Series Of Tetrazole Derivatives Research Articles

Synthesis, Characterization, and Evaluation of Tetrazole Derivatives with Pyrrole‐2,5‐Dione Moieties as Urease Inhibitors: Exploring Structure‐Activity Relationships and Computational Insights

AbstractA series of Tetrazole derivatives containing pyrrole‐2,5‐dione groups (5 a–e) were synthesized and comprehensively characterized using HRMS, FT‐IR, and 1H−, 13C‐NMR spectroscopic techniques. These compounds were evaluated for their ability to inhibit urease activity in vitro, demonstrating remarkable inhibitory potential with IC50 values ranging from 4.325±1 to 18.28±1 μM, surpassing the standard thiourea (IC50=17.386±1 μM). Notably, compounds 5 b (IC50=4.325±1 μM), 5 e (IC50=7.411±1 μM), 5 c (IC50=9.313±1 μM), and 5 a (IC50=10.46±1 μM) exhibited notably higher activity compared to the standard thiourea. In our exploration of the structure‐activity relationship (SAR), we investigated the impact of differently substituted aryl rings on inhibitory potential. Our results highlight the crucial role of substituent positioning on the aryl ring, independent of the nature of the substituents. Additionally, computational studies were conducted on all compounds, supporting our experimental findings. Molecular docking simulations revealed a strong correlation between biological evaluation results and computational predictions, affirming the promising inhibitory activity of the compounds.

Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase with Tetrazole Core.

The attractive biological actions of the eicosatrienoic acids (EETs) and endocannabinoids (eCBs) are terminated by means of enzymatic hydrolysis via soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) enzymes. Simultaneous inhibition of both enzymes is considered a novel approach in the treatment of inflammatory and neuropathic pain. In this study, a novel series of tetrazole derivatives as dual sEH/FAAH inhibitors were designed, synthesized, and biologically evaluated. Compounds 6c, 7d, and 8a, the most potent inhibitors against FAAH and sEH enzymes with acceptable IC50 values, significantly decreased carrageenan- induced paw edema 5h after carrageenan injection compared to the control group compound. In addition, compound 7d exhibited a significant reduction in pain scores compared to the control group. Docking studies showed that the presented dual inhibitors could bind to the essential residues in the catalytic sites of both enzymes. In silico prediction of several pharmacokinetic properties suggests that these dual inhibitors could potentially be orally active agents. These structures will be a valuable scaffold to develop soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.

Synthesis, Characterization and Antioxidant Evaluation of Some Tetrazole Derivatives

The present study introduces the synthesis of two series of tetrazole derivatives. Firstly, monosubstituted S1 was prepared by the reaction of ethyl 4-aminobenzoate with an amount of sodium azide and triethyl orthoformate in hot glacial acetic acid. Then, ethyl 4-(1H-tetrazol-1-yl) benzoate S1 was treated with a solution of hydrazine hydrate to prepare acetohydrazide S2. After that, tetrazole derivatives S3-S4 were prepared via the reaction of acetohydrazide S2 with various aromatic aldehydes. Secondly, compound 1,5-disubstituted tetrazole S5 was prepared from the reaction of aryl isothiocyanate with sodium azide in water presence. Then alkylation to compound S5 was made with ethyl chloroacetate to produce S6. In the next step, S6 was reacted with hydrazine hydrate to get acetohydrazide S7. Moreover, the produced S7 was reacted with some aromatic aldehydes for the synthesis of S8-S10. The structures of synthesized compounds were confirmed by the different available spectral methods, i.e., FTIR, 1H-NMR and 13C-NMR spectroscopy. The antioxidant activity of the synthesized compounds was evaluated by the use of 2,2-diphenyl-1-picrylhydrazyl. The results showed that compound S10 has the highest value as radical scavenging among the synthesized compounds.

Synthesis, fungicidal activity, and 3D-QSAR of tetrazole derivatives containing phenyloxadiazole moieties

In an effort to discover new agents with good fungicidal activities against CDM (cucumber downy mildew), a series of tetrazole derivatives containing phenyloxadiazole moieties were designed and synthesized. The EC50 values for fungicidal activities against CDM were determined. Bioassay results indicated that most synthesized compounds exhibited potential in vivo fungicidal activity against CDM. A CoMFA (comparative molecular field analysis) model based on the bioactivity was developed to identify some primary structural quality for the efficiency. The values of q2 and r2 for the established model were 0.791 and 0.982 respectively, which reliability and predict abilities were verified. Three analogues (q3, q4, q5) were designed and synthesized based on the model. All these compounds exhibited significant fungicidal activity on CDM with the EC50 of 1.43, 1.52, 1.77 mg·L−1. This work could provide a useful instruction for the further structure optimization.

Synthesis, X-ray characterization, Hirshfeld surface analysis and DFT calculations on tetrazolyl-phenol derivatives: H-bonds vs C–H…π/π…π interactions

Tetrazoles are nitrogen rich heterocycles with a broad spectrum of medicinal properties and potential for use as drugs. A significant number of FDA approved drugs incorporate the tetrazole moiety indicating the versatile pharmaceutical potential associated with this heteroaromatic skeleton. Owing to the higher number of nitrogen atoms and σ-lone pairs, tetrazoles offer the opportunity to control structural topology through non-covalent interactions. In this perspective, the present research is focused on the investigation of various non-covalent interactions in a series of tetrazole derivatives (5a–c) incorporating a linear aliphatic chain (eight to fifteen carbon atoms) at N-2 and with a phenol moiety at the only carbon atom of the tetrazole ring. The detailed X-ray crystallographic investigations revealed the formation of various supramolecular architectures employing non-covalent interactions of a diverse nature. Further insights into these intermolecular interactions were obtained using Hirshfeld surface analysis and DFT calculations focusing on the H-bonds, C–H…π and π–π interactions in the structures. These contacts have been characterized by combining the quantum theory of “atoms-in-molecules” (QTAIM) with the non-covalent interaction index (NCIplot).

Synthesis, Cytotoxic Analysis, and Molecular Docking Studies of Tetrazole Derivatives via N-Mannich Base Condensation as Potential Antimicrobials.

PurposeA new series of tetrazole derivatives, which are renowned antimicrobials possessing a five-membered aromatic heterocyclic group, are synthesized herein and subjected to antimicrobial and cytotoxicity screening.MethodsThe tetrazole derivatives were synthesized via ultrasonication using Mannich base condensation. Structural verification of the products was performed using IR, 1H NMR, and 13C NMR spectroscopy, as well as mass spectroscopic and elemental analyses. The compounds were then screened for antimicrobial and cytotoxic activity against HepG2 (liver), MCF-7 (breast), and HeLa (cervical) cell lines. Inter- and intra-molecular binding interactions were determined using molecular docking studies. The exact binding mode between the most active tetrazole derivatives (ie, 1b, 2a, and 2b) and the proteins (ie, 4OR7, 1AI9, and 4FM9) was established using Autodock Vina 1.1.2 software and compared to the binding mode of the reference compounds (ie, cefazolin, clotrimazole, and fluorouracil).ResultsCompound 1b was extremely active against Enterococcus faecalis relative to the positive control cefazolin. Compounds 1b and 1e were active against Candida albicans and Microsporum audouinii compared to the positive control clotrimazole in antifungal screening. The HepG2 (liver) and MCF-7 (breast) cancer cell lines were particularly susceptible to the synthesized compounds. Compared to the control compound fluorouracil, 2a and 2b were extremely active against all three cancer cell lines. Molecular docking studies showed that 2b exhibited higher binding affinity (−7.8 kcal/mol) to the 4OR7 protein than the control cefazolin (−7.2 kcal/mol).ConclusionGenerally, 1b, 2a, and 2b exhibited impressive inhibitory capabilities in antibacterial, antifungal, and cytotoxic screenings relative to the reference compounds. The results of the molecular docking studies and both the microbial and anticancer screenings indicate that these novel derivatives could be developed into potential therapeutic agents for medical applications.

Novel tetrazole-based selective COX-2 inhibitors: Design, synthesis, anti-inflammatory activity, evaluation of PGE2, TNF-α, IL-6 and histopathological study

To search for effective and selective COX-2 inhibitors, four novel series of tetrazole derivatives were designed based on bioisosteric replacement of SO2NH2 in celecoxib with tetrazole ring incorporating different central moieties as chalcone (2a-f), isoxazole (3a-c) or pyrazole (4a-c &5a-c). Target tetrazoles were synthesized and their structures were confirmed by spectroscopic techniques and elemental analyses. All target compounds were more selective for COX-2 isozyme than COX-1 when compared to standard drugs indomethacin and celecoxib. Compounds 3b, 3c, 4b, 4c, 5b and 5c exhibited potent in vitro COX-2 inhibitory activity (IC50 = 0.039–0.065 μM). Trimethoxy derivatives 3c, 4c and 5c acquired superior COX-2 selectivity index values (SI = 297.67–317.95) and were 1.1 fold higher than celecoxib (SI = 282.22). The most active six compounds were evaluated for their in vivo anti-inflammatory activity and serum levels of PGE2, TNF-α and IL-6 in addition to their ulcerogenic liability and histopathological profile. At a dose of 50 mg/Kg, compounds 3c and 5c showed better anti-inflammatory activity (% edema inhibition = 29.209–42.643) than celecoxib (% edema inhibition = 28.694–40.114) at different time intervals and were less ulcerogenic (UI = 0.123 and 0.11 in sequent) than celecoxib (UI = 0.167). Also, they displayed potent inhibitory effect on the production of PGE2 (% inhibition = 81.042 and 82.724 in sequent) greater than celecoxib (% inhibition = 79.666). Compound 5c decreased rat serum concentrations of both TNF-α (% inhibition = 55.349) and IL-6 (% inhibition = 61.561) in a comparable or better activity to celecoxib as reference drug. Finally, docking poses of the most active compounds showed strong binding interactions and effective overall docking energy scores explaining their remarkable COX-2 inhibitory activity.

Synthesis of tetrazole compounds as a novel type of potential antimicrobial agents and their synergistic effects with clinical drugs and interactions with calf thymus DNA

A series of tetrazole derivatives were synthesized and characterized by NMR, IR, MS and HRMS spectroscopy.

ZnS nanoparticles as an efficient and reusable heterogeneous catalyst for synthesis of 1-substituted-1H-tetrazoles under solvent-free conditions

An efficient and green protocol for the synthesis of 1-substituted-1H-tetrazoles through cyclization reaction of various primary amines, sodium azide, and triethyl orthoformate was described. In this method, a series of tetrazole derivatives was synthesized by using ZnS nanoparticles as an effective, recoverable, and reusable catalyst under solvent-free conditions. This strategy is a magnificent improvement for the synthesis of these heterocycles due to the non-acidic, clean, and solvent-free conditions via a solid recyclable catalyst. The catalyst was separated by simple filtration and reused seven times without significant loss of activity. The ZnS nanoparticles with high surface area and fine monodisperse particles were prepared using the simple microwave-assisted method without using any surfactant. The ZnS nanoparticle catalyst is a good candidate to replace bronsted acids and metal salts or other catalyst for the preparation of 1-substituted-1H-tetrazoles in high yields and has potential values for industrial applications.

Hybrid molecules of estrone: New compounds with potential antibacterial, antifungal, and antiproliferative activities

New hybrid molecules of estrone were synthesized as compounds indicating promising biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). The prepared molecules contained various heterocyclic units (pyridine, benzylsulfanyl derivatives of pyridine or derivatives of tetrazole) linked to estrone by n-heptyl bridges. The compounds with charge on molecule (the hybrid pyridinium or benzylsulfanylpyridinium salts) exhibited significant biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). On the other hand, the compounds not in the form of salts (ω-(1-phenyl-5-tetrazolylthio)heptylethers of estrone) were inactive. The antimycobacterial activities of three different series of tetrazole derivatives (i.e., the hybrid molecules with estrone, tetrazole-5-thiols, and 5-benzylsulfanyl-1-phenyltetrazoles) with the same substituents on phenyl ring were compared. Amongst them, the 5-benzylsulfanyl-1-phenyltetrazoles were the most potent.

Impact sensitivity and activation energy of pyrolysis for tetrazole compounds

Calculations with both DFT-B3LYP and semiempirical quantum chemical PM3 methods are carried out on a series of tetrazole derivatives and their metal salts to investigate the relationship between the relative order of impact sensitivity and activation energy of thermal decomposition. The results show that the relative order of sensitivity for the titled compounds can be predicted by examining the activation energy for breaking down of tetrazole ring. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 79: 350–357, 2000