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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

The synthesis of triazoles has attracted a lot of interest in the field of organic chemistry because of its versatile chemical characteristics and possible biological uses. This review offers an extensive overview of the different pathways used in the production of triazoles. A detailed analysis of recent research indicates that triazole compounds have a potential range of pharmacological activities, including the ability to inhibit enzymes, and have antibacterial, anticancer, and antifungal activities. The integration of computational and experimental methods provides a thorough understanding of the structure–activity connection, promoting sensible drug design and optimization. By including triazoles as essential components in drug discovery, researchers can further explore and innovate in the synthesis, biological assessment, and computational studies of triazoles as drugs, exploring the potential therapeutic significance of triazoles. Graphical abstract 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

Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications. 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

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

Few data are available on the clinical impact of drug-drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI. Our objective was to describe the characteristics of ADRs resulting from DDIs reported to the French Pharmacovigilance system and to identify the drugs most often implicated in these ADRs. Considering all ADR reports from January 01, 2012, to December 31, 2016, we identified all cases of ADR resulting from a DDI (DDI-ADRs). We then described these in terms of patients' characteristics, ADR seriousness, drugs involved (two or more per case), and ADR type. Of the 4,027 reports relating to DDI-ADRs, 3,303 were related to serious ADRs. Patients with serious DDI-ADRs had a median age of 76 years (interquartile range: 63-84); 53% were male. Of all serious DDI-ADRs, 11% were life-threatening and 8% fatal. In 36% of cases, the DDI causing the ADR involved at least three drugs. Overall, 8,424 different drugs were mentioned in the 3,303 serious DDI-ADRs considered. Altogether, drugs from the "antithrombotic agents" subgroup were incriminated in 34% of serious DDI-ADRs. Antidepressants were the second most represented therapeutic/pharmacological subgroup (5% of serious DDI-ADRs). Among the 3,843 ADR types reported in the 3,303 serious DDI-ADRs considered, the most frequently represented were hemorrhage (40% clinical hemorrhage; 6% biological hemorrhage), renal failure (8%), pharmacokinetic alteration (5%), and cardiac arrhythmias (4%). Hemorrhagic accidents are still an important part of serious ADRs resulting from DDIs reported in France. The other clinical consequences of DDIs seem less well identified by pharmacovigilance. Moreover, more than one-third of serious DDI-ADRs involved at least three drugs. Show less

Herein, we describe a new family of tris chelate homoleptic Ru (II) complexes, [Ru(N^N)3]2+, where the role of the diimine‐type ligands (N^N) was fulfilled by 2‐pyridyl (PTZ) or 2‐quinolyl tetrazole (QTZ) derivatives decorated with various alkyl substituents at the N‐2 position of the tetrazole ring. The new Ru (II) complexes with general formula [Ru (PTZ‐R)3]2+ and [Ru (QTZ‐R)3]2+, were obtained as mixtures of facial (fac) and meridional (mer) isomers, as suggested by NMR (1H, 13C) experiments, and confirmed in the case of mer‐[Ru (QTZ‐Me)3]2+, by X‐ray crystallography. The photophysical behavior of the tetrazole‐based [Ru(N^N)3]2+ type species was investigated by UV–vis absorption spectroscopy, providing trends typical of polypyridyl Ru (II) complexes. The new homoleptic complexes fac/mer‐[Ru (PTZ‐R)3]2+ and fac/mer‐[Ru (QTZ‐R)3]2+ have been assessed for any eventual antimicrobial activity towards two different bacteria such as Gram‐negative Escherichia coli and Gram‐positive Deinococcus radiodurans. Whereas being inactive toward E. coli, the response of agar disks diffusion tests suggested that some of the new fac/mer Ru (II) complexes could inhibit the growth of D. radiodurans. This effect was further investigated by determining the growth kinetics in liquid medium of D. radiodurans exposed to the fac/mer‐[Ru (PTZ‐R)3]2+ and fac/mer‐[Ru (QTZ‐R)3]2+ complexes at different concentrations. The outcome of these experiments highlighted that the turn‐on of the growth inhibitory effect took place as the linear hexyl chain was appended to the PTZ or QTZ scaffold, suggesting also how the inhibitory activity appeared more pronouncedly exerted by the facial isomers fac‐[Ru (PTZ‐Hex)3]2+ and fac‐[Ru (QTZ‐Hex)3]2+ (MIC = ca. 3.0 μg/ml) with respect to the corresponding meridional isomers (MIC = ca. 6.0 μg/ml). Show less

Ten manganese(I) tricarbonyl diimine complexes bound to variably functionalised 5‐aryl‐tetrazolato ligands were prepared, and their photochemical properties were investigated. Upon exposure to light at 365 nm, each complex decomposed to its free diimine and tetrazolato ligands, simultaneously dissociating three CO ligands, as evidenced by changes in the IR spectra of the irradiated complexes over time. The anti‐bacterial properties of one of these complexes were tested against Escherichia coli. While the complex displayed no effect on the bacterial growth in the dark, pre‐irradiated solutions inhibited bacterial growth. Comparative studies revealed that the antibacterial properties originate from the presence of free 1,10‐phenanthroline. 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

Despite substantial advances in the treatment of various cancers, many patients still receive anti-cancer therapies that hardly eradicate tumor cells but inflict considerable side effects. To provide the best treatment regimen for an individual patient, a major goal in molecular oncology is to identify predictive markers for a personalized therapeutic strategy. Regarding novel targeted anti-cancer therapies, there are usually good markers available. Unfortunately, however, targeted therapies alone often result in rather short remissions and little cytotoxic effect on the cancer cells. Therefore, classical chemotherapy with frequent long remissions, cures, and a clear effect on cancer cell eradication remains a corner stone in current anti-cancer therapy. Reliable biomarkers which predict the response of tumors to classical chemotherapy are rare, in contrast to the situation for targeted therapy. For the bulk of cytotoxic therapeutic agents, including DNA-damaging drugs, drugs targeting microtubules or antimetabolites, there are still no reliable biomarkers used in the clinic to predict tumor response. To make progress in this direction, meticulous studies of classical chemotherapeutic drug action and resistance mechanisms are required. For this purpose, novel functional screening technologies have emerged as successful technologies to study chemotherapeutic drug response in a variety of models. They allow a systematic analysis of genetic contributions to a drug-responsive or -sensitive phenotype and facilitate a better understanding of the mode of action of these drugs. These functional genomic approaches are not only useful for the development of novel targeted anti-cancer drugs but may also guide the use of classical chemotherapeutic drugs by deciphering novel mechanisms influencing a tumor's drug response. Moreover, due to the advances of 3D organoid cultures from patient tumors and in vivo screens in mice, these genetic screens can be applied using conditions that are more representative of the clinical setting. Patient-derived 3D organoid lines furthermore allow the characterization of the "essentialome", the specific set of genes required for survival of these cells, of an individual tumor, which could be monitored over the course of treatment and help understanding how drug resistance evolves in clinical tumors. Thus, we expect that these functional screens will enable the discovery of novel cancer-specific vulnerabilities, and through clinical validation, move the field of predictive biomarkers forward. This review focuses on novel advanced techniques to decipher the interplay between genetic alterations and drug response. Show less

Uropathogenic E. coli (UPEC) are responsible for 80% of community-acquired and 65% of nosocomial urinary tract infections (UTI), which together affect 150 million people annually. UPEC establishes reservoirs in the gut, but the factors involved in this process have remained unknown. Here, Scott Hultgren and colleagues show that both F17-like and type 1 pili promote intestinal colonization and bind to distinct glycans on epithelial cells distributed along colonic crypts. Using the high-affinity mannose analogue, mannoside M4284, which inhibits the adhesive function of type 1 pili, the authors demonstrate that it effectively reduces intestinal colonization of UPEC, while simultaneously treating UTI without significantly disrupting the composition of the gut microbiota. The authors suggest that this selective depletion of intestinal UPEC by mannosides could be used to reduce the occurrence of UTIs. Show less

Organometallic compounds currently occupy an important place in the field of medicinal inorganic chemistry due to the unique chemical properties of metal coordination compounds. Particularly, metal compounds ligated by N-heterocyclic carbenes (NHC) have shown high potential for biomedical applications as antimicrobial and anticancer agents during the recent 15 years. Although further studies are necessary to validate the modes of action of this family of compounds, a number of biological targets have been identified, including DNA secondary structures. This perspective review aims at providing an overview of the most representative examples of metal NHC complexes reacting with nucleic acids via different binding modes. It is organized according to the type of DNA secondary structure targeted by metal NHCs, highlighting the possible advantages of biomedical applications, including therapy and imaging. Show less

Five mixed thiolatobismuth(III) complexes [BiPh(5‐MMTD)2{4‐MMT(H)}] (1), [Bi(1‐MMTZ)2{(PYM)(PYM(H))2}] (2), [Bi(MBT)2(5‐MMTD)] (3), [Bi(4‐BrMTD)3{2‐MMI(H)}] (4) and [Bi(1‐MMTZ)2{1‐MMTZ(H)}(2‐MMI){2‐MMI(H)2}] (5) were synthesised from imidazole‐, thiazole‐, thiadiazole‐, triazole‐, tetrazole‐ and pyrimidine‐based heterocyclic thiones. Four of these complexes 1–4 were synthesized from BiPh3, while complex 5 was obtained from Bi[4‐(MeO)Ph]3. Complexes 1–5 were structurally characterised by XRD. Evaluation of the antibacterial properties against Mycobacterium smegmatis, Staphylococcus aureus, Methicillin‐resistant S. aureus (MRSA), Vancomycin‐resistant Enterococcus (VRE), Enterococcus faecalis and Escherichia coli showed that mixed thiolato complexes containing the anionic thiazole‐based ligands MBT and 4‐BrMTD are most effective. The mixed thiolato complexes [Bi(MBT)2(5‐MMTD)] (3) having thiazole‐ and thiadiazole‐ and [Bi(4‐BrMBT)3{2‐MMI(H)}] (4) containing thiazole‐ and imidazole‐based ligands proved to be more efficient, with low minimum inhibitory concentrations of 1.73 and 3.45 µm for 3 against VRE and E. faecalis, respectively, and 2.20 µm for 4 against M. smegmatis and E. faecalis. All complexes showed little or no toxicity towards mammalian COS‐7 cell lines at 20 µg mL–1. Show less