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This study investigates the application of machine learning techniques to predict the toxicity of tetrazole derivatives, aiding in the identification of environmental risks from chemical exposure. Utilizing LD50 data sourced from the scientific literature and the ChemIDplus database, regression models were developed to forecast acute intraperitoneal toxicity in mice. A machine learning regression model for acute intraperitoneal toxicity in mice was constructed and validated on a test dataset, achieving high accuracy (R2 = 0.76 and MSE below 10−4) and surpassing most of the comparable literature models. Molecular descriptors were computed via Mordred software to explore quantitative structure–activity relationships, and additionally, the model's robustness was demonstrated by measuring the acute toxicity of tetrazole derivatives synthesized through the azido-Ugi reaction. Show less

The first comprehensive study of a series of seven mesoionic tetrazolylidene gold(I) chloride complexes (1-7) featuring a range of alkyl and aryl substituents (Me, t-Bu, iPr, Ph, Tol, Dipp, Mes) is reported. Three synthetic pathways enabling access to scarcely explored abnormal 1,3-disubstituted tetrazolium ligand precursors (L₁-L₇) have been established. All complexes are characterized by NMR spectroscopy, mass spectrometry, and elemental analysis, confirming their composition and purity. Single-crystal X-ray crystallography of six gold(I) complexes (1-6) reveals nearly linear coordination (176.49(11)-179.0(2)°) at the gold(I) center and a distinct geometric arrangement across the series. NMR stability studies with model nucleophiles L-cysteine (Cys) and glutathione (GSH) support the structural findings, demonstrating rapid and complete reaction of complexes 1-7 with thiols, as confirmed by ¹H NMR and ESI-MS. The antiproliferative activity of the obtained complexes (1-7) and selected precursors (L₂, L₃, L₅, L₇) has been evaluated using MTT assays against human A2780 (ovarian) and A549 (lung) cancer cell lines, alongside noncancerous VERO E6 kidney cells for comparison. Most of the complexes display high selectivity indices (SI^A2780 = 63.2-86.7) and potent antiproliferative effects in the low submicromolar range against A2780, outperforming cisplatin and matching the activity of auranofin. Overall, the results presented here demonstrate the potential of gold(I) tetrazolylidene-based complexes for medicinal applications. Show less

Tetrazoles are nitrogen-rich heterocycles that have attracted interest because of their numerous applications in pharmaceutical and medicinal chemistry. Four nitrogen atoms and one carbon atom make up these five-membered rings, which have special physicochemical and electrical characteristics, including acidity, resonance stabilization, and aromaticity. This article highlights the structure, spectroscopic characteristics, and physical and chemical characteristics of tetrazoles. It also describes how overlapping mechanisms, such as DNA replication inhibition, protein synthesis disruption, and oxidative stress induction, as well as similar therapeutic targets, enable inhibitors to serve as both antibacterial and anticancer agents. Tetrazole moieties have been fused with a range of pharmacophores, such as indoles, pyrazoles, quinolines, and pyrimidines, yielding fused derivatives that display substantial inhibitory activity against bacterial, fungal, and cancer cell lines, with certain compounds exhibiting efficacy comparable to or exceeding that of established therapeutic agents. The rational design of more efficacious tetrazole-based therapies is facilitated by structure-activity relationship analysis, which further highlights significant functional groups and scaffolds that contribute to increasing activity. We investigate the relationship between microbial inhibition and anticancer efficacy, opening up new avenues for the creation of multifunctional therapeutic agents. We hope that this study will offer significant guidance and serve as a valued resource for medicinal and organic researchers working on drug development and discovery in multifunctional therapeutics. The review involves a thorough investigation of tetrazole in recent years. Show less

In this work, three iridium(III) tetrazolato complexes have been used in antibacterial, biofilm removal and for other bioactivities for the first time. Notably, these iridium(III) tetrazolato complexes with high antibacterial, especially, Ir-CF3TAZ showed the best antimicrobial activity and the most effective hemolytic performance, which may pave the way to explore the value of the complexes for clinical applications in the future. Show less

Abstract Complex compounds [CuL(phen)(H2O)(NO3)]NO3 (1), [CuL(bipy)(NO3)2]·2EtOH (2), [CuL2(H2O)2 (NO3)2] (2a), [CuL(dmbipy)(NO3)2]·3EtOH (3), and [CuL2(NO3)2] (3a), where L is 3-(5-phenyl-2H-tetrazol-2-yl)pyridine, phen is 1,10-phenanthroline, bipy is 2,2′-bipyridine, and dmbipy is 4,4′-dimethyl-2,2′-bipyridine, are obtained and structurally characterized. It is shown that L behaves as the monodentate ligand being coordinated by the nitrogen atom of the pyridine ring. The coordination polyhedron made of copper atoms is a square pyramid in complexes 1 and 3, a distorted octahedron and a distorted square in complexes 2a and 3a respectively. Complex 1 is characterized by the elemental analysis, powder X-ray diffraction, and IR spectroscopy. Furthermore, its cytotoxic properties are studied on human larynx carcinoma (Hep2), breast adenocarcinoma (MCF7), and non-tumor human fibroblast (MRC5) cell lines. Complex 1 is shown to exhibit the pronounced cytotoxic action (LC50(Hep2) = 4.1±0.4 µM and LC50(MCF7) = 4.9±0.1 µM), however, does not exhibit selectivity against tumor cell lines (LC50(MRC5) = = 3.06 ±0.02 µM). Show less

Three cytotoxic copper(ii) complexes – [Cu2(bipy)2L4] (1), [Cu2(phen)2L4] (2) and [Cu2(dmphen)2L4]·2H2O (3) – were synthesized based on 5-methyltetrazole (HL) and 2,2′-bipyridine/1,10-phenanthroline derivatives. Show less

The preparation of a new series of Ir(III) tetrazolato complexes with the general formula [Ir(C^N)2(N^N)]0/+, where the ancillary ligand (N^N) is represented in turn by 2-pyridyltetrazolato (PTZ−), 2-pyrazinyltetrazolato (PYZ−) or 2-pyridyl 5-trifluoromethyl tetrazolato (PTZ-CF3−), is described herein. The design of the cyclometalated (C^N) ligands, namely 2-phenylisonicotinonitrile (ppyCN) and 2-(2,4-difluorophenyl)isonicotinonitrile (F2ppy-CN), features the well-known ppy- or F2ppy core, with the introduction of one electron-withdrawing cyano (–CN) group at the para position of the pyridyl ring. The photophysical and electrochemical properties of the new Ir(III) cyclometalated complexes have been investigated and the resulting data suggest how the (C^N) ligands significantly rule the luminescence behavior of the new complexes. Further blue or red shifting of the emission profiles of the neutral complexes was observed upon their conversion into cationic species through the regioselective addition of a methyl moiety to the coordinated tetrazolato ring. Lastly, neutral [Ir(F2ppy-CN)2(PTZ)] was used as an emissive phosphor for the fabrication of an OLED-type device. Show less

Three copper(II) complexes – [Cu2(bipy)2L4] (1), [Cu2(phen)2L4] (2) and [Cu2(dmphen)2L4]·2H2O (3) – were synthesized based on 5-methyltetrazole (HL) and 2,2′-bipyridine/1,10-phenanthroline derivatives. A crystallographic study revealed that complexes 1–3 have a binuclear structure with coordination polyhedron close to the square pyramid. Stability of the complexes in aqueous solution was studied by UV-Vis spectroscopy and conductometry. In vitro cytotoxicity study was carried out in 2D and 3D cell culture models and showed that complexes 2 and 3 possess cytotoxic activity against tumor cells (A549, Hep2, HepG2, MCF7) with LC50 values exceeding those of the medical drug cisplatin. At the same time, being less active, compound 1 has a selectivity index of 3.1 to hepatocellular carcinoma (HepG2 cell line) compared to non-tumor MRC5 cells. The Hoechst/Propidium iodide staining assay and ROS generation assay on Hep2 cells indicated that the cytotoxic effects of the complexes involved apoptosis induction without ROS accumulation. Show less

The [3+2] cycloaddition of sodium azide to nitriles to give 5-substituted 1H-tetrazoles is efficiently catalyzed by a Cobalt(II) complex (1) with a tetradentate ligand N,N-bis(pyridin-2-ylmethyl)quinolin-8-amine. Detailed mechanistic investigation shows the intermediacy of the cobalt(II) diazido complex (2), which has been isolated and structurally characterized. Complex 2 also shows good catalytic activity for the synthesis of 5-substituted 1H-tetrazoles. These are the first examples of cobalt complexes used for the [3+2] cycloaddition reaction for the synthesis of 1H-tetrazoles under homogeneous conditions. Show less

AbstractThe reaction of Re(CO)5Br with deprotonated 1H‐(5‐(2,2′:6′,2′′‐terpyridine)pyrid‐2‐yl)tetrazole yields a triangular assembly formed by tricarbonyl Re(I) vertices. Photophysical measurements reveal blue‐green emission with a maximum at 520 nm, 32 % quantum yield, and 2430 ns long‐lived excited state decay lifetime in deaerated dichloromethane solution. Coordination of lanthanoid ions to the terpyridine units red‐shifts the emission to 570 nm and also reveals efficient (90 %) and fast sensitisation of both Eu(III) and Yb(III) at room temperature, with a similar rate constant kET on the order of 107 s−1. Efficient sensitisation of Eu(III) from Re(I) is unprecedented, especially when considering the close proximity in energy between the donor and acceptor excited states. On the other hand, comparative measurements at 77 K reveal that energy transfer to Yb(III) is two orders of magnitude slower than that to Eu(III). A two‐step mechanism of sensitisation is therefore proposed, whereby the rate‐determining step is a thermally activated energy transfer step between the Re(I) centre and the terpyridine functionality, followed by rapid energy transfer to the respective Ln(III) excited states. At 77 K, the direct Re(I) to Eu(III) energy transfer seems to proceed via a ligand‐mediated superexchange Dexter‐type mechanism. Show less

Nickel(II) complexes of 1H-tetrazol-5-acetic acid (H2L) and oligopyridines (1,10-phenanthroline /2,2’-bipyridine derivatives) have been synthesized and characterized by physicochemical methods (elemental and thermogravimetric analysis, powder X-ray diffraction, and IR spectroscopy). The behavior of the complexes in solution was studied by UV–Vis spectroscopy, conductometry, and mass spectrometry. The stability of the complexes over 48 h in aqueous solution and in phosphate-buffered saline was demonstrated using UV–Vis spectroscopy. These compounds were investigated for their cytotoxic and cytostatic activity against HepG2 (hepatocellular carcinoma), and Hep2 (larynx carcinoma) human cancer cell lines. Cytotoxicity was also studied on human non-cancerous cell line MRC-5 (lung fibroblast). All the compounds did not show cytotoxic activity against the tested cell lines in 1–50-µM concentration range. However, compounds showed a cytostatic effect against HepG2 and Hep2 cell lines. The most pronounced cytostatic properties were found for the complex [Ni(dmphen)2L]·2C2H5OH·2H2O (1). In addition, we report three new crystal structures: [Ni(phen)2L]·H2O, [Ni(dmbipy)2L]·2C2H5OH, and [Ni(dmphen)2L]·2C2H5OH·2H2O, where L2– behaves as a bidentate ligand which is coordinated to the Ni(II) ion via N,O atoms. Show less

Nitrogen-rich energetic materials are of interest due to their potential use as high-energy-density materials in various applications. However, most compounds with a high nitrogen content show poor thermal stabilities, which may limit their use in certain applications. In pursuit of nitrogen-rich energetic materials, this study presents the synthesis and characterization of two nitrogen rich energetic compounds, namely 3-azido-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-amine (3, C₃H₃N₁₁, N%: 79.78) and (E)-1,2-bis(3-azido-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-yl) diazene (7, C₆H₂N₂₂, N%: 80.62). Compounds 3 and 7 have high thermal stabilities of 216 and 221 °C, respectively, making them the most thermally stable among metal-free primary explosives. Additionally, they show good energetic performance (v_D: 8345 m s^-1; P: 25.17 GPa; v_D: 8275 m s^-1; P: 25.57 GPa), making them potential candidates for metal-free high energy primary explosive. The energetic salts of 3 and 7 were also investigated. Among them, hydrazinium salt 11 displays better energetic performance (v_D: 9089 m s^-1; P: 30.55 GPa), which was on par with those of cyclotetramethylene tetranitramine (HMX). This research contributes to the exploration of nitrogen-rich energetic materials with potential applications in various fields. Show less

The unique physicochemical properties and fascinating bioisosterism of tetrazole scaffolds have received significant attention in medicinal chemistry. We report recent efforts using tetrazoles in drug design strategies in this context. Despite the increasing prevalence of tetrazoles in FDA-approved drugs for various conditions such as cancer, bacterial viral and fungal infections, asthma, hypertension, Alzheimer's disease, malaria, and tuberculosis, our understanding of their structure-activity relationships, multifunctional mechanisms, binding modes, and biochemical properties remains limited. We explore the potential of tetrazole bioisosteres in optimising lead molecules for innovative therapies, discussing applications, trends, advantages, limitations, and challenges. Additionally, we assess future research directions to drive further progress in this field. Show less

Mono or bis(tetrazole–thiolato) Pd(II) or Pt(II) complexes were obtained from the reactions of dialkyl Pd(II) or Pt(II) complexes with organic tetrazole–thiones (1-aryl- or 1-alkyl-1H-tetrazole-5-thiones) via deprotonation. In contrast, equimolar reactions of zerovalent Pt(0) or Pd(0) complexes with organic tetrazole–thiones afforded hydrido or bis(tetrazole–thiolato) Pt(II) and Pd(II) complexes, and cyclometallated Pt(II) or Pd(II) complexes bearing a tetrazole–thiolato moiety via oxidative addition, depending on the organic substituents on the tetrazole–thiones. In particular, variable (time and temperature)-dependent 1H-NMR spectra of the hydrido Pt(II) tetrazole–thiolates reveal an upfield shift of the hydride signal, suggesting N,S-coordination behavior of the tetrazole–thiolato ligand. Additionally, the N-CH2 signal corresponds to the six-membered ring of platinacycle or palladacycle exhibiting geminal coupling with multiple protons and PR3 ligands; these coupling values were further determined using 1H{31P} experiments. Finally, treatment of the alkyl Pd(II) tetrazole–thiolate or Pd(II) bis(tetrazole–thiolates) with organic tert-butyl isocyanide, thiophenol, and organic halides caused the selective insertion of the isocyanide into the Pd–C bond or deprotonation to afford a Pd(II) disulfide complex and substitution to afford new organic tetrazolyl sulfides. Show less

Developing a new generation of increased energy, stability, and easily applicable N-rich energetic materials to replace RDX and HMX has posed significant challenges over the past decade. This work presents the design and synthesis of a series of novel N-rich energetic materials (N1 to N3 series) based on the triazole–tetrazole system. Among these, the N3 series demonstrates exceptional detonation performance and stability. It is noteworthy that the N3-3 molecule has achieved the best overall performance among N-rich energetic materials, with an onset decomposition temperature of 302 °C and a detonation velocity of 9341 m s−1, which significantly surpasses that of HMX. Additionally, structural studies of the N1 molecule reveal that the positioning effect of the nitro group and steric hindrance within the molecule disrupt the planar characteristics of the triazole–tetrazole system. In contrast, the amino group in the N3 series enhances molecular planarity, facilitating the formation of large conjugated systems and extensive hydrogen bond networks in N-rich energetic materials. This approach effectively enhances the stability of energetic material molecules and offers valuable insights for the development and design of stable N-rich energetic compounds. Show less

Neurological disorders are the leading cause of a large number of mortalities and morbidities. Nitrogen heterocyclic compounds have been pivotal in exhibiting wide array of therapeutic applications. Among them, tetrazole is a ubiquitous class of organic heterocyclic compounds that have attracted much attention because of its unique structural and chemical properties, and a wide range of pharmacological activities comprising anti-convulsant effect, antibiotic, anti-allergic, anti-hypertensive to name a few. Owing to significant chemical and biological properties, the present review aimed at highlighting the recent advances in tetrazole derivatives with special emphasis on their role in the management of neurological diseases. Besides, in-depth structure-activity relationships, molecular docking studies, and associated modes of action of tetrazole derivatives evident in in vitro, in vivo preclinical, and clinical studies have been discussed. Show less

Twelve Re(I) tricarbonyl diimine (2,2′-bipyridine and 1,10-phenanthroline) complexes with thiotetrazolato ligands have been synthesised and fully characterised. Structural characterisation revealed the capacity of the tetrazolato ligand to bind to the Re(I) centre through either the S atom or the N atom with crystallography revealing most complexes being bound to the N atom. However, an example where the Re(I) centre is linked via the S atom has been identified. In solution, the complexes exist as an equilibrating mixture of linkage isomers, as suggested by comparison of their NMR spectra at room temperature and 373 K, as well as 2D exchange spectroscopy. The complexes are photoluminescent in fluid solution at room temperature, with emission either at 625 or 640 nm from the metal-to-ligand charge transfer excited states of triplet multiplicity, which seems to be exclusively dependent on the nature of the diimine ligand. The oxygen-sensitive excited state lifetime decay ranges between 12.5 and 27.5 ns for the complexes bound to 2,2′-bipyrdine, or between 130.6 and 155.2 ns for those bound to 1.10-phenanthroline. Quantum yields were measured within 0.4 and 1.5%. The complexes were incubated with human lung (A549), brain (T98g), and breast (MDA-MB-231) cancer cells, as well as with normal human skin fibroblasts (HFF-1), revealing low to moderate cytotoxicity, which for some compounds exceeded that of a standard anti-cancer drug, cisplatin. Low cytotoxicity combined with significant cellular uptake and photoluminescence properties provides potential for their use as cellular imaging agents. Furthermore, the complexes were assessed in disc diffusion and broth microdilution assays against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Escherichia coli (E. coli), and Pseudomonas aeruginosa (P. aeruginosa) bacterial strains, which revealed negligible antibacterial activity in the dark or after irradiation. Show less

In this study, a new ligand, 5-(4-pyrimidinecarboxamido)-1H-tetrazol (4-H2pat), was synthesized by connecting the pyrimidine group and tetrazole group through an amide bond for the first time, aiming to construct new POM-based metal–organic complexes (POMOCs). By using the ligand 4-H2pat, two new POMOCs, [Cu4(4-pat)2(μ2-OH)(CrMo6(OH)6O18)(H2O)3]·2H2O (1) and [Cu2(4-pat)(β-Mo8O26)0.5(H2O)3] (2), were successfully synthesized under solvothermal and hydrothermal conditions, respectively. The structures were characterized by single crystal X-ray diffraction analysis, IR spectroscopy and powder X-ray diffraction (PXRD). In complex 1, the 1D [Cu4(μ2-OH)(4-pat)2]n3n+ metal–organic chains were connected by μ2-bridging [CrMo6(OH)6O18]3− (CrMo6) anions to construct a 2D layered structure. In complex 2, the 2D [Cu2(4-pat)]n2n+ metal–organic grid framework was consolidated by the μ4-bridging [β-Mo8O26]4− (Mo8) anions. The use of two different POM anion clusters results in the formation of two diverse 2D framework structures. Complexes 1 and 2 can effectively catalyze the oxidation of methyl phenyl sulfide as non-homogeneous catalysts with 97% and 95% conversions, respectively. They can also be used as electrocatalysts to prepare bulk-modified electrodes for detecting Cr(VI) and Fe(III) ions with low detection limits. In addition, the effects of different POMs on the structures and catalytic/electrocatalytic performances of the title complexes were discussed. Show less

Abstract The complex [Zn(Phen)(H2O)L2] (I), where HL is 5-benzyltetrazole, Phen is 1,10-phenanthroline, was synthesized. The compound was characterized by standard physicochemical methods (elemental analysis, powder X-ray diffraction, IR spectroscopy). According to X-ray diffraction data (CCDC no. 2220597), zinc coordination environment in the crystal structure of I corresponds to a distorted trigonal bipyramid. The ligand HL is monodentate and is coordinated via tetrazolate ring nitrogen. The stability of complex I was studied by NMR spectroscopy in DMSO. The cytotoxic properties of the compound were assessed against HepG-2 (hepatocellular carcinoma) and MRC-5 (noncancerous human fibroblasts) cells. Complex I exhibits weak cytotoxic properties in the studied concentration range (1–100 µM). Show less

1,10-Phenanthroline and 2,2′-bipyridine based copper(ii) complexes with 1H-tetrazole-5-acetic acid as anticancer agents selective against hepatocellular carcinoma cells have been synthesized. Show less

Five coordination compounds [Cu2(Bipy)2L4]·C2H5OH (Iа, Ib), [Cu2(Dmbipy)2L4] (II),[Cu2(Phen)2L4]·H2O (IIIa), [Cu2(Dmphen)2L4] (IVa), and [Cu2(Phendione’)2L4]·2C2H5OH·2H2O (V) aresynthesized from 5-(4-chlorophenyl)-1H-tetrazole (HL), where Bipy is 2,2'-bipyridine, Dmbipy is 4,4'-dimethyl-2,2'-bipyridine, Phen is 1,10-phenanthroline, Dmphen is 4,7-dimethyl-1,10-phenanthroline, andPhendione’ is 6-ethoxy-6-hydroxy-1,10-phenanthrolin-5-one. The crystal structures of the complexes aredetermined by X-ray diffraction (XRD) of single crystals (CIF files CCDC nos. 2225368 (Ia), 2225369 (Ib),2225370 (II), 2225372 (IIIa), 2225373 (IVa), and 2225371 (V)). The compounds are binuclear due to thebridging function of the tetrazolate anion, and the coordination number of copper is five in all synthesizedcomplexes. The cytotoxic activity of the complexes against the Hep2 and HepG2 cancer cell lines and noncanceroushuman fibroblasts MRC-5 is studied. The complexes exhibit pronounced cytotoxic properties, andcompound V has the maximum selectivity index with respect to the cancer cells. Show less

Herein, we present the synthesis, characterization, and in vitro investigation of cytotoxic activity against cancer (HepG-2, MCF-7) and non-cancerous (Hek-293, MRC-5) cell lines of six copper(II) complexes with 1H-tetrazole-5-acetic acid (H2L) and secondary ligands, such as olygopyridines (dmphen – 4,7-dimethyl-1,10-phenanthroline, phendione – 1,10 phenanthroline-5,6-dione, 5-Cl-phen – 5-chloro-1,10-phenanthroline, phen – 1,10 phenanthroline, dmbipy – 2,2′-bi-4-picoline, bipy – 2,2′-bipyridine). These compounds were characterized by powder X-ray diffraction, IR spectroscopy, elemental, and thermogravimetric analysis. The behavior of the complexes in solution was studied by optical spectroscopy, conductometry, and EPR. The DNA binding constant has been obtained for complex 5 using UV–vis spectroscopy. The antimicrobial activity of the complexes has been investigated against E. coli, S. aureus, P. italicum, and C. steinii. In addition, eight new crystal structures were obtained: [Cu(5-Cl-phen)L]n·0.5DMSO·1.5H2O (3a), [Cu(phen)L]n·2.5nH2O (4·2.5nH2O), [Cu3(phen)2(H2O)(HL)2L2]n·6nH2O (4a), [Cu(dmbipy)L]n (5), [Cu(dmbipy)(HL)2] (5a), [Cu3(dmpiby)2(HL)2L2]n·2nH2O·2nC2H5OH (5b), [Cu(bipy)L]n (6), and [Cu(bipy)(H2O)L] (6a). Show less