Synthesis, FT-IR, 1H, 13C NMR, ESI MS and PM5 studies of a new Mannich base of polyether antibiotic – Lasalocid acid and its complexes with Li+, Na+ and K+ cations

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Abstract

The polyether antibiotic Lasalocid acid has been converted to its Mannich base derivative by a chemoselective one-pot reaction with formaldehyde and morpholine through the decarboxylation process. Spectroscopic studies of the structure of this new derivative have shown that in this ortho-phenol Mannich base the Osingle bondH⋯N intarmolecular hydrogen bond is present. The compound forms complexes with Li+, Na+ and K+ cations of exclusively 1:1 stoichiometry. The structures of these complexes have been studied and visualized by semi-empirical calculation based on results of spectrometric and spectroscopic investigation. It is demonstrated that in contrast to Lasalocid acid the novel Mannich type derivative forms preferential complexes with Li+ cation.

Highlights

► A new ortho-phenol Mannich base of Lasalocid was synthesized by chemoselective one-pot reaction. ► The compound obtained is a useful ligand for complexation of monovalent cations. ► Spectroscopic characterization of the ligand and prepared complexes is given. ► Semiempirical calculations of structures of the complexes studied are presented.

Introduction

Lasalocid acid (Scheme 1) and its derivatives represent a large class of ionophore antibiotics. These compounds show a broad spectrum of bioactivity e.g. antibacterial, antifungal, antiparasitic and antiviral [1], [2], [3], [4], [5], [6], [7]. Lasalocid acid sodium salt is used as an antibiotic for poultry and as a growth promoter for ruminants [1], [2]. Lasalocid acid isolated from Streptomyces lasaliensis is able to form complexes with monovalent and divalent cations and transport them across lipid bilayer. The influx of Na+ into the cell of Gram-positive bacteria leads to changes in pH and to an increase in the osmotic pressure inside the cell, causing swelling and vacuolization, eventually leading to cell death. The effectiveness of this process strongly depends on the structure of the Lasalocid metal cation complexes [1], [2], [3], [4]. In previous studies we have shown that the complex of Lasalocid with allylamine has higher anti-bacterial activity than pure Lasalocid acid [8]. We found also that Lasalocid acid and its complexes are strong cytotoxic agents towards cancer cell lines. The cytostatic activity of Lasalocid and its complexes with amines against human cancer cell lines is higher than that of cisplatin, indicating that Lasalocid and its complexes are promising candidates for new anticancer drugs [9].

Since various N-functionalized morpholines show pharmacological activity, we synthesized a new morpholine Mannich base derivative of Lasalocid acid. Such compounds are reported to exert a number of important physiological activities such as antiemetic or growth stimulant. They are also used in the treatment of inflammatory diseases, pain, migraine, and asthma [10], [11], [12]. In this contribution, the nature of complexes formed between Mannich base of Lasalocid acid with morpholine (2) and monovalent cations (Li+, Na+ and K+) is studied using 1H NMR, 13C NMR, FTIR, ESI-MS as well as PM5 semiempirical methods. The structures of these complexes with metal cations are discussed in detail.

Section snippets

Materials and methods

Lasalocid sodium salt was isolated from veterinary premix – Avatec® 20 (Alpharma Inc.), which contains about 20% pure Lasalocid sodium salt. Formaldehyde, morpholine and the perchlorates LiClO4, NaClO4 and KClO4 were commercial products of Sigma and used without any further purification. Since the salts were hydrates, it was necessary to dehydrate them at several (6–10 times) evaporation steps from a 1:5 mixture of acetonitrile and absolute ethanol. The dehydration of perchlorates was followed

Synthesis of Mannich base of Lasalocid acid (2)

Design of procedures to obtain semi-synthetic derivatives of Lasalocid acid (1) (Scheme 1) is challenging because its structure is stable neither in strongly acidic nor in strongly basic conditions. Additionally, since the structure of Lasalocid comprises many different functional groups (i.e. carboxylic, ketone, aromatic, etheric hydroxyl groups) it was important for the synthetic transformation to be highly chemoselective. Taking into account the above it was deduced that a Mannich reaction

Conclusions

For the first time the Lasalocid Mannich base derivative (2) and its 1:1 monovalent metal cation complexes have been obtained and characterized by spectroscopic (FT-IR, 1H- and 13C NMR), mass spectrometry (ESI-MS) and PM5 semiempirical methods. Lasalocid acid (1) a well known polyether antibiotic has been converted to its Mannich base derivative (2) by a simple one-pot reaction. Spectroscopic studies of the structure of 2 have shown that in this ortho-phenol Mannich base the O–H⋅⋅⋅N

Acknowledgements

Financial support from budget funds for science in years 2012–2013 – Grant ”Iuventus Plus” of the Polish Ministry of Science and Higher Education-No. 0179/IP3/2011/71, is gratefully acknowledged. The financial support of the DAAD (The German Academic Exchange Service) is gratefully acknowledged by Adam Huczyński.

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