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Drugs Jun 2019Azole antifungals are first-line options in the prophylaxis and treatment of invasive fungal infections. They are often used for prolonged (weeks to months) periods of... (Review)
Review
Azole antifungals are first-line options in the prophylaxis and treatment of invasive fungal infections. They are often used for prolonged (weeks to months) periods of time, particularly in patients with hematologic malignancies, or in those who have received a solid organ or hematopoietic stem cell transplant. Long-term use of azoles is associated with hepatotoxicity and hormone-related effects, including gynecomastia, alopecia, decreased libido, oligospermia, azoospermia, impotence, hypokalemia, hyponatremia, and (rarely) adrenal insufficiency. Voriconazole and posaconazole have been associated with peripheral neuropathies, and itraconazole and voriconazole with pancreatitis. In addition, voriconazole has been associated with periostitis, phototoxic reactions, and squamous cell carcinoma. Since many at-risk patients are commonly receiving multiple medications, it can be difficult for care providers to identify antifungal agent causality or contribution to patient symptoms. Knowledge and recognition of adverse events caused by azoles, leading to dose reduction or discontinuation, can generally reverse these adverse events.
Topics: Antifungal Agents; Azoles; Chemical and Drug Induced Liver Injury; Databases, Factual; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Time Factors
PubMed: 31093949
DOI: 10.1007/s40265-019-01127-8 -
Archiv Der Pharmazie Jan 2020Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug... (Review)
Review
Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin-azole hybrids as novel anticancer agents, and some of the isatin-azole hybrids exhibited considerable activity. This review emphasizes isatin-azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure-activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.
Topics: Animals; Antineoplastic Agents; Azoles; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Isatin; Molecular Structure; Neoplasms; Structure-Activity Relationship
PubMed: 31691360
DOI: 10.1002/ardp.201900272 -
APMIS : Acta Pathologica,... Aug 2023Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is... (Review)
Review
Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is associated with nosocomial infections that cause invasive candidiasis in immunocompromised patients. Several antifungal drugs with distinct mechanisms of action are clinically approved for the treatment of fungal infections. The high rates of intrinsic and acquired drug resistance, particularly to azoles, reported in characterized clinical isolates of C. auris make treatment extremely problematic. In systemic infections, azoles are the first-line treatment for most Candida species; however, the increasing use of drugs results in the frequent emergence of drug resistance. More than 90% of the clinical isolates of C. auris is shown to be highly resistant to azole drugs especially fluconazole, with some strains (types) resistant to all three classes of commonly used antifungals. This presents a huge challenge for researchers in terms of completely understanding the molecular mechanism of azole resistance to develop more efficient drugs. Due to the scarcity of C. auris therapeutic alternatives, the development of successful drug combinations provides an alternative for clinical therapy. Taking advantage of various action mechanisms, such drugs in combination with azole are likely to have synergistic effects, improving treatment efficacy and overcoming C. auris azole drug resistance. In this review, we outline the current state of understanding about the mechanisms of azole resistance mainly fluconazole, and the current advancement in therapeutic approaches such as drug combinations toward C. auris infections.
Topics: Humans; Azoles; Fluconazole; Candida auris; Antifungal Agents; Candidiasis, Invasive; Microbial Sensitivity Tests
PubMed: 37337929
DOI: 10.1111/apm.13336 -
The Journal of Infection Jun 2015Azole-resistance in Aspergillus fumigatus is emerging and is becoming an increasing problem in the management of aspergillosis. Two types of development of resistance... (Review)
Review
Azole-resistance in Aspergillus fumigatus is emerging and is becoming an increasing problem in the management of aspergillosis. Two types of development of resistance have been described; resistance acquired during azole treatment in an individual patient and through environmental exposure to fungicides. The main molecular mechanism of azole resistance in A. fumigatus is explained by mutations in the cyp51A-gene. The environmental route of resistance development is particularly worrying and may affect all patients whether azole exposed or naïve, and whether suffering from acute or chronic aspergillosis. No management guidelines to assist clinicians confronted with azole-resistant aspergillosis are available and pre-clinical and clinical evidence supporting treatment choices is scarce.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Humans
PubMed: 25917808
DOI: 10.1016/j.jinf.2015.04.023 -
Medecine Et Maladies Infectieuses Aug 2020Aspergillus fumigatus is the predominant etiological agent of invasive aspergillosis (IA), a difficult-to-manage fungal disease associated with a high case fatality... (Review)
Review
Aspergillus fumigatus is the predominant etiological agent of invasive aspergillosis (IA), a difficult-to-manage fungal disease associated with a high case fatality rate. Azole antifungals, particularly voriconazole, have significantly improved the survival rate of patients with IA. However, the clinical advances made possible through the use of medical azoles could be threatened by the emergence of azole-resistant strains which has been reported in an ever-increasing number of countries over the last 10 years. The major resistance mechanism, that combines point mutation(s) in the coding sequence of cyp51A gene and an insertion of a tandem repeat in the promoter region of this gene which leads to its overexpression (TR/L98H and TR/Y121F/T289A), is presumed to be of environmental origin. However, the emergence of clinical and environmental azole-resistant strains without the cyp51A gene mutation suggests that other mechanisms could also be responsible for azole resistance (for example, overexpression of efflux pumps). The development of resistance may be linked to either long-term use of azole antifungals in patients with chronic aspergillosis (patient-acquired route) or selection pressure of the fungicides in the environment (environmental route). The fungicide-driven route could be responsible for resistance in azole-naive patients with IA. This literature review aims to summarize recent findings, focusing on the current situation of azole-resistance in A. fumigatus, and provides better understanding of the importance of the environmental route in resistance acquisition.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Fungal Proteins; Genotype; Humans; Microbial Sensitivity Tests; Voriconazole
PubMed: 31472992
DOI: 10.1016/j.medmal.2019.07.014 -
Current Topics in Medicinal Chemistry 20201,3,5-Triazine and azole can interact with various therapeutic targets, and their derivatives possess promising in vitro and in vivo anticancer activity. Hybrid... (Review)
Review
1,3,5-Triazine and azole can interact with various therapeutic targets, and their derivatives possess promising in vitro and in vivo anticancer activity. Hybrid molecules have the potential to enhance efficiency, overcome drug resistance and reduce side effects, and many hybrid molecules are under different phases of clinical trials, so hybridization of 1,3,5-triazine with azole may provide valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop azole-containing 1,3,5-triazine hybrids as novel anticancer agents, and some of them exhibited excellent activity. This review emphasizes azole-containing 1,3,5-triazine hybrids with potential anticancer activity, and the structure-activity relationships as well as the mechanisms of action are also discussed to provide comprehensive and target-oriented information for the development of this kind of anticancer drugs.
Topics: Antineoplastic Agents; Azoles; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Triazines
PubMed: 32156236
DOI: 10.2174/1568026620666200310122741 -
Drug Development Research Apr 2021An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the... (Review)
Review
An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.
Topics: Animals; Azoles; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Delivery Systems; Heterocyclic Compounds; Humans
PubMed: 33137216
DOI: 10.1002/ddr.21753 -
Current Medicinal Chemistry 2023Azoles are the famous and widespread scaffold in the pharmaceutical industry due to their wide range of activities, high efficacy, good tolerability, and oral... (Review)
Review
BACKGROUND
Azoles are the famous and widespread scaffold in the pharmaceutical industry due to their wide range of activities, high efficacy, good tolerability, and oral availability. Furthermore, azole derivatives have attracted attention as potent antimicrobial agents.
INTRODUCTION
The purpose of this review is to provide an overview of pharmacological aspects of the main scaffolds of azoles, including imidazole, benzimidazole, triazole, and tetrazole, which possess antimicrobial activity, reported from 2016 to 2020, as well as all of our publication in this field. In addition, we discuss the relationship between structure and activity and molecular docking studies of the azole derivatives to provide critical features and valuable information for the synthesis of novel azole compounds with desirable biological activities. The presented structures in this review have been tested against several bacteria and fungi, such as E. coli and C. albicans, which have been common in all of these studies.
RESULTS
A comparison of the reported MIC for tested compounds showed fluconazole base structures as the most active antifungal agents, and triazole derivatives bearing nitrophenyl and coumarin moieties to have the most dominant antibacterial activity.
CONCLUSION
Triazole and imidazole scaffolds are more important for designing antimicrobial compounds than other azole derivatives, like benzimidazole or tetrazole. All the most active compounds were observed to fulfill the Lipinski rule.
Topics: Humans; Antifungal Agents; Azoles; Structure-Activity Relationship; Molecular Docking Simulation; Escherichia coli; Microbial Sensitivity Tests; Imidazoles; Candida albicans; Anti-Bacterial Agents; Triazoles; Tetrazoles; Benzimidazoles
PubMed: 35392780
DOI: 10.2174/0929867329666220407094430 -
PLoS Pathogens Aug 2023Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk...
Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.
Topics: Animals; Candida; Candida albicans; Candidiasis; Antifungal Agents; Azoles
PubMed: 37651385
DOI: 10.1371/journal.ppat.1011583 -
Organic & Biomolecular Chemistry Dec 2017This review discusses the chemistry of cyclic azole-homologated peptides (AHPs) from the marine sponges, Theonella swinhoei, other Theonella species, Calyx spp. and... (Review)
Review
This review discusses the chemistry of cyclic azole-homologated peptides (AHPs) from the marine sponges, Theonella swinhoei, other Theonella species, Calyx spp. and Plakina jamaicensis. The origin, distribution of AHPs and molecular structure elucidations of AHPs are described followed by their biosynthesis, bioactivity, and synthetic efforts towards their total synthesis. Reports of partial and total synthesis of AHPs extend beyond peptide coupling reactions and include creative construction of the non-proteinogenic amino acid components, mainly the homologated heteroaromatic and α-keto-β-amino acids. A useful conclusion is drawn regarding AHPs: despite their rarity, exotic structures and the potent protease inhibitory properties of some members, their synthesis is under-developed and beckons solutions for outstanding problems towards their efficient assembly.
Topics: Animals; Azoles; Molecular Conformation; Peptides; Porifera
PubMed: 29210421
DOI: 10.1039/c7ob02628e