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Antimicrobial Agents and Chemotherapy Sep 2022Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi.... (Review)
Review
Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi. Its current FDA-approved indications include the management of invasive aspergillosis as well as mucormycosis, though the latter indication is supported by limited clinical data. Isavuconazole did not achieve noninferiority to caspofungin for the treatment of invasive candidiasis and therefore lacks an FDA-approved indication for this invasive disease. Significant advantages of isavuconazole, primarily over voriconazole but in some circumstances posaconazole as well, make it an appealing option for the management of complex patients with invasive fungal infections. These potential advantages include lack of QTc interval prolongation, more predictable pharmacokinetics, a less complicated drug interaction profile, and improved tolerability, particularly when compared to voriconazole. This review discusses these topics in addition to addressing the activity of the compound against a variety of fungi and provides insight into other distinguishing factors among isavuconazole, voriconazole, and posaconazole. The review concludes with an opinion section in which the authors provide the reader with a framework for the current role of isavuconazole in the antifungal armamentarium and where further data are required.
Topics: Antifungal Agents; Candidiasis, Invasive; Caspofungin; Fungi; Humans; Invasive Fungal Infections; Nitriles; Pyridines; Triazoles; Voriconazole
PubMed: 35969068
DOI: 10.1128/aac.00177-22 -
Molecules (Basel, Switzerland) Jul 2022Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these... (Review)
Review
Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABA modulating activity) as fluorescent probes and as structural units of polymers.
Topics: Pyrazines; Pyridazines; Quinoxalines; Triazoles
PubMed: 35897857
DOI: 10.3390/molecules27154681 -
Triazole resistance in Aspergillus fumigatus: recent insights and challenges for patient management.Clinical Microbiology and Infection :... Jul 2019Triazole resistance in Aspergillus fumigatus is widespread and threatens first-line triazole therapy in patients with Aspergillus diseases. (Review)
Review
BACKGROUND
Triazole resistance in Aspergillus fumigatus is widespread and threatens first-line triazole therapy in patients with Aspergillus diseases.
OBJECTIVES
To give an overview of the microbiology, epidemiology and clinical significance of triazole resistance in aspergillosis.
SOURCES
PubMed search for articles on resistance in Aspergillus species.
CONTENT
Triazoles are not mutagenic but select resistance when spontaneous mutations occur that are better able to proliferate in the triazole-containing environment. The major target for resistance mutations involves the Cyp51A gene, encoding an enzyme involved in cell wall synthesis. Triazole-resistance selection environments include patient treatment and organic matter containing triazole fungicide residues. Reported resistance frequencies vary widely between countries and hospitals, and resistance significantly complicates the diagnosis and treatment of Aspergillus diseases. Cultures may harbour various resistance phenotypes and multiple colonies must be analysed to detect resistance. PCR tests have become available for resistance detection in culture-negative patients, but show limited sensitivity. Individuals with triazole-resistant invasive aspergillosis have a 21% higher day-42 mortality compared with triazole-susceptible infection, and to prevent excess mortality resistant cases require first-line therapy that covers resistance. The recent ESCMID-ECMM-ERS Aspergillus guideline recommends resistance testing in A. fumigatus and local resistance surveillance. If resistance rates exceed 10% liposomal amphotericin B or triazole and echinocandin first-line therapy should be considered.
IMPLICATIONS
Triazole resistance significantly complicates the management of aspergillosis and multidisciplinary research from a 'One-health' perspective is required to retain the triazole class for medical use.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Management; Drug Resistance, Fungal; Humans; Invasive Fungal Infections; Microbial Sensitivity Tests; Mutation; Polymerase Chain Reaction; Triazoles
PubMed: 30580035
DOI: 10.1016/j.cmi.2018.11.027 -
Molecules (Basel, Switzerland) May 2021Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low... (Review)
Review
Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.
Topics: Amino Acid Sequence; Biomimetics; Click Chemistry; Molecular Conformation; Peptides; Peptidomimetics; Triazoles
PubMed: 34069302
DOI: 10.3390/molecules26102937 -
BioMed Research International 2022The development of innovative antifungal agents is essential. Some fungicidal agents are no longer effective due to resistance development, various side effects, and... (Review)
Review
The development of innovative antifungal agents is essential. Some fungicidal agents are no longer effective due to resistance development, various side effects, and high toxicity. Therefore, the synthesis and development of some new antifungal agents are necessary. 1,2,4-Triazole is one of the most essential pharmacophore systems between five-membered heterocycles. The structure-activity relationship (SAR) of this nitrogen-containing heterocyclic compound showed potential antifungal activity. The 1,2,4-triazole core is present as the nucleus in a variety of antifungal drug categories. The most potent and broad activity of triazoles have confirmed them as pharmacologically significant moieties. The goal of this review is to highlight recent developments in the synthesis and SAR study of 1,2,4-triazole as a potential fungicidal compound. In this study, we provide the results of a biological activity evaluation using various structures and figures. Literature investigation showed that 1, 2, 4-triazole derivatives reveal the extensive span of antifungal activity. This review will assist researchers in the development of new potential antifungal drug candidates with high effectiveness and selectivity.
Topics: Antifungal Agents; Microbial Sensitivity Tests; Structure-Activity Relationship; Triazoles
PubMed: 35360519
DOI: 10.1155/2022/4584846 -
Food Chemistry Jan 2022Two extraction methods based on solid liquid extraction and Quick, Easy, Cheap, Effective, Rugged and Safe procedure were developed for the determination of 21 triazole...
Two extraction methods based on solid liquid extraction and Quick, Easy, Cheap, Effective, Rugged and Safe procedure were developed for the determination of 21 triazole compounds and 5 metabolites, including triazole derivative metabolites as 1,2,4-triazole and 1,2,4-triazol 1-yl-acetic, in courgette, orange, grape and strawberry. The analysis was performed in 10.5 min, using ultra-high performance liquid chromatography coupled to Q-Orbitrap mass analyser. The proposed method was validated according to SANTE 12682/2019. Limits of quantification were ≤10 µg kg for all the compounds, except for 1,2,4-triazol, 1,2,4-triazol 1-yl-acetic, difenoconazole-alcohol and prothioconazole that were 50 µg kg. Finally, the method was successfully applied to the analysis of 30 samples. More than 30% of these samples contained residues of triazole compounds. The fungicide most frequently found was myclobutanil. Furthermore, a suspect screening analysis was carried out to search pesticides present in the samples, detecting some of them at concentrations higher than Maximum Residue Limits.
Topics: Chromatography, High Pressure Liquid; Fruit; Fungicides, Industrial; Pesticide Residues; Tandem Mass Spectrometry; Triazoles; Vegetables
PubMed: 34425340
DOI: 10.1016/j.foodchem.2021.130860 -
Current Topics in Medicinal Chemistry 2019Mycobacterium Tuberculosis (Mtb) is the causative pathogen of Tuberculosis (TB) and outbreaks are more common among immunosuppressed persons infected with HIV. The...
BACKGROUND
Mycobacterium Tuberculosis (Mtb) is the causative pathogen of Tuberculosis (TB) and outbreaks are more common among immunosuppressed persons infected with HIV. The current treatment regimens are lengthy and toxic, yet the therapy has remained unchanged for many decades, so there is a need to find new structures with selective mechanism of action. Moreover, the increased incidence of severe disseminated infections produced by undiagnosed Multidrug-resistant (MDR), worsen clinical treatment and contribute the spread of the disease.
OBJECTIVE
The aim of our study was to evaluate the potential of imidazole and triazole moieties for antimycobacterial activity, by synthesizing some 1-(1-(aryl)-2-(2,6-dichlorophenyl)hydrazono)ethyl- 1H-imidazole and 1H-1,2,4-triazole derivatives 2a-l.
METHODS
The title compounds were obtained via classical organic synthesis. The antimicrobial activity was evaluated using the method of microdilution and the cytotoxicity assay was performed by MTT method.
RESULTS
The results indicated that the presence of both the imidazole ring and that of the 2,6- dichlorosubstituted phenyl moiety, is more relevant for inhibitory activity against Mtb than the triazole nucleus and the unsubstituted phenyl ring. Among the series, (E)-1-(2-(5-chlorothiophen-2-yl)-2-(2- (2,6-dichlorophenyl)hydrazono)ethyl)-1H-imidazole derivative 2f and (Z)-1-(2-([1,1'-biphenyl]-4-yl)- 2-(2-(2,6-dichlorophenyl)hydrazono)ethyl]-1H-imidazole derivatives 2e exhibited a promising antimycobacterial property and the latter also displayed a safe cytotoxic profile.
CONCLUSION
The synthesized compounds were studied for their antitubercular activity. Among the series, the compounds 2e and 2f appeared to be the most promising agents and, according to the docking assessment, the compounds could be CYP51 inhibitors. These evidences could be useful for the future development of new antimycobacterial derivatives targeting CYP51 with more specificity for the mycobacterial cell enzyme.
Topics: Animals; Antitubercular Agents; Bacterial Proteins; Cell Survival; Chlorocebus aethiops; Models, Molecular; Molecular Docking Simulation; Mycobacterium tuberculosis; Protein Conformation; Triazoles; Vero Cells
PubMed: 30827247
DOI: 10.2174/1568026619666190227183826 -
Bioorganic & Medicinal Chemistry Aug 2019The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms... (Review)
Review
The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using 'click' chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the 'linker' property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.
Topics: Chemistry, Pharmaceutical; Triazoles
PubMed: 31300317
DOI: 10.1016/j.bmc.2019.07.005 -
Expert Review of Clinical Pharmacology May 2015Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of... (Review)
Review
Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances.
Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Chemistry, Pharmaceutical; Critical Illness; Delayed-Action Preparations; Humans; Mycoses; Triazoles
PubMed: 25916666
DOI: 10.1586/17512433.2015.1034689 -
European Journal of Medicinal Chemistry Nov 2020The present review aims to summarize the pharmacological profile of 1,2,4-triazole, one of the emerging privileged scaffold, as antifungal, antibacterial, anticancer,... (Review)
Review
The present review aims to summarize the pharmacological profile of 1,2,4-triazole, one of the emerging privileged scaffold, as antifungal, antibacterial, anticancer, anticonvulsant, antituberculosis, antiviral, antiparasitic, analgesic and anti-inflammatory agents, etc. along with structure-activity relationship. The comprehensive compilation of work carried out in the last decade on 1,2,4-triazole nucleus will provide inevitable scope for researchers for the advancement of novel potential drug candidates having better efficacy and selectivity.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Anticonvulsants; Antineoplastic Agents; Humans; Structure-Activity Relationship; Triazoles
PubMed: 32771798
DOI: 10.1016/j.ejmech.2020.112652