Tetrazole Group Research Articles

Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn2+) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2', suggesting interference with SARS-CoV-2's spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies.

Taming of Triazole, Tetrazole, and Azido Groups: Nitrogen-Rich Energetic Materials with High Thermal Stabilities.

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 (vD: 8345 m s-1; P: 25.17 GPa; vD: 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 (vD: 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.

Mesoscale Acid-Base Complexes Display Size-Associated Photophysical Property and Photochemical Activity.

The properties of single molecules and molecular aggregates can differ dramatically, leading to a long-standing interest in mesoscale aggregation processes. Herein, a series of acid-base molecular complexes is developed by using a tetraphenylethylene-backboned fluorophore, and investigated the photophysical properties and photochemical activities at different aggregation length scales. This fluorophore, with two basic diethylamine groups and two acidic tetrazole groups, exhibits sparse solubility due to multivalent interactions that cause infinite aggregation. The addition of a third acid leads to the formation of fluorophore/acid complexes with good dispersibility and colloidal stability. This assembly process can be controlled by the use of different acids and their stoichiometry, resulting in aggregates ranging in size from a few to hundreds of nanometers. A crystalline structure is obtained to illustrate the complex properties of the acid-base network. Unlike the single molecule, these complexes show a trend of size-related properties for photoluminescence efficiency and photochemical activity. As the amount of acid added increases, the size of the complexes decreases, the aggregation effect of the complexes on fluorescence emission increases, and the rates of the oxidative photocyclization and photodecomposition slow down. This work may help to understand size-controlled molecular materials at the mesoscale for functional design.

Innovative synthesis of drug-like molecules using tetrazole as core building blocks.

Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.

Naphthalene Tetrazole-Based Nickel Metal-Organic Framework as a Filler of Polycarbonate Membranes to Improve CO2 and H2 Separation.

A tetrazole-naphthalene linker was used to prepare a nickel MOF (metal-organic framework) (NiNDTz) with interesting properties: a specific surface area SBET of 320 m2g-1 (SLangmuir 436 m2g-1), high thermal stability (Tdonset = 300 °C), and CO2 uptake of 1.85 mmolg-1, attributed to the tetrazole groups to be used as fillers in gas separation membranes. The role of these groups was crucial in the mechanical properties of mixed membranes prepared using polycarbonate as a polymer matrix, providing a very homogeneous filler distribution and also in the gas separation properties since a simultaneous increase in permeability and selectivity was achieved, especially in the hybrid membrane containing 20% filler (PC@NiNDTz-20%). This membrane exhibited an excellent balance between permeability (P) and selectivity (α) with an increase in the permeability of CO2 and H2, 177 and 185%, respectively, and improvements in the selectivity of these gases against greenhouse gases such as methane and ethylene (between 15 and 28% improvement). These results make this membrane competitive to deal with separations in which these gases are involved, and are of special interest for the H2/CH4 separation since it clearly improves the performance of pure PC and no better PC-based membranes have been reported in the literature for this separation.

Spidroin-Inspired Hierarchical Structure Binder Achieves Highly Integrated Silicon-Based Electrodes.

As a promising component for next-generation high energy lithium-ion batteries, silicon-based electrode has attracted increasing attention by virtue of ultrahigh theoretical specific capacities. Nevertheless, fast capacity fade posed by tremendous silicon-based electrode volume changes during cycling remains a huge challenge before large-scale applications. Herein we develop an aqueous-oil binary solution based blend (AOB) binder characterized by a spidroin-like hierarchical structure for tolerating huge volume change of silicon-based electrodes. In AOB binder, the hydrophobic tetrazole groups-containing polymer (donate as PPB) and water-soluble amorphous poly(acrylic acid) mimicks the β-sheet and α-helix structure of spidroin, respectively. Benefitted by such biomimetic design, AOB binder enables both high tensile strength and elasticity, and strong electrode adhesion, therefore apparently stabilizing silicon-based electrode structure and rendering prolonged electrode cycle life. Such a strategy endows a 3.3 Ah soft package cells assembled with Si/C composite anode and NCM811 cathode with a discharge specific capacity of 2.92 Ah after 700 cycles. This work marks a milestone in developing state-of-the-art silicon-based electrodes towards high energy density lithium battery applications. This article is protected by copyright. All rights reserved.

Copper MOFs performance in the cycloaddition reaction of CO2 and epoxides

The research in advanced materials for effective CO2 capture and conversion is an imperative duty for the next years. In this sense MOF materials are being intensively tested for this purpose. Herein, seven different copper-based MOF materials with different functional organic groups in their linkers have been assessed to comprehend some structural features that influence the CO2 transformation via cycloaddition reaction with epoxides: Cu-URJC-1 (tetrazole group), Cu-URJC-8 (primary amine group), Cu-MOF-74 (hydroxyl group), JUC-62 (azo group), PCN-16 (triple bond group), HNUST-1 (amide group) and HKUST-1. When epichlorohydrin was used as a substrate, Cu-URJC-8 produced the best epoxide conversion (90%) and selectivity to cyclic carbonate (>99%), despite showing a modest surface area. This result can be explained by the higher basicity of primary amines than other basic functional organic groups of the MOFs. However, when styrene oxide was used as substrate, Cu-URJC-1 led to the best reaction results with a conversion and selectivity toward cyclic carbonate of 60 and 86%, respectively. This result was achieved because this material presents the synergic effect of having in its flexible structure 12 Å channels, that favors the styrene oxide diffusion, and a great number of basic nitrogen atoms, which can increase the reactivity of carbon dioxide. In summary, the presence of nitrogen atoms in the organic linker increases the CO2 conversion by promoting the reactivity of this molecule.

Effect of Cyano and Tetrazole Side Groups on the Photophysical and Chelating Properties of Anthracene‐Based Polymers

AbstractThis paper covers the conception of new soluble and filmogene conjugated polymers (PAnSCN and PAnSCN‐Tet) for heavy metal sensing application. The prepared materials are based on the highly emissive anthracene chromophore and contain tetrazole and/or cyanide groups in their molecular chain backbones. The effect of the electron withdrawing groups on photophysical properties and the chelating abilities of the elaborated organic materials were investigated. The optical analysis shows that the CN groups reduced slightly the optical band‐gap of the polymer, however the steric hindrance of tetrazole units dominates their electronic effects leading to a blue‐shift of its absorption spectrum. Also, the electrochemical study reveals a considerable electronic affinity increase by 0.84 eV when passing from PAnSCN into PAnSCN‐Tet. DFT calculations has been employed to estimate the optimized macromolecular structure of both polymers and a notable change in geometry in terms of planarity was observed depending on the incorporated withdrawing group. The synthesized polymers were studied as optical sensors. The changes in the photoluminescence intensity were used to evaluate the binding affinity of the two materials to different metal ions. The obtained results showed considerable decrease in photoluminescence (quenching) responses with Mn2+ cations a short time after adding the cations to both polymer solutions with better sensitivity and selectivity in the case of the PAnSCN‐Tet.

New pyrimidine-amide-tetrazole ligand derived polyoxometalate-based copper complexes as catalysts for sulfide-sulfoxide transformation and electrochemical sensors

A new organic ligand was constructed by linking pyrimidine and tetrazole group through amide bond and used to build POM-based metal–organic complexes that can be used as catalysts for the catalytic oxidation of sulfides and electrochemical sensors.

A DFT approach towards understanding the thermal stability of TKX-50 and their key precursors through band gaps and MESP.

TKX-50 (dihydroxylammonium 5,5'-bistetrazolate-1,1'-dioxide) is a recent time invention by Klapotke et. al. in the field of high energy materials, and it outperforms all the existing materials by means of performance parameters. It is rising as potential energetic material due to favorable thermal insensitivity, low toxicity and safe handling. The decomposition temperature (Tmax) values of precursors such as glyoxime (I), 1,2-dichloroglyoxime (II), 1,2-diazidoglyoxime (III), and bistetrazoledihydroxide (IV) and ending products TKX-50 (V) and ABTOX (VI) have been attempted to correlate with the results obtained from molecular electrostatic potentials and band gaps calculated from the difference of ionization potential and electron affinity. The molecular electrostatic potential values of azido attached -NO group of III are much less than that of hydro/chloro attached -NO group of I/II and that of tetrazole groups IV, V, and VI. The band gaps calculated from stability trend in the increasing order of III < II < I < IV < V < VI are well corroborated with stability trend drawn from experimentally determined decomposition temperatures. Further, employing conceptual density functional theory (DFT) molecular descriptors, band gap values were calculated via the difference of ionization potential and electron affinity to understand the thermal stability of TKX-50, ABTOX, and its precursors.

Fluorogenic detection of mercury ion in aqueous environment using hydrogel‐based AIE sensing films

AbstractA “turn‐on” fluorescent sensing strategy was developed for ultrasensitive detection of heavy metal mercury ion (Hg2+) directly in water. It utilized an aqueous soluble aggregation‐induced emission (AIE)‐active probe, named 1,1,2,2‐tetrakis(4‐(1H‐tetrazol‐5‐yl)phenyl)ethene (TPE‐4TA), composing of a luminescent tetraphenylene core and multiple anionic tetrazolate spawns. The probe retained dark when molecularly dissolved in water. However, mercury ions can ligate with multiple tetrazolate groups to form infinite coordination polymer particles spontaneously, thus inducing a fluorogenic AIE response for in situ analysis. Moreover, by embedding this AIE sensing molecules in a hydrophilic polyvinyl alcohol substrate, the resulting hydrogel film allowed in situ detection of Hg2+ on a laser‐induced fluorescence analysis setup in aqueous environment. This strategy worked effectively in common aqueous environments with pH from 4 to 7.5 and showed high sensitivity (limit of detection down to 0.38 ppb/1.9 nM), good selectivity and a wide linearity range for quantification. This work may lead to a reliable and promising platform for on‐site environmental water analysis.

Self‐Organized Small Molecules in Robust MOFs for High‐Performance Perovskite Solar Cells with Enhanced Degradation Activation Energy

AbstractA brand new strategy to improve the volatility and disordered arrangement of small organic molecule additives within doped perovskite solar cells through the construction of metal–organic frameworks (MOFs) is proposed. The Zn‐TTB, self‐assembling from Zn2+ and 1‐(triazol‐1‐ly)‐4‐tetrazol‐5‐ylmethyl)benzene (TTB), inherits and arranges triazole and tetrazole groups and forms a long‐chain structure surrounding metal nodes. The perovskite precursors grow along with the skeleton of Zn‐TTB and produce a macromolecular intermediate phase via the MOFs‐perovskite interconnection, subsequently forming superior perovskite films with enhanced stability with respect to molecular additives, as evidenced by in situ thermogravimetry‐Fourier transform infrared spectroscopy measurements. Thermal analyses suggest MOF‐doping increases degradation activation energies by up to &gt;174.01 kJ mol–1 compared to the reference sample (162.45 kJ mol–1). Zn‐TTB‐modified devices exhibit promising efficiencies (up to 23.14%) and operational stability in unencapsulated state, even under constant solar light illumination.

Oteseconazole: First Approval.

Oteseconazole (VIVJOA™) is an orally administered azole antifungal agent developed by Mycovia Pharmaceuticals for the treatment of fungal infections. It inhibits cytochrome P450 (CYP) 51, thereby affecting the formation and integrity of the fungal cell membrane, but has a low affinity for human CYP enzymes due to its tetrazole metal-binding group. Oteseconazole is the first agent to be approved (in April 2022) for recurrent vulvovaginal candidiasis (RVVC) in the USA, where it is indicated to reduce the incidence of RVVC in females with a history of RVVC who are NOT of reproductive potential. Clinical development for the treatment of onychomycosis, and invasive and opportunistic infections is ongoing. This article summarizes the milestones in the development of oteseconazole leading to this first approval for reducing the incidence of RVVC in females with a history of RVVC who are NOT of reproductive potential.

Uncoordinated tetrazole ligands in metal–organic frameworks for proton‐conductivity studies

AbstractZr‐based metal–organic frameworks (MOFs) were modified with pendant tetrazole ligands for proton conductivity studies. Although tetrazolate ligands coordinated to metal cations have been widely utilized to construct MOFs or porous coordination polymers, to date, the use of uncoordinated tetrazole groups in MOFs has been limited. In this study, a benzene‐1,4‐dicarboxylic acid with pendant tetrazole groups (BDC‐N4) was synthesized and used to prepare a Zr‐based UiO‐66 MOF using a mixed‐ligand strategy. The tetrazole‐functionalized UiO‐66‐N4 was compared to MOFs containing other acidic functional groups (hydroxyl, carboxylic acid, and sulfonic acid) with respect to their proton conductivities and acidities (calculated pKa). Interestingly, UiO‐66‐N4 showed a significant decrease in the activation energy with increase in the amount of added tetrazole groups, suggesting the Grotthuss proton conduction mechanism for uncoordinated tetrazole‐containing MOFs.

Discovery of a new generation of angiotensin receptor blocking drugs: Receptor mechanisms and in silico binding to enzymes relevant to SARS-CoV-2

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as “bisartans” is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2+ domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681–686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric “warhead” of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

Understanding the Binding Mode of Losartan Upon GPVI via a Molecular Simulation Study

Glycoprotein VI (GPVI) plays an important role in platelet aggregation, and inhibition of GPVI may block thrombosis with a low bleeding risk, thus making GPVI a promising antithrombotic target. In this paper, the binding mode of losartan, a known GPVI inhibitor, was investigated using molecular docking and molecular dynamics methods as well. Docking results can determine the location site of the phenyl tetrazole group of losartan, but the direction of the two substitute groups on imidazole ring is uncertain. Therefore, two sample conformations were selected, and long-time molecular dynamics simulations were carried out. The rotatable bond of C–N connecting the imidazole ring and the middle benzene ring was monitored during the simulation. The results showed that this dihedral angle is mostly distributed at about [Formula: see text] for both systems, implying that this conformation is the dominant conformation. The switchable conformation may be the reason for low activity of losartan to GPVI. Losartan1 system was well equilibrated and selected as the receptor to perform drug repurposing screening, and several drugs with a similar binding mode as losartan were identified. Our study may enhance the mechanism understanding of GPVI receptor, giving insights into the design and discovery of novel GPVI inhibitors.

Synthesis of new Tetrazole based-semiconducting polymers for optoelectronic application: Study of the effect of anthracene group on photophysical properties

This work aims to synthesize and characterize a new semiconducting anthracene-based polymer Poly-Tet-An-Is and its analogue anthracene-free Poly-Tet-Is. The two materials contain the Tetrazole group in the backbone and the Isosorbide group in the side chain. The polymers have been prepared through click chemistry polymerization. The effect of the anthracene group on photophysical and electrochemical proprieties, is investigated. Thermal characterization shows that the two polymers have a good thermal stability up to 330°C. The optical properties of these materials were explored by UV-vis absorption and photoluminescence spectroscopies. The UV-vis absorption spectrum reveals that the presence of anthracene group in the backbone limits the intramolecular interaction in dilute solution and the π-stacking in the thin film by its steric effect. The photoluminescence spectra reveals that the polymer Poly-Tet-Is has a blue emission in dilute solution and thin film. However, the Poly-Tet-An-Is emission shifted from blue to green, going from dilute solution to the thin film, respectively. Density Functional Density (DFT) has been used to evaluate the macromolecular geometry of both polymers and showed a remarkable variation in geometry depending on the incorporation of the anthracene group. An analysis by RDG was carried out on the optimized structures of the two organic materials in order to prove the intarmolecular interactions and its influence on their geometries.The interested photophysical properties of our new materials as well as the presence of the Tetrazole group in the main chain, could be applied in the design of chemical sensors and blue Organic light-emitting diode (OLED).

Isomeric tetrazole-based organic dyes for dye-sensitized solar cells: Structure-property relationships

Two new organic dyes (SD-1 and SD-2) featured with donor–π–acceptor architecture were synthesized and applied to dye-sensitized solar cells (DSSCs). In these sensitizers, an azo bridge π-spacer is used to link the phenyl tetrazole acceptor with 2-naphthol donors. To amplify the pull-push effect, the nitro group was connected to the electron acceptor group. The effect of the position of the nitro group and the tetrazole group linked to the benzene ring on the photophysical, electrochemical, and photovoltaic properties of sensitizers are investigated in detail. They all show intense UV–Vis absorptions around 400 nm and 510 nm. The co-sensitizations of SD-1 and SD-2 with ruthenium complex HD-2 are further evaluated and the co-sensitization results were compared with DCA. Co-sensitization of HD-2 with SD-2 was more efficient than found for co-sensitization with DCA (5.6% higher). Moreover, the influences of molecular geometry on charge recombination and photovoltaic performance of DSSCs were systematically investigated by incident photon to current efficiency (IPCE) spectra and electrochemical impedance spectroscopy (EIS) investigations.

The determination of two analogues of 4-(azidomethyl)-1,1'-biphenyl as potential genotoxic impurities in the active pharmaceutical ingredient of several sartans containing a tetrazole group

4'-(azidomethyl)-[1,1'-biphenyl]-2-carbonitrile (GTI-azide-1) and 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (GTI-azide-2) are potentially genotoxic impurities that can be present at trace levels in the active pharmaceutical ingredients and drug products of sartans containing a tetrazole group. A method of high-performance liquid chromatography coupled with mass spectrometry, that allows the determination of those genotoxic impurities at sub-ppm level relative to the active pharmaceutical ingredient, was developed.The method utilises a very efficient liquid chromatograph Waters Acquity I-Class coupled with a highly sensitive tandem mass spectrometer Xevo TQ-XS. The separation was achieved on a column Acquity UPLC BEH Shield RP18 1.7 μm employing a linear elution gradient. The mass spectrometer was used with a heated electrospray ionization. The method was found to be sufficient in terms of sensitivity, linearity, precision, accuracy, selectivity and robustness and is easily applicable in the pharmaceutical quality control environment. The method allows for accurate quantification of both impurities GTI-azide-1 and GTI-azide-2 at levels below 1/10th of the specification limit, which is crucial in the context of pharmaceutical analysis. The limit of quantification was determined to be 0.033 ppm and 0.025 ppm for GTI-azide-1 and GTI-azide-2, respectively.

Advances in anti-fungal therapies.

Anti-fungal therapies remain sub-optimal, and resistant pathogens are increasing. New therapies are desperately needed, especially options that are less toxic than most of the currently available selection. In this review, I will discuss anti-fungal therapies that are in at least phase I human trials. These include VT-1161 and VT-1598, modified azoles with a tetrazole metal-binding group; the echinocandin rezafugin; the novel β-1,3-d-glucan synthase inhibitor ibrexafungerp; fosmanogepix, a novel anti-fungal targeting Gwt1; the arylamidine T-2307; the dihydroorotate inhibitor olorofim; and the cyclic hexapeptide ASP2397. The available data including spectrum of activity, toxicity and stage of clinical development will be discussed for each of these so clinicians are aware of promising anti-fungal agents with a strong likelihood of clinical availability in the next 5–7 years.