New Developments in Invasive Fungal Disease

Groll, Andreas H.; Lumb, Joanna

doi:10.2217/fmb.11.154

Cited by 45 publications

(27 citation statements)

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“…Presumably, this could be due to the presence of the 1,2,4-triazole moiety, which conferred antifungal activity. These results are in agreement with the literature, where the excellent antifungal activity exhibited by several commercial antifungal drugs, including fl uconazole, itraconazole, voriconazole and posaconazole, was att ributed to the incorporation of the 1,2,4-triazole core in their structures (29,30).…”

Section: Antimicrobiological Activity and Sarsupporting

confidence: 92%

Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation

Rezki

Aouad

2017

Acta Pharmaceutica

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Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fl uorinated--1,2,4-triazole conjugates and their antimicrobial evaluationThe present study describes an effi cient and ecofriendly, ultrasound, one-pot click cycloaddition approach for the construction of a novel series of 1,4-disubstituted-1,2,3-triazoles tethered with fl uorinated 1,2,4-triazole-benzothiazole molecular conjugates. It involved three-component condensation of the appropriate bromoacetamide benzothiazole, sodium azide and 4-alkyl/aryl-5-(2-fluorophenyl)-3-(prop-2-ynylthio)-1,2,4-triazoles 4a-e through a Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. This approach involves in situ generation of azidoacetamide benzothiazole, followed by condensation with terminal alkynes in the presence of CuSO 4 /Na-ascorbate in aqueous DMSO under both conventional and ultrasound conditions. Some of the designed 1,2,3-triazole conjugates 6a-o were recognized for their antimicrobial activity against some bacterial and fungal pathogenic strains.Keywords: benzothiazoles, 1,2,3-triazoles, 1,2,4-triazoles, click synthesis, antimicrobialBenzothiazole heterocycles constitute an important class of nitrogen-containing hete rocycles associated with a wide array of biological and pharmaceutical activities (1, 2). Similarly, 1,2,4-triazoles are the most signifi cant scaff olds in many drug structures, including fl uconazole (3), isavuconazole (4), itraconazole (5) and voriconazole (6) as antifungal agents. In addition, 1,2,3-triazoles have emerged as relevant bioactive azoles with promising medicinal potentials, including anti-infl ammatory (7), antitubercular (8), antiproliferative (9), anticancer (10, 11) antimicrobial and cytotoxic (12).Synthesis of regioisomeric 1,4-disubstituted 1,2,3-triazoles through copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of terminal alkynes with organoazides is one of the most popular examples of the so-called click chemistry in modern heterocycle synthesis (13). In addition, the copper catalyzed one-pot multicomponent regioselective preparation of 1,2,3-triazoles has att racted a great deal of interest owing to its many advantages, NADJET including simple experimental procedures or mild reaction conditions, reduction of waste, energy effi ciency, reduced reaction time and minimized risk of handling hazardous azides, along with the introduction of eco-friendly sonochemistry for rapid synthesis (14, 15).Ultrasound methods have gained a great deal of interest as alternative sources of energy and have an outstanding status in organic synthesis. Most of the research concerning the application of ultrasound (US) in organic synthesis has been characterized by signifi cant reduction in reaction time and improvement of product yields (16). The obvious advantage of this technique is that its application in organic reactions makes this tool more eff ective and ecofriendly (17).In our early work, we investigated the synthesis and antimicrobial screening of new 1,2,3-triazoles b...

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Section: Antimicrobiological Activity and Sarsupporting

confidence: 92%

Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation

Rezki

Aouad

2017

Acta Pharmaceutica

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“…1 These compounds target the biosynthesis of ergosterol by inhibiting the cytochrome P450-dependent lanosterol 14α-demethylase (Erg11p, CYP51), encoded by the ERG11 gene, resulting in accumulation of toxic methylsterols in membranes that may culminate in fungistatic effect or fungal death. 2 Most azoles are orally active, show a broad-spectrum against most yeasts and filamentous fungi, and are relatively nontoxic.…”

Section: Abstract: Candida Aspergillus Zygomycetes Antifungal Agenmentioning

confidence: 99%

Discovery of a Novel Broad-Spectrum Antifungal Agent Derived from Albaconazole

Guillon

Pagniez

Picot

et al. 2013

ACS Med. Chem. Lett.

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Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed preliminary in vivo antifungal efficacy in a mice model of systemic candidiasis.KEYWORDS: Candida, Aspergillus, zygomycetes, antifungal agents, azoles, thiazolo[4,5-g]quinazolin-8(7H)-one A zoles (fluconazole, itraconazole, voriconazole, and posaconazole) are important drugs for the treatment of invasive fungal infections (IFIs), which continue to be a major cause of morbidity and mortality in immunocompromised or severely ill patients. 1 These compounds target the biosynthesis of ergosterol by inhibiting the cytochrome P450-dependent lanosterol 14α-demethylase (Erg11p, CYP51), encoded by the ERG11 gene, resulting in accumulation of toxic methylsterols in membranes that may culminate in fungistatic effect or fungal death. 2 Most azoles are orally active, show a broad-spectrum against most yeasts and filamentous fungi, and are relatively nontoxic. Unfortunately, the increasing number of fungal infections, coupled with emerging resistance, has resulted in a need to develop new, more effective agents. Among these molecules, albaconazole (UR-9825, Palau Pharma S.A., Figure 1) 3 is a new oral triazole antifungal agent with broad-spectrum antifungal activity against resistant and emerging pathogens as compared with fluconazole and itraconazole, good pharmacokinetics, and excellent oral bioavailability. 4 It has demonstrated high in vitro activities against pathogenic yeasts, dermatophytes, and other filamentous fungi and has been shown to be effective in animal models of systemic aspergillosis, candidiasis, cryptococcosis, and scedosporiosis. 4 Albaconazole has been assayed in several clinical trials, including phase I/II studies in candidal vulvovaginitis, tinea pedis, and onychomycosis (clinicaltrials.gov: NCT00199264, NCT00509275, and NCT00730405). However, phase III studies are not available until now, and the lack of an intravenous form makes studies in the acute infection setting very difficult. 5 As part of our research program focused on the synthesis and SAR studies of novel broad-spectrum antifungal agents, 6−10 we aimed to develop a strict structural analogue of albaconazole in which the quinazolinone ring will be replaced by a thiazoloquinazolinone scaffold (compounds I and II, Figure 1) via Appel salt chemistry. Our goal was to slightly increase the size of the inhibitor to cover a larger area within the active site of fungal

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“…Although sincere efforts are being continuously made for discovering new antifungal targets and drugs, the frequency of human fungal infections has increased drastically worldwide, [1–3]. Of particular concern are the ever-increasing incidences of hospital-acquired systemic mycoses caused by Candida species responsible for crude mortality rates of up to 50% in the United States alone [4].…”

Section: Introductionmentioning

confidence: 99%

Effect of quinoline based 1,2,3-triazole and its structural analogues on growth and virulence attributes of Candida albicans

et al. 2017

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Candida albicans, along with some other non-albicans Candida species, is a group of yeast, which causes serious infections in humans that can be both systemic and superficial. Despite the fact that extensive efforts have been put into the discovery of novel antifungal agents, the frequency of these fungal infections has increased drastically worldwide. In our quest for the discovery of novel antifungal compounds, we had previously synthesized and screened quinoline containing 1,2,3-triazole (3a) as a potent Candida spp inhibitor. In the present study, two structural analogues of 3a (3b and 3c) have been synthesized to determine the role of quinoline and their anti-Candida activities have been evaluated. Preliminary results helped us to determine 3a and 3b as lead inhibitors. The IC50 values of compound 3a for C. albicans ATCC 90028 (standard) and C. albicans (fluconazole resistant) strains were 0.044 and 2.3 μg/ml, respectively while compound 3b gave 25.4 and 32.8 μg/ml values for the same strains. Disk diffusion, growth and time kill curve assays showed significant inhibition of C. albicans in the presence of compounds 3a and 3b. Moreover, 3a showed fungicidal nature while 3b was fungistatic. Both the test compounds significantly lower the secretion of proteinases and phospholipases. While, 3a inhibited proteinase secretion in C. albicans (resistant strain) by 45%, 3b reduced phospholipase secretion by 68% in C. albicans ATCC90028 at their respective MIC values. Proton extrusion and intracellular pH measurement studies suggested that both compounds potentially inhibit the activity of H+ ATPase, a membrane protein that is crucial for various cell functions. Similarly, 95–97% reduction in ergosterol content was measured in the presence of the test compounds at MIC and MIC/2. The study led to identification of two quinoline based potent inhibitors of C. albicans for further structural optimization and pharmacological investigation.

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New Developments in Invasive Fungal Disease

Cited by 45 publications

References 1 publication

Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation

Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation

Discovery of a Novel Broad-Spectrum Antifungal Agent Derived from Albaconazole

Effect of quinoline based 1,2,3-triazole and its structural analogues on growth and virulence attributes of Candida albicans

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