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Tetrazole, a bioisostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects. Tetrazole derivatives possess a broad-spectrum of biological properties including anti-tubercular and anti-malarial activities, and some tetrazole-based compounds have already been used in clinics for the treatment of various diseases. Therefore, tetrazole is an important pharmacophore in the development of new drugs. This review covers the recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents, and the structure-activity relationship is also discussed for the further rational design of tetrazole derivatives. Show less

A series of N-benzoylated mononuclear copper(II) complexes of the type [Cu(L1−6)Cl2] (1–6), where L1= ethyl 4-benzoyl-5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L2= ethyl 4-(4-nitrobenzoyl)-5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L3 = ethyl 4-benzoyl-5-methyl-7-(4-methoxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L4 = ethyl 4-(4-nitrobenzoyl)-5-methyl-7-(4-methoxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L5 = ethyl 4-benzoyl-5-methyl-7-(4-chlorophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate and L6 = ethyl 4-(4-nitrobenzoyl)-5-methyl-7-(4-chlorophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate have been synthesized and characterized by spectral methods. Electron paramagnetic resonance spectra of complexes show four lines, characteristic of square planar geometry. The binding studies of the complexes with calf thymus DNA (CT–DNA) revealed groove mode of binding, which were further supported by molecular docking studies. Gel electrophoresis experiments demonstrated the ability of the complexes to cleave plasmid DNA in the absence of activators. Further, the cytotoxicity activity of the complexes were examined on three cancerous cell lines (lung (A549), cervical (HeLa) and colon (HCT-15)), and on two normal cells (human embryonic kidney (HEK) and peripheral blood mononuclear cells (PBMC)) by MTT assay. Show less

Cancer is one of the main causes of death throughout the world. The anticancer agents are indispensable for the treatment of various cancers, but most of them currently on the market are not specific, resulting in series of side effects of chemotherapy. Moreover, the emergency of drug-resistance towards cancers has already increased up to alarming level in the recent decades. Therefore, it's imperative to develop novel anticancer candidates with excellent activity against both drug-susceptible and drug-resistant cancers, and low toxicity as well. Tetrazole is the bioisoster of carboxylic acid, and its derivatives demonstrated promising anticancer activity. Hybridization of tetrazole with other anticancer pharmacophores may provide novel candidates with anticancer potency. The present review described the anticancer activity of tetrazole hybrids, and the structure-activity relationship (SAR) is also discussed to provide an insight for rational designs of tetrazole anticancer candidates with higher efficiency. Show less

Four new complexes of Au(III), Pd(II), Ni(II), and Cu(II) ions were synthesized, derived from a novel heterocyclic ligand (L) that has both triazole and tetrazole rings. The ligand synthesis was through successive steps to achieve both heterocyclic rings. The synthesized compounds were characterized using conventional techniques like infrared, ultra violet—visible and proton/carbon nuclear magnetic resonance spectroscopy, metal and thermal analyses, and molar conductivity. All complexes were suggested to have square planar geometry, gold, nickel, and palladium complexes were salts while copper neutral complexes have the chemical formulas; [AuL2]Cl.2H2O, [PdL2]Cl2.2H2O, [NiL2]Cl2.2H2O, and [CuL2]. The cytotoxic effect was studied on breast cancer cell line (MCF‐7 cell line) at different concentrations by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay method, for the ligand (L) and complexes. The results showed that gold(III) and nickel(II) complexes have the highest cytotoxicity among all compounds against cancer cell lines. Show less

Fungi, which can cause serious infections, results in more than 1.35 million deaths annually throughout the world. Azole antifungal drugs which could inhibit the enzyme lanosterol 14α-demethylase, occupy an important position in the treatment of fungal infections. Tetrazoles, practically non-metabolized bioisosteric analog of carboxylic acid and cis-amide, possess a variety of chemotherapeutic properties, including antifungal activities. Hybridization represents a promising strategy to develop novel drugs, and hybridization of tetrazole with other antifungal pharmacophores has the potential to increase the activity and overcome the drug resistance. Various tetrazole hybrids have been designed, synthesized and screened for their antifungal activities, and some of them showed promising activity against both drug-susceptible and drug-resistant fungi. In this review, we present tetrazole hybrids for fighting against fungi. The structure-activity relationship (SAR) is also discussed to provide an insight for rational designs of more effective candidates. Show less

The incidence of invasive bacterial infections has increased remarkably over the past two decades, which was mainly attributed to the increasing emergence of drug-resistant bacteria especially multidrug-resistant strains, intractable pathogens and newly arising pathogenic organisms. Tetrazoles, the bioisoster of carboxylic acid, possess considerable antibacterial property. Hybridization of tetrazole with other antibacterial pharmacophores has the potential to enhance the efficacy against both drug-sensitive and drug-resistant pathogens. Some tetrazole hybrids such as tetrazole-oxazolidinone hybrid Tedizolid 25 and Tedizolid phosphate 26 have already been marketed for the treatment of acute bacterial skin and skin structure infections caused by various bacteria. DA-7867 (27), the amide analog of Tedizolid, also exhibited promising activities against a panel of clinically important pathogens including drug-resistant organisms, demonstrating the possible utility of the tetrazole scaffolds in the development of new antibacterial agents. Thus, hybridization of tetrazole with other antibacterial pharmacophores represents a promising strategy to develop novel antibacterial candidates. This work is attempted to systematically review the research of tetrazole hybrids in the design and development of antibacterial agents during the past two decades. The structure-activity relationship (SAR) is also discussed to provide an insight for rational design of more effective tetrazole antibacterial candidates. Show less

For many years various tetrazolium salts and their formazan products have been employed in histochemistry and for assessing cell viability. For the latter application, the most widely used are 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and 5-cyano-2,3-di-(p-tolyl)-tetrazolium chloride (CTC) for viability assays of eukaryotic cells and bacteria, respectively. In these cases, the nicotinamide-adenine-dinucleotide (NAD(P)H) coenzyme and dehydrogenases from metabolically active cells reduce tetrazolium salts to strongly colored and lipophilic formazan products, which are then quantified by absorbance (MTT) or fluorescence (CTC). More recently, certain sulfonated tetrazolium, which give rise to water-soluble formazans, have also proved useful for cytotoxicity assays. We describe several aspects of the application of tetrazolium salts and formazans in biomedical cell biology research, mainly regarding formazan-based colorimetric assays, cellular reduction of MTT, and localization and fluorescence of the MTT formazan in lipidic cell structures. In addition, some pharmacological and labeling perspectives of these compounds are also described. Show less

A novel high-nitrogen compound, 1,2-bis(3-nitro-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-yl)diazene, was designed and synthesized. The corresponding hydrazine energetic salts were prepared through spontaneous reductive conversion by structurally varied amino salts. All energetic salts showed good thermal stabilities with decomposition temperatures ranging from 212 to 259 °C, and high positive heats of formation in the range of 411.1 to 1554.7 kJ mol−1. Furthermore, hydroxyammonium salt featured a promising integrated energetic performance (vD = 9038 m s−1, IS = 8 J, and FS = 360 N), which is superior to that of RDX (vD = 8890 m s−1, IS = 7.4 J, FS = 120 N), showing promising properties for new high-nitrogen high-energy-density materials. Show less

Tetrazole cycle is a promising pharmacophore fragment frequently used in the development of novel drugs. This moiety is a stable, practically non-metabolized bioisosteric analog of carboxylic, cis-amide, and other functional groups. Over recent 10-15 years, various isomeric forms of tetrazole (NH-unsubstituted, 1H-1- substituted, and 2H-2-substituted tetrazoles) have been successfully used in the design of promising anticancer drugs. Coordination compounds of transition metals containing tetrazoles as ligands, semisynthetic tetrazolyl derivatives of natural compounds (biogenic acids, peptides, steroids, combretastatin, etc.), 5-oxo and 5- thiotetrazoles, and some other related compounds have been recognized as promising antineoplastic agents. This review presents a comprehensive analysis of modern approaches to synthesis of these tetrazole derivatives as well as their biological (anticancer) properties. The most promising structure types of tetrazoles to be used as anticancer agents have been picked out. Show less

RuII compounds have been universally investigated due to their unique physical and chemical properties. In this paper, a new RuII compound based on 2,2′‐bipy and Hpmtz [2,2′‐bipy = 2,2′‐bipyridine, Hpmtz = 5‐(2‐pyrimidyl)‐1H‐tetrazole], namely [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O was prepared and characterized by elemental analysis, IR and single‐crystal X‐ray diffraction. [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O shows a mononuclear structure and forms a three‐dimensional network by non‐classic hydrogen bonds. The ability of generation of ROS (reactive oxygen species) makes it has a low phototoxicity IC50 (half‐maximal inhibitory concentration) after Xenon lamp irradiation on Hela cells in vitro. The results demonstrate that [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O with high light toxicity and low dark toxicity may be a potential candidate for photodynamic therapy. Show less

The main aim of this study is to assess the safety and antitumor efficacy of a palladium(II) (Pd)-saccharinate complex with terpyridine. To characterize the Pd(II) complex in vitro, its cytotoxicity was evaluated using a water-soluble tetrazolium salt cell viability assay and the mechanism of cell death was assessed by DNA fragmentation/condensation and live cell imaging analyses. The antitumor efficacy and safety of the Pd(II) complex in-vivo were examined by analyzing reduction in tumor size, changes in body and organ weight, histopathological analysis of liver, kidney, and tumor sections, and biochemical analysis of serum in C57BL/6 mice. Our results showed that the Pd(II) complex was more cytotoxic to cancer cells than noncancer cell lines and caused cell death through apoptotic pathways. The treatment of the Pd(II) complex in tumor-bearing mice effectively reduced the tumor size at half the dose used for cisplatin. The Pd(II) complex appeared to exert less liver damage than the cisplatin-based complex on changes in the hepatic enzymes levels in the serum. Hence, the complex appears to be a potential chemotherapeutic drug with high antitumor efficacy and fewer hepatotoxic complications, providing an avenue for further studies. Show less

We report on the exploitation of a new tetrazole-substituted 1,10-phenanthroline and a 2,2′-bipyridine (bpy) ancillary ligand modified with an electron-donating group in cationic ruthenium complexes. This complex, placed in between two electrodes without any polymer, demonstrates high efficiency near-infrared (NIR) electroluminescence (EL). The comparison between bpy and its methyl-substituted ancillary ligand shows that the cationic Ru tetrazolate complex containing methyl groups exhibits a red shift in the EL wavelength from 620 to 800 nm compared to [Ru(bpy)3]2+ and an almost twofold reduction in the turn-on voltage, i.e., from 5 to 3 V, with respect to 5-tetrazole-1,10-phenanthroline. An external quantum efficiency of 0.95% for the dimethyl derivative is demonstrated, which is a remarkable result for non-doped NIR light electrochemical cells based on ruthenium polypyridyl. Show less

The role of copper in the proliferation of cancer cells is under investigation and has been explored in the context of cancer chemotherapy. The evidence that proliferation of cancer cells requires a higher abundance of Cu(II) than their normal counterparts has prompted the development of new copper chelators that can avidly bind copper ions, forming redox active metal complexes that ultimately lead to harmful reactive oxygen species (ROS) in neoplasms. In this context, the mandatory properties of the chelators for medical applications are safety (neglectable cytotoxicity), high binding affinity and selectivity towards Cu(II). We report the synthesis, structure (calculations and single crystal X-ray diffraction), spectroscopic (IR; UV-Vis) and magnetic properties of two novel copper(II) complexes based on 5-(3-aminosaccharyl)-tetrazoles (TS and 2MTS), as well as their in vitro cytotoxicity against the human hepatic carcinoma cell line HepG2. Quite interestingly, we found that the saccharinate-tetrazoles tested exhibit strong binding selectivity to Cu(II), over Fe(II) and Ca(II). Additionally, the corresponding copper complexes have shown a huge increase in the in vitro cytotoxicity against tumoral cells, compared to the corresponding nontoxic ligands. Thus, the new ligands may be viewed as potential precursors of selective cytotoxic agents, acting as non-cytotoxic pro-drugs that can be activated inside neoplastic cells, known to be richer in Cu(II) than the corresponding normal cells. Show less