Organofluorine derivatives of nystatin

Abstract

The polyene macrolide antibiotic nystatin finds wide application in practice for the therapy of all clinical forms of candidiasis [1,2]. The main disadvantages of this antimycotic antibiotic, as well as of the other polyene macrolides, are rather high toxicity, poor solubility in water, instability during storage, and decreasing sensitivity (adaptation) of the pathogenic fungous microorganisms to the action of this agent. In order to increase the chemotherapeutic efficacy of nystatin, pharmacists are searching for its semisynthetic analogs. In recent years, the interest of researchers is drawn to the synthesis of functionally-substituted derivatives of this antibiotic [3 -5]. Previously we have reported on the synthesis of organosilicon [6] and hydrophosphoryl [7] derivatives of nystatin.In this communication we report on the reactions between nystatin and organofluorine compounds and the medico-biological properties of the resulting nystatin derivatives.It was established that interactions of nystatin with trifluoroacetic and perfluoropropionic anhydrides lead to the formation of the corresponding N-perfluoroacylnystatin derivatives (I and II).The structures of these organofiuorine derivatives were determined by methods of IH and 19F NMR spectroscopy and IR and UV spectrophotometry. The compositions are verified by elemental analyses whose data coincide with the results of analytical calculations based on the empirical formulas. The IH NMR spectra of compounds I and II show the signals due to protons characteristic of nystatin; protons at the nitrogen atoms are manifested by a broadened singlet in the region of 5.79 ppm. The 19F NMR spectrum of compound I contains a singlet at 7.51 ppm, and the spectrum of compound II exhibits a pair of singlets at 7.39 ppm (CF3) and 45.76 ppm (CF2), which are typical of N-perfluoroacyl derivatives of amino sugars [8,9]. The spin-spin coupling constant JF-F (CF2, CF3) can hardly be determined in practice since the value ex-

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

“…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.…”

“…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].…”

Synthesis and antifungal activity of N-trialkylsilyl derivatives of nystatin

“…The literature contains descriptions of a whole series of nystatin derivatives: esters [9 -12], N-acyl derivatives [13 -15], N-glycoside derivatives [16 -18], amides [19], hydrazides [10], and enamine and amidine [21], hydrophosphoryl [22], and organofluorine [23] derivatives, along with water-soluble salts and complexes [24 -28]. Special attention has in recent years been paid to liposomal derivatives of nystatin, which have significantly lower toxicity, better pharmacokinetic characteristics, and greater antibiotic stability [29 -32].…”

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

“…We have previously prepared hydrophosphoryl [37] and fluoroorganic [38] derivatives of amphotericin B. In continuation of research on the preparation of semisynthetic deriva-tives of amphotericin B, we studied the reaction of this polyene antibiotic with benzaldehydes and cyanoborohydride and produced the corresponding N-benzyl derivatives I -XI.…”