, 3b, 3e, 5a, 5b, 5d and 5e showed low MIC values against A. niger whereas 3a, 5a, 5b, 7a, 7b and 7e against P. Chrysogenum. The MFC is 2×MIC and is equal to standard drug, Fluconazole. The structure-activity relationship of the compounds revealed that unsubstituted, methyl and nitro substituted compounds showed greater antimicrobial activity than those with chloro and bromo substituents. [Display omitted] [Display omitted] [ABSTRACT FROM AUTHOR]

• Thirty novel triazole-urea hybrids were synthesized starting from paracetamol. • Synthesized compounds 9–38 were screened against pancreatic cancer cells. • Six derivatives showed effects on PANC-1 cells at sub-micromolar level. • Most active four compounds inhibited colony formation and gave rise to apoptosis. • Compounds 33 and 38 significantly downregulated eEF2K protein levels. Pancreatic cancer is one of the deadliest cancers with its highly aggressive and metastatic character and there is a huge unmet need for new drugs treating pancreatic cancer. In the present study, a series of 1,2,4-triazole-urea conjugates have been designed and synthesized as novel candidates of antiproliferative agents against pancreatic cancer cells. Among them, compounds 33, 34, 35 and 38 possesing IC 50 values between 0.231 and 0.488 μM against PANC-1 cells demonstrated the highest anti-proliferative activity. These compounds presenting the highest antiproliferative activity were evaluated for further biological studies. The same four compounds inhibited colony formation in pancreatic cancer cells dose dependently. Western blot study on the selected compounds showed that compounds 33 and 38 significantly reduced eEF2K protein levels in cancer cells. These compounds displayed an effective eEF2K activity suppression by down-regulated levels of unphosphorylated eEF2 in PANC-1 cells. Compounds 33, 34, 35 and 38 were also demonstrated to induce apoptosis and activate caspase 3/7. In silico studies were performed to predict the druggability and ADMET/ properties of the active molecules. In summary, 1,2,4-triazole-urea conjugates developed in this study represent a novel and promising lead structure with anticancer activity against pancreatic cancer achieved through eEF2K activity suppression. Compounds being referred to are the first "triazole-urea hybrid" molecules found to be effective against pancreatic cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel 1,2,4-triazoles tetrahydroisoquinoline hybrids 9a - g , 11a - g and 12a - g were designed and synthesized. • Inhibitory activities of all derivatives were evaluated in vitro towards COX-1 and COX-2 isoenzymes. • Compounds 9e , 9 g and 11f potently inhibited COX-2 with moderate selectivity indices. • Compound 11f displayed remarkable in vivo anti-inflammatory activity with negligible ulcerogenicity. Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a - g , 11a - g and 12a - g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e , 9 g and 11f are the most effective derivatives against COX-2 with IC 50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC 50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e , 9 g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e , 9 g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e , 9 g and 11f on both isoenzymes. [ABSTRACT FROM AUTHOR]

• A series of six new benzisoxazole tethered 1,2,4-Triazoles were synthesized and characterized. • The synthesized compounds were evaluated for in vitro anticancer and antimicrobial activity. Compound 6c with nitro substituent showed comparatively better activity. • Docking and density functional theory (DFT) studies reveal the reasons for the activity of the synthesized compounds. • Molecular dynamics (MD) simulation show the stability of the molecule. A novel series of six compounds, benzisoxazole tethered 1,2,4-triazoles were synthesized in five steps with good yields and characterized. 1H NMR, 13C NMR and mass spectrometry confirmed the formation of the derivatives. Antimicrobial activity was evaluated for the synthesized derivatives against three bacterial strains (Escherichia coli, Mycobacterium smegmatis and Staphylococcus aureus) and a fungal strain (Candida albicans). Similarly, anticancer activity was assessed against MCF-7 cell lines. The biological analysis disclosed that, out of the six compounds, derivative 6c showed better antimicrobial and anticancer activity with MIC of 12.5 μg/mL against Staphylococcus aureus and Mycobacterium smegmatis ; and IC 50 of 35.57 μM against MCF-7 cancer cell line. Theoretical evaluation provides an insight about ligand interaction with proteins, highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), electronegativity, hardness, softness, electrophilicity and neucleophilicity of the ligands via molecular docking and density functional theory (DFT) studies; this presents probable evidence for the biological activity of the derivatives. Molecular Dynamics (MD) simulation of the ligand 6c with protein HDAC7 (PDB ID: 3ZNR) was studied. [ABSTRACT FROM AUTHOR]

We report here a mechanochemical Cu‐catalyzed [3+2] cycloaddition of azinium‐N‐imines with nitriles under solventless grinding conditions. Various 1,2,4‐triazolos derivatives were obtained in 51–80% yields. The developed protocol offers advantages in functional‐group compatibility, scalability, no use of solvents, shorter reaction time, and without external heating. In addition, heterocyclic N‐imines such as quinolinium and isoquinolinium salts are also suitable substrates, resulting in the production of 1,2,4‐triazolo[1,5‐a]quinoline and 1,2,4‐triazolo[5,1‐a]isoquinoline derivatives under mechanochemical conditions. [ABSTRACT FROM AUTHOR]

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 μM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 μM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 μM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field. [ABSTRACT FROM AUTHOR]

In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure–activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04–1.5 μM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 μM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis, and characterization of a new series of 1,3,4-oxadiazole and 1,2,4-triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1 H NMR, 13 C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b , 6d , and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 μg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 μg/mL respectively. Particularly, the prepared scaffolds 8c , 8d , and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 μg/mL against A. flavus and 6d , 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 μg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H 37 Rv with MICs 3.26, and 6.48 μg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H-bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.Communicated by Ramaswamy H. Sarma.

One of the triazole tautomers, 1,2,4-triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti-inflammatory, anti-cancer, anti-bacterial, anti-tuberculosis, and anti-diabetic effects. Using computational simulations and models, we investigate the structure-activity relationships of 1,2,4-triazoles, showing how various modifications to the triazole core yield a variety of clinical therapeutic benefits. The review highlights the anti-inflammatory effect of 1,2,4-triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in-silico data that illuminate the triazoles' capacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4-triazole derivatives, with a focus on their potential efficacy against multi-drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti-diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness. Coordinated efforts are required to translate the efficacy of 1,2,4-triazole compounds in preclinical models into practical therapeutic benefits. Based on the information provided, it can be concluded that 1,2,4-triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and the medical community as a whole. This comprehensive research, which is further reinforced by in-silico investigations, highlights the great medicinal potential of 1,2,4-triazoles. Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Fluorinated heterocycles have attracted extensive attention not only in organic synthesis but also in pharmaceutical and medicinal sciences due to their enhanced biological activities than their non-fluorinated counterparts. Triazole is a simple five-membered heterocycle with three nitrogen atoms found in both natural and synthetic molecules that impart a broad spectrum of biological properties including but not limited to anticancer, antiproliferative, inhibitory, antiviral, antibacterial, antifungal, antiallergic, and antioxidant properties. In addition, incorporation of fluorine into triazole and its derivatives has been reported to enhance their pharmacological activity, making them promising drug candidates. This mini-review explores the current developments of backbone-fluorinated triazoles and functionalized fluorinated triazoles with established biological activities and pharmacological properties.

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin. However, the spectrum of antibacterial activity was quite different, as the new compounds showed no activity against Pseudomonas aeruginosa. Among the prepared and tested compounds, the broadest range of activity (five pathogens of the six in the ESKAPE panel) and the highest level of activity were demonstrated by 1-yclopropyl-7-[8-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-azaspiro[3.4]oct-6-yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the lead compound nominated for further characterization and development.

An efficient approach to the gram-scale synthesis of 3(5)-substituted, 1,3- and 1,5-disubstituted 1,2,4-triazole-derived building blocks is described. The key synthetic precursors – 1,2,4-triazole-3(5)-carboxylates (20 examples, 35–89% yield) were prepared from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydrochloride. Further transformations were performed following the convergent synthetic strategy and allowed the preparation of 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters (16 examples, 25–75% yield), 3(5)-substituted, 1,3- and 1,5-disubstituted carboxylate salts (18 examples, 78–93% yield), amides (5 examples, 82–93% yield), nitriles (5 examples, 30–85% yield), hydrazides (6 examples, 84–89% yield), and hydroxamic acids (3 examples, 73–78% yield). Considering wide applications of the 1,2,4-triazole motif in medicinal chemistry, these compounds are valuable building blocks for lead-oriented synthesis; they have also great potential for coordination chemistry. [ABSTRACT FROM AUTHOR]

The thermal behavior and luminescent properties of palladium(II) Pd(LR)2 complexes with 3-(2-pyridyl)-5-R-1,2,4-triazoles (LR , where R = H, Ph, Me) in cristalline state were studied. Analysis of the stationary and time-resolved Pd(LMe)2 photoluminescence spectra showed that the introduction of electron–donor methyl substituent into a coordinated ligand is accompanied by emission in the green range of the spectrum (fluorescence, λmax = 442 nm). Molecule aggregation in Pd(LH)2 and Pd(LPh)2 complexes leads to a bathochromic shift of emission (phosphorescence, 𝜆max = 712 and 691 nm). [ABSTRACT FROM AUTHOR]

Several substituted carboxamido pyrimidine derivatives (3a-g) were synthesized by conventional methodology. Structure of different substituted pyrimidines characterized by IR, 1H-NMR, Mass and elemental analysis (C, H, N). Furthermore, these substituted pyrimidines were screened for their different biologically activity viz. antibacterial, antifungal, insecticidal and anthelmintic activities. Some substituted pyrimidines displayed significant biological potential under applied pharmacological conditions. [ABSTRACT FROM AUTHOR]

Two new N-{[4-(3-aryl-4-sydnonylideneamino)-5-sulfanylidene-1H-1,2,4-triazol-3-yl]methyl}benzamides have been prepared by acid-promoted condensation reactions between 3-aryl-4-formylsydnones and N-[(4-amino-5-sulfanylidene-1H-1,2,4-triazol-3-yl)methyl]benzamide, and both have been crystallized as ethanol monosolvates. N-{[4-(3-Phenyl-4-sydnonylideneamino)-5-sulfanylidene-1H-1,2,4-triazol-3-yl]methyl}benzamide ethanol monosolvate, C19H15N7O3S·C2H6O (I), and N-({4-[3-(4-methylphenyl)-4-sydnonylideneamino]-5-sulfanylidene-1H-1,2,4-triazol-3-yl}methyl)benzamide ethanol monosolvate, C20H17N7O3S·C2H6O (II), differ only in the presence of a methyl group for (II) instead of a hydrogen atom for (I), and in both of them the ethanol component is disordered over two sets of atomic sites having occupancies of 0.836 (6) and 0.164 (6) in (I), and 0.906 (6) and 0.094 (6) in (II). Combinations of O—H...O and N—H...O hydrogen bonds link the molecules into cyclic, centrosymmetric four-molecule aggregates. Comparisons are made with the structures of some related compounds.

A novel facile method for the synthesis of 1-iso-propyl-1H-1,2,4-triazole (L) is described. This method is based on alkylation of 1,2,4-triazole with isopropyl alcohol in sulfuric acid media. It allows to synthesize the target product selectively with a yield of near 98 %. New coordination compounds [CuL2(Н2О)2Cl2] and [СuL4Cl2] were synthesized by the interaction of 1-iso-propyl-1H-1,2,4-triazole with copper(II) chloride dihydrate. Composition and structure of prepared complexes were studied by elemental analysis, X-ray diffraction analysis and IR spectroscopy. Both coordination compounds were found to be mononuclear complexes with octahedral coordination of copper atoms. Ligand L shows monodentate coordination through the triazole ring N4 atom. The analysis of the changes observed in the IR-spectrum of L under coordination with CuII atom was carried out. It was shown that IR spectroscopy can be used in order to study some structural peculiarities of azole complexes, in particular presence of bounded or coordinated water molecules and hydrogen bonds as well as localization of coordination bonds.

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

The reaction of 3-amino-4-[(3-nitro-1H-1,2,4-triazol-1-yl)-NNO-azoxy]furazan (4a) with 2,2,2-trifluoro-N-(4-nitrosofurazan-3-yl)acetamide (6) in the presence of dibromoisocyanuric acid (DBI) followed by removal of the protective trifluoroacetyl group gives 3-amino-4-({4-[(3-nitro-1H-1,2,4-triazol-1-yl)-NNO-azoxy]furazan-3-yl}-NNO-azoxy)furazan (5a). This compound contains a new explosophore (3-nitro-1H-1,2,4-triazol-1-yl)-NNO-azoxy moiety. The oxidation of the amino group in aminofurazan 5a with an excess N2O5 of resulted in the corresponding nitro derivative 5b. Aminofurazan 5a reacted with DBI to give the corresponding azo compound 5c. Compounds 5a,c may be of interest as energetic substances due to the combination of good thermal stability and high calculated enthalpy of formation (827 and 953 kcal kg−1, respectively). [ABSTRACT FROM AUTHOR]

Herein we report the synthesis of (E)‐3‐aryl‐2‐(5‐aryl‐4H‐1,2,4‐triazol‐3‐yl)acrylonitriles 3 a–k whose fluorescence properties have been investigated for the first time. A plausible reaction mechanism has been proposed to explain the total observed stereospecific formation of the E‐isomers of compounds 3 a–k. The fluorescence analysis of compounds 3a‐f has revealed relatively low values of the fluorescence emission quantum yields in a range of ∼1 to 10 %, depending in the nature of the substituents. [ABSTRACT FROM AUTHOR]

A series of 1,3 and 1,4-bis[5-(R-sulfanyl)-1,2,4-triazol-3-yl)benzene derivatives were synthesized by the reaction of isophthalic and terephthalic acid hydrazides with methyl and aryl isothiocyanates, followed by base-catalyzed cyclization and alkylation of the resulting bis-triazolethiols with alkyl bromides. The suggested obesity–colorectal cancer association initiated evaluation of the antiproliferative activity of the newly synthesized compounds against a panel of obesity-related colorectal cells and inhibition of pancreatic lipase (PL). In vitro enzymatic, colorimetric, and cell culture bioassays were carried out with respective reference agents. Among the tested compounds, 1,3-bis{5-[(4-bromobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzene showed clearly promising, though unselective, cytotoxicity in HT29, HCT116, SW620, CACO2, and SW480 cancer cells with a PL-IC50 value of 9.57±1.21 μM (<10 μM). Hence, the pharmacophores of most promising compounds can be druggable leads with a novel duality of antidiabesity–antineoplastic capacities and optimized potency and safety. Mechanistic examinations for hindrance of lipolysis catalysis and apoptogenic growth inhibition propensity may be attempted. [ABSTRACT FROM AUTHOR]

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 μM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 μM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 μM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.

In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure–activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04–1.5 μM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 μM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity.

A divergent efficient assembly of disubstituted 1,2,4-triazoles was established by cyclization of readily accessible N ′-nitro-2-hydrocarbylidene-hydrazinecarboximidamides with moderate to excellent yields under mild reaction conditions. This divergent synthetic strategy was achieved simply by varying the reaction conditions. Under acidic conditions, amino-1,2,4-triazoles were obtained by an intramolecular redox reaction involving the NO2 group. Control experiments and DFT studies revealed that this transformation proceeds via an intramolecular 1,3-hydride transfer pathway leading to HNO2 elimination. Under neutral conditions with water as the solvent, nitroimino-1,2,4-triazoles were obtained by oxidative intramolecular annulation under air. [ABSTRACT FROM AUTHOR]