Synthesis and antifungal activity of N-benzyl derivatives of amphotericin B

Belakhov, V. V.; Shenin, Yu. D.

doi:10.1007/s11094-007-0082-6

Cited by 5 publications

(6 citation statements)

References 29 publications

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“…In particular, many of the substituted amidophosphates exhibited antifungal [60,61], antibacterial [61], or antitumor [62][63][64] activity. The reported results and our earlier studies of phosphorylation of polyene macrolide antibiotics [40][41][42][43][65][66][67][68] attracted our interest to investigation of medicinal and biological properties of the prepared derivatives I-V.…”

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confidence: 85%

“…However, Amphotericin B is known for high toxicity (mainly nephrotoxicity) [9,11,31], low gastroenteric absorptivity [32,33], a number of side effects [3,14], and a reduced resistance of certain pathogenic fungi to Amphotericin B action [34,35]; therefore studies of various derivatives of this antibiotics have been emerging [36][37][38][39]. In earlier studies we prepared hydrophosphoryl [40], fluoroorganic [41], and N-benzyl derivatives of Amphotericin B [42].…”

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confidence: 99%

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Chemical modification of heptaene macrolide antibiotic Amphotericin B under conditions of the Atherton-Todd reaction

2014

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Chemical modification of heptaene macrolide antibiotic Amphotericin B with dialkyl(diaryl)phosphites has been performed under conditions of the Atherton-Todd reaction. As a result, the corresponding dialkyl(aryl)amidophosphonate derivatives of Amphotericin B have been formed. The prepared derivatives have been characterized by their physicochemical properties, toxicity, and antifungal activity against a set of test cultures of pathogenic fungi and yeast-like fungi of the Candida species.

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confidence: 85%

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confidence: 99%

Chemical modification of heptaene macrolide antibiotic Amphotericin B under conditions of the Atherton-Todd reaction

2014

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“…In 1988, Chéron et al [ 141 ] were the pioneers in studying the correlation between AMB derivates and their biological activity. Such compounds represent a unique basis for the study of the antifungal structure–activity relationship and the understanding of its properties [ 142 , 143 ]. Basically, the four axes that support its structure–activity relationship are (1) the derivation of a hydroxyl group at C-13; (2) the absence of a negative charge in the acid group; (3) the polyene itself; and (4) an ionizable nitrogen [ 144 , 145 ].…”

Section: Structure–activity Relationship and Drug–target Interactionsmentioning

confidence: 99%

Sixty years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections

Cavassin

Baú-Carneiro²,

Vilas-Boas³

et al. 2021

Infect Dis Ther

167

123

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Introduced in the late 1950s, polyenes represent the oldest family of antifungal drugs. The discovery of amphotericin B and its therapeutic uses is considered one of the most important scientific milestones of the twentieth century . Despite its toxic potential, it remains useful in the treatment of invasive fungal diseases owing to its broad spectrum of activity, low resistance rate, and excellent clinical and pharmacological action. The well-reported and defined toxicity of the conventional drug has meant that much attention has been paid to the development of new products that could minimize this effect. As a result, lipid-based formulations of amphotericin B have emerged and, even keeping the active principle in common, present distinct characteristics that may influence therapeutic results. This study presents an overview of the pharmacological properties of the different formulations for systemic use of amphotericin B available for the treatment of invasive fungal infections, highlighting the characteristics related to their chemical, pharmacokinetic structures, drug–target interactions, stability, and others, and points out the most relevant aspects for clinical practice.

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“…2 to 4 and Table 2. Compounds 1, 2, 2j, 3,5,6, and 6j were also tested against additional numbers of yeasts (see the supplemental material).…”

Section: ) N-fructosyl-s44hp (Compound 2k) N-(4-nn-dimethylaminobementioning

confidence: 99%

“…Chemical modifications of the C-16 carboxyl and/or mycosamine 3= amino groups of AMB were extensively studied and several semisynthetic derivatives of AMB with improved characteristics have been described (2)(3)(4)(5). However, despite some promising initial results obtained for such derivatives, no new AMBbased antifungal agent has appeared on the market, except for the lipid and liposomal formulations (1,6).…”

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Structure-Antifungal Activity Relationships of Polyene Antibiotics of the Amphotericin B Group

Tevyashova

Olsufyeva

Solovieva

et al. 2013

Antimicrob Agents Chemother

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A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10. Antibiotics with OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH 3 or COOH group in the position C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis sepsis in leukopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (compound 3n) and, especially, L-glutamate of 2-(N,N-dimethylamino)ethyl amide of S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties.

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Synthesis and antifungal activity of N-benzyl derivatives of amphotericin B

Cited by 5 publications

References 29 publications

Chemical modification of heptaene macrolide antibiotic Amphotericin B under conditions of the Atherton-Todd reaction

Chemical modification of heptaene macrolide antibiotic Amphotericin B under conditions of the Atherton-Todd reaction

Sixty years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections

Structure-Antifungal Activity Relationships of Polyene Antibiotics of the Amphotericin B Group

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