Synthesis and antimicrobial properties of steroid-based imidazolium salts

doi:10.1016/j.jsbmb.2019.02.006

The Journal of Steroid Biochemistry and Molecular Biology

Volume 189, May 2019, Pages 65-72

https://doi.org/10.1016/j.jsbmb.2019.02.006 Get rights and content

Highlights

•
An efficient and convenient preparation of new imidazolium salts based on steroids.
•
New salts showed a broad spectrum of antimicrobial activity.
•
Better antifungal activity against C. albicans than amphotericin B.
•
High inhibitory effect against B. cinerea at a concentration of 5 μg/mL.

Abstract

Imidazolium salts reveal interesting biological properties, especially regarding antitumor and antimicrobial activities. Two series of imidazolium salts based on steroids were obtained in an efficient and convenient synthesis. They were biologically tested to evaluate their antibacterial and antifungal properties. The activities of new salts, especially in relation to Gram-positive bacterial strains are comparable to the activities of known antibiotics. The most promising activity was that against C. albicans, which exceeded the antifungal activity of commonly used drugs. Some of the new salts exhibited improved antifungal activities against phytopathogenic fungi: B. cinerea and C. beticola. Our research showed that new compounds could be potentially useful as antifungal antibiotics or inhibiting agents against pathogenic fungi.

Graphical abstract

Introduction

Imidazolium salts are very important imidazole derivatives that consist of discrete cation and anion pairs [1]. They are widely utilized in organic synthesis, especially as ionic liquids [2] or precursors of N-heterocyclic carbenes [3]. They have a tremendous potential in biological applications, because of their antitumor [[4], [5], [6]] and antimicrobial activities [[7], [8], [9]] or antioxidative properties [10,11]. They are also widely utilized in bioengineering as drug/gene delivery systems [12] or biosensors [13]. Imidazolium salts were also reported to exhibit fungicidal activity [14]. These biological activities are related to their ionic structure, the presence of azole core [15] and various substituents attached to nitrogen atoms. The intrinsic biological activity of an azole moiety is often expressed when it is introduced to some bioactive compounds [16]. Moreover, it should be noted that combining two bioactive molecules as a way to improve biological properties of starting compounds is an emerging practice in medicinal chemistry. In this context, it was expected that a hybrid compound formed by attaching an imidazole moiety to a biologically active steroid may enhance the biological properties of both fragments [17,18]. The basicity and hydrophilicity of an azole moiety might alter the biological function of a steroid. Lithocholic acid (LCA, 1) was chosen because of its wide range of biological activities such as α-2,3-sialyltransferase inhibition [19], vitamin D receptor modulation [20], antibacterial and antifungal effect [21], and antitumor activity [22,23]. These interesting properties are connected with its large, rigid, and curved steroidal skeleton, enantiomeric purity and unique amphiphilicity. The pharmacological interest in lithocholic acid is directly related to the fact that liver cells can speciﬁcally recognize such a natural ligand, which makes LCA ideal building block for the synthesis of novel molecules that can be recognized at the molecular level [24]. Derivatives of 1 with oxazole fragment itself display some antifungal activity against Candida albicans [25].

Syntheses of some steroids with an imidazole ring attached to different positions of the skeleton were reported by substitution of halogeno- or epoxy-steroids with lithiated imidazole either under standard conditions [26,27] or using microwave irradiation [28]. These compounds exhibit cytotoxic activity against cancer cells [29,30], inhibit 17α-lyase [31], show potent skeletal muscle relaxant and neuromuscular blocking properties [32]. They can also be utilized as receptors for ﬂuoride ion recognition [33]. However, to the best of our knowledge, there is no report about antimicrobial activity, including activity against plant pathogens, of imidazolium salts, especially steroid derivatives substituted in the side chain (22- or 24-imidazolo). We designed and synthesized two series of imidazolium salts starting from lithocholic acid and a steroid compound similar to one of LCA metabolites [34] with a 4-en-3-one group in ring A and a shorter side chain: 3-oxo-23,24-dinorchol-4-en-22-al (2) (Fig. 1).

Section snippets

General remarks

Melting points were determined on an MP70 (Mettler Toledo) apparatus and were uncorrected. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance II spectrometer (400 and 100 MHz, respectively). Spectra are referenced relative to the chemical shift of TMS. Mass spectra were obtained with Micromass LCT TOF and Accurate-Mass Q-TOF LC/MS 6530 spectrometers. IR spectra were recorded on a Nicolet series II Magna-IR 550 FT-IR spectrometer. Column chromatography was performed on silica gel 230–400

Synthesis of imidazolium salts

Two series of imidazolium iodides based on lithocholic acid (1, Scheme 1) and 3-oxo-23,24-dinorchol-4-en-22-al (2, Scheme 2) were prepared. LCA was subjected to reduction with LiAlH₄ [35] followed by p-tosylation of the 24-hydroxy group. Selective tosylation was achieved using Et₃N as a base at 0–4 °C in THF [36,37]. The crude product needed chromatographic purification due to contamination by 3,24-ditosylate (20%) then was isolated in 60% yield. The 24-iodide (3, Scheme 1) was synthesized by

Conclusion

Two series of steroid-based imidazolium salts were synthesized in a short, straightforward route and their antimicrobial activities were investigated. New compounds were tested against human and plant pathogens. The most promising finding was the activity against C. albicans, which exceeded the antifungal activity of commonly used antibiotics. Additionally, new salts with N-ethyl substituent at the imidazole moiety showed greater activity compared to known fungicides against phytopathogenic

Acknowledgement

The authors gratefully acknowledge financial support from the National Science Centre, Poland, Grant No. UMO-2015/17/B/ST5/02892.

References (42)

X.H. Zeng et al.
Synthesis and antitumor activity of 1-mesityl-3-(2-naphthoylmethano)-1H-imidazolium bromide
Bioorg. Med. Chem. Lett.
(2010)
C.A. Clausen et al.
Azole-based antimycotic agents inhibit mold on unseasoned pine
Int. Biodeter. Biodeg.
(2005)
S. Raghavan et al.
Synthesis and anticancer activity of novel curcumin-quinolone hybrids
Bioorg. Med. Chem. Lett.
(2015)
J.C. Coa et al.
Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids
Eur. J. Med. Chem.
(2015)
R. Adachi et al.
Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative
J. Lipid Res.
(2005)
H. Schneider et al.
Inhibitory potency of lithocholic acid analogs and other bile acids on glucuronosyltransferase activity in a colon cancer cell line
Bioorg. Med. Chem. Lett.
(1996)
O. Bortolini et al.
Biotransformations on steroid nucleus of bile acids
Steroids
(1997)
L.R. Fernández et al.
Synthesis and antifungal activity of bile acid-derived oxazoles
Steroids
(2016)
F.F. Wong et al.
Synthesis of 3α-hydroxy-21-(1′-imidazolyl)-3β-methoxyl-methyl-5α-pregnan-20-one via lithium imidazole with 17α-acetylbromopregnanone
Steroids
(2006)
P. Saikia et al.
Synthesis of steroidal and nonsteroidal vicinal heterocyclic alcohols, N-(1-cycloalkenyl)heterocycles and their antibacterial studies
Steroids
(2014)

R. Bansal et al.

Design, synthesis and evaluation of novel 16-imidazolyl substituted steroidal derivatives possessing potent diversified pharmacological properties

Steroids

(2012)

A.V. Silva-Ortiz et al.

Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells

Bioorg. Med. Chem.

(2017)

V.C.O. Njar et al.

Nucleophilic vinylic “addition-elimination” substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene: a novel and general route to 17-substituted steroids

Bioorg. Med. Chem. Lett.

(1996)

H. Hu et al.

3,16-Bisquaternary ammonium steroid derivatives as neuromuscular blocking agents: synthesis and biological evaluation

Steroids

(2015)

M. Chahar et al.

Design of steroid-based imidazolium receptors for fluoride ion recognition

Tetrahedron

(2008)

A. Valkonen et al.

Novel lithocholaphanes: syntheses, NMR, MS, and molecular modeling studies

J. Mol. Struct.

(2007)

L. Nahar et al.

Synthesis of 3β,6α-dihydroxy-5α-cholan-23-one

Tetrahedron

(2003)

X. Wang et al.

Design and synthesis of novel 3-(thiophen-2-yl)-1,5-dihydro-2H-pyrrol-2-one derivatives bearing a hydrazone moiety as potential fungicides

Chem. Cent. J.

(2018)

S.N. Riduan et al.

Imidazolium salts and their polymeric materials for biological applications

Chem. Soc. Rev.

(2013)

Y.G. Zhang et al.

Sustainable chemistry: imidazolium salts in biomass conversion and CO₂ fixation

Energy Environ. Sci.

(2010)

N. Marion et al.

N-Heterocyclic carbenes as organocatalysts

Angew. Chem. Int. Ed.

(2007)

Cited by (29)

Design, synthesis and molecular docking of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives that act as iNOS/COX-2 inhibitors with potent anti-inflammatory activity against LPS-induced RAW264.7 macrophage cells
2024, Journal of Steroid Biochemistry and Molecular Biology
Inflammation, an important biological protective response to tissue damage or microbial invasion, is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of pyrazole and thiazole scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives were synthesized and evaluated their anti-inflammatory activities in vitro. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in lipopolysaccharide (LPS)-induced RAW 264.7 cells, and the optimal compound 12b [3β-hydroxy-pregn-5-en-17β-yl-5′- (o- chlorophenyl)− 1′-(4′′- phenyl -[1′′, 3′′]- thiazol-2′′- yl) − 4′,5′-dihydro − 1′H-pyrazol − 3′- yl] exhibited more potent anti-inflammatory activity than the positive control treatment methylprednisolone (MPS), with an IC₅₀ value of 2.59 μM on NO production and low cytotoxicity against RAW 264.7 cells. In further mechanism study, our results showed that compound 12b significantly suppressed the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking NF-κB p65 nuclear translocation and phosphorylation of IκBα. Compound 12b also attenuated LPS-induced activation of c-Jun amino-terminal kinase (JNK) and p38 phosphorylation in RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 12b to the active site of the COX-2 proteins, which confirmed that compound 12b acted as an anti-inflammatory mediator. These results indicate that steroidal derivatives bearing 4,5-dihydropyrazole thiazole structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 12b might be a promising therapeutic anti-inflammatory drug candidate.
Synthesis and antagonistic evaluation of fluorinated imidazolium salt [1-(2,6-diisopropylphenyl)-3-(2-fluoro-benzyl)-1H-imidazol-3-ium bromide] against significant phytopathogens in agriculture
2024, Journal of Fluorine Chemistry
The current investigation evaluated the in vitro bioefficacy of a newly synthesized unsymmetrical imidazolium salt [1-(2,6-diisopropylphenyl)-3-(2-fluoro-benzyl)-1H-imidazol-3-ium bromide] that contains the electron-withdrawing fluorine atom at the ortho position against agriculturally significant phytopathogens. The molecular structure of the imidazolium salt was characterized by various spectroscopic techniques such as ¹H, ¹³C, and ¹⁹F NMR, FTIR, and high-resolution mass spectrometry (HRMS). Antimicrobial bioassay of the compound has been tested against two Gram-negative, bacterial phytopathogens namely Ralstonia solanacearum (Rs) (Gen Bank accession no. OQ743450) [causal agent: bacterial wilt of solanaceous crops], and Xanthomonas citri pv. citri (Xcc) (Gen Bank accession no. OR7036310) [causal agent: citrus canker in citrus trees] and two fungal phytopathogens namely Fusarium solani (Gen Bank accession no. OR140825) [causal agent: Fusarium die-back in tea] and Pseudopestalotiopsis chinensis (Gen Bank accession no. OR140826) [causal agent: grey blight in tea]. Different concentrations of imidazolium salt was tested against the target phytopathogens using the in vitro antimicrobial bioassay through disc diffusion method. The imidazolium salt demonstrated a maximum percentage inhibition of 16.70 and 21.78 against the bacterial phytopathogens R. solanacearum, and X. citri pv. citri, respectively, at a concentration of 2000 ppm over negative control. Similarly, the compound demonstrated promising antagonism against the tea fungal pathogens F. solani and P. chinensis (percentage inhibition up to 61.43 and 80.84, respectively at 2000 ppm) over negative control. Five replications were maintained in each of the cases. The present investigation demonstrated the potential of fluorinated imidazolium salt as commercial antimicrobial agent in integrated disease management schedule to control significant phytopathogenesis in agriculture including in tea.
Antibacterial activity of withanolides and their structure-activity relationship
2023, Steroids
Two new withanolides, (17R,20S,22R)-4β-acetoxy-5β,6β-epoxy-19,27-dihydroxy-1-oxo-witha-2,24-dienolide (withalongolide A 4-acetate (5) and (17R,20S,22R)-5β,6β-epoxy-27-hydroxy-1,4-dioxo-witha-24-enolide (9), and seven known withanolides with normal structure (1–4, 6–8) were isolated from aerial parts of Cuatresia colombiana. Several semisynthetic derivatives were prepared from the natural metabolites withaferin A and jaborosalactone 38. The compounds were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS). The compounds isolated from C. colombiana, sixteen withanolides previously isolated from different Solanaceae species with different skeletons and semisynthetic derivatives were evaluated for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. According to the bioactivity against S. aureus and E. faecalis, the compounds evaluated were divided into three groups: compounds with high activity (MIC 0.063 mM), compounds with moderate activity (0.5 mM > MIC > 0.125 mM) and non-active compounds (MIC ≥1 mM); in addition, some structure-activity relationship keys could be inferred.
Concise synthesis of E/F ring spiroethers from tigogenin. Carbaanalogs of steroidal sapogenins and their biological activity
2022, Journal of Steroid Biochemistry and Molecular Biology
A four-step synthesis of five- and six-membered E/F ring spiroethers from tigogenin has been developed. An efficient strategy that features bis-Grignard reaction of dinorcholanic lactone with appropriate bis(bromomagnesio)alkanes followed by acid-mediated spirocyclization was employed to construct a new class of steroid compounds having E and F ring junction as an oxa-carbacyclic system. The synthesized carbaanalogs interact with liposomes and albumin, and also exhibit antibacterial and antifungal activity, demonstrating their pharmacological potential.
Synthesis, characterization and application of new imino-functionalized 1,3-diazolium salts as antimicrobial agents
2022, Journal of Molecular Structure
Citation Excerpt :
The ease with which the structure, properties and reactivity of azolium compounds bearing either an imidazole or a benzimidazole moiety may be tuned has made them good templates for diverse applications in the chemical and allied industries [1,2], cosmetics, nanotechnology, and as pharmaceuticals [3–5].
The simple solventless quaternization of N-substituted 1,3-diazoles with 2-bromoethyliminomethylnaphthol yielded three new Schiff base (SB or imine)-functionalized 1,3-diazolium [3 (SB-imidazolium), 4 and 5 (SB-benzimidazolium)] salts. The compounds were characterized spectroscopically, and the single-crystal solid-state structure of compound 3 [3-(2-(2-hydroxynaphthalen-1-yl) methylene) amino) ethyl) methylimidazol-3-ium hexafluorophosphate] was analyzed by X-ray diffraction. When tested as antimicrobials, each salt gave significant activity against the Gram-positive Staphylococcus aureus ATCC 25923 strain and the Methicinin resistant Staphylococcus aureus ATCC 700699 (MRSA) strain with the best minimum inhibitory concentration (MIC) value of 1.25 µg/mL recorded for 4. Although not as active as the positive control, Ciprofloxacin, the observed activities of the compounds are comparable to those reported for some standard antibiotics and significantly better than similar 1,3-diazolium salts that are already reported in the literature. The use of theoretical molecular docking supports the experimental MIC values for the salts. This is because the estimated negative binding energies of -6.45, -7.27 and -7.84, kcal/mol for 3, 4 and 5, respectively, indicated favourable binding with the MRSA lipase enzyme complexes. Furthermore, the results of a hemolytic assay corroborated the antimicrobial test results, which showed ≤5% hemolysis of red blood cells at the most active concentration (lowest MIC value) recorded for the salts. In summary, the results of the antibacterial activity study and the negative Gibbs binding energies that are within safe hemolysis percentages make the new azolium salts good templates in drug design.
Pregnane steroids from the twigs and leaves of Strophanthus divaricatus and their cytotoxic activities
2022, Tetrahedron Letters

View all citing articles on Scopus

View full text

Synthesis and antimicrobial properties of steroid-based imidazolium salts

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

General remarks

Synthesis of imidazolium salts

Conclusion

Acknowledgement

Bioorg. Med. Chem. Lett.

Int. Biodeter. Biodeg.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

J. Lipid Res.

Bioorg. Med. Chem. Lett.

Steroids

Steroids

Steroids

Steroids

Steroids

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Steroids

Tetrahedron

J. Mol. Struct.

Tetrahedron

Chem. Cent. J.

Imidazolium salts and their polymeric materials for biological applications

Chem. Soc. Rev.

Sustainable chemistry: imidazolium salts in biomass conversion and CO2 fixation

Energy Environ. Sci.

N-Heterocyclic carbenes as organocatalysts

Angew. Chem. Int. Ed.

Sustainable chemistry: imidazolium salts in biomass conversion and CO₂ fixation