History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action

Shafiei, Mohammad; Peyton, Lee; Hashemzadeh, Mehrtash; Foroumadi, Alireza

doi:10.1016/j.bioorg.2020.104240

Cited by 171 publications

(144 citation statements)

References 137 publications

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“…The azoles are used extensively because they are significantly less expensive than other antifungal treatments and their overall antimycotic activity is relatively broad spectrum [6]. Azole drugs are used in: (1) treatment and prophylaxis of livestock (e.g., ringworm in cattle, aspergillosis in poultry, oomycete infections in aquaculture [7][8][9][10], (2) treatment in veterinary medicine (e.g., pets and zoo animals) [11,12], (3) crop protection (e.g., mildews and rusts of grains, fruits, vegetables), (4) plant protection (e.g., leaf spot on flowers, scrubs and trees, including the timber industry) [4], (5) protection of buildings (e.g., antifouling coatings) [13], (f) cosmetic and hygiene products [14], and (6) prophylaxis and treatment in medicine [15].…”

Section: Introductionmentioning

confidence: 99%

Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens

Rosam

Monk

Lackner

2020

JoF

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The fungal cytochrome P450 enzyme sterol 14α-demethylase (SDM) is a key enzyme in the ergosterol biosynthesis pathway. The binding of azoles to the active site of SDM results in a depletion of ergosterol, the accumulation of toxic intermediates and growth inhibition. The prevalence of azole-resistant strains and fungi is increasing in both agriculture and medicine. This can lead to major yield loss during food production and therapeutic failure in medical settings. Diverse mechanisms are responsible for azole resistance. They include amino acid (AA) substitutions in SDM and overexpression of SDM and/or efflux pumps. This review considers AA affecting the ligand-binding pocket of SDMs with a primary focus on substitutions that affect interactions between the active site and the substrate and inhibitory ligands. Some of these interactions are particularly important for the binding of short-tailed azoles (e.g., voriconazole). We highlight the occurrence throughout the fungal kingdom of some key AA substitutions. Elucidation of the role of these AAs and their substitutions may assist drug design in overcoming some common forms of innate and acquired azole resistance.

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Section: Introductionmentioning

confidence: 99%

Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens

Rosam

Monk

Lackner

2020

JoF

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“…The biological properties such as antimicrobial, antifungal and antimycobacterial activities of IIa-IIg derivatives were tested against four Gram-positive and five Gram-negative bacteria, four fungi species and M. tuberculosis H37Rv using the microdilution broth method and REMA according to recommendations techniques [22][23][24][25]. Ampicilline.3H2O, fluconazole, isoniazid and rifampicin were used as a reference in antibacterial, antifungal and antimycobacterial activity test, respectively (Table 1 and 2 [28]. This result suggests that compound IIb may be worth further study in terms of their antifungal activity.…”

Section: Resultsmentioning

confidence: 99%

Study on Synthesis and Antimicrobial Activities of Some Micheal-Type Addition Compounds

Bayram¹,

Nzeyimana²,

Utku³

et al. 2021

Ankara Universitesi Eczacilik Fakultesi Dergisi

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Objective: Multidrug-resistant pathogenic bacteria, fungi, and Mycobacterium tuberculosis infections continue to be increasingly widespread worldwide. In organic chemistry, the tiya-Michael type addition is also significant reaction in the synthesis of bioactive compounds. In this study, the aim is to synthesize the series of new Michael type addition products 2-amino-3-[(2-nitro-1-phenylpropyl)thio]propanoic acid (IIa-IIg) and to investigate their in vitro, antibacterial, antifungal and antitubercular activity.Material and Method: IIa-IIg derivatives were performed combining β-methyl-β-nitrostyrenes (Ia-Ig) with L-cysteine using Michael addition reaction and characterized by 1 HNMR, FTIR, ESI-LC/MS and elemental analysis. Microdilution method and resazurin microtiter assay were used to determine antimicrobial activities.Result and Discussion: Comparing the activities of the synthesized compounds, IIa, IId and IIe were found to have significant activity, with a MIC value of 1.95 µg/ml, against Mycobacterium tuberculosis H37Rv strain.

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“…Thus, drug interaction is a limiting factor that should be taken seriously. Despite the advent of newer-generation triazoles, such as voriconazole and posaconazole, itraconazole is considered the main azole derivative used in clinical practice, with satisfactory results in non-hospitalized PCM patients [76,77]. This generation of antifungals can be considered as potential substitutes for itraconazole; however, they are still high cost and new clinical evidence needs to be published [5,66].…”

Section: Search For New Therapeutic Options-a Journey 21 a Starting Point-available Therapeutic Optionsmentioning

confidence: 99%

“…Thus, by homology modeling, protein structure prediction is a reality for the groups working with Paracoccidioides spp. Indeed, Abadio et al [77] obtained three-dimensional structures of two proteins by homology modeling from P. lutzii: thioredoxin reductase and alfa-1,2-mannosyltransferase. The three-dimensional models allowed the identification of relevant information about these proteins, such as the conserved domains and the residues of the active site [77].…”

Section: In Silico Strategy For New Antifungal Developmentmentioning

confidence: 99%

“…Indeed, Abadio et al [77] obtained three-dimensional structures of two proteins by homology modeling from P. lutzii: thioredoxin reductase and alfa-1,2-mannosyltransferase. The three-dimensional models allowed the identification of relevant information about these proteins, such as the conserved domains and the residues of the active site [77]. The 3D-structure of other Paracoccidioides proteins was built by in silico tools for virtual screening application, such as homoserine dehydrogenase (EC 1.1.1.3) [140], chorismate synthase (EC 4.2.3.5) [141] and isocitrate lyase [142].…”

Section: In Silico Strategy For New Antifungal Developmentmentioning

confidence: 99%

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One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

Kioshima

Mendonca

Teixeira

et al. 2021

JoF

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Paracoccidioidomycosis (PCM) is a notable fungal infection restricted to Latin America. Since the first description of the disease by Lutz up to the present day, Brazilian researchers have contributed to the understanding of the life cycle of this pathogen and provided the possibility of new targets for antifungal therapy based on the structural and functional genomics of Paracoccidioides. In this context, in silico approaches have selected molecules that act on specific targets, such as the thioredoxin system, with promising antifungal activity against Paracoccidioides. Some of these are already in advanced development stages. In addition, the application of nanostructured systems has addressed issues related to the high toxicity of conventional PCM therapy. Thus, the contribution of molecular biology and biotechnology to the advances achieved is unquestionable. However, it is still necessary to transcend the boundaries of synthetic chemistry, pharmaco-technics, and pharmacodynamics, aiming to turn promising molecules into newly available drugs for the treatment of fungal diseases.

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History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action

Cited by 171 publications

References 137 publications

Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens

Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens

Study on Synthesis and Antimicrobial Activities of Some Micheal-Type Addition Compounds

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

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