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Molecules 2014, 19(4), 4212-4233; doi:10.3390/molecules19044212

Synthesis, Spectroscopic and Theoretical Studies of New Quaternary N,N-Dimethyl-3-phthalimidopropylammonium Conjugates of Sterols and Bile Acids
Bogumil Brycki *, Hanna Koenig, Iwona Kowalczyk and Tomasz Pospieszny *
Laboratory of Microbiocide Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, Poznań 60-780, Poland
Authors to whom correspondence should be addressed; Tel.: +48-61-829-13-14 (B.B.); +48-61-829-13-07 (T.P.).
Received: 12 February 2014; in revised form: 19 March 2014 / Accepted: 21 March 2014 / Published: 3 April 2014


: New quaternary 3-phthalimidopropylammonium conjugates of steroids were obtained by reaction of sterols (ergosterol, cholesterol, cholestanol) and bile acids (lithocholic, deoxycholic, cholic) with bromoacetic acid bromide to give sterol 3β-bromoacetates and bile acid 3α-bromoacetates, respectively. These intermediates were subjected to nuclephilic substitution with N,N-dimethyl-3-phthalimidopropylamine to give the final quaternary ammonium salts. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry (ESI-MS, MALDI) as well as PM5 semiempirical methods and B3LYP ab initio methods. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS).
sterols; bile acids; quaternary ammonium salt; conjugates; N,N-dimethyl-3-phthalimidopropylamine; PASS; PM5 calculations; B3LYP ab initio methods

1. Introduction

Steroids are a large class of organic compounds. They play a very important role in animals, plants and microorganisms. The best known steroid is certainly cholesterol. Cholesterol was isolated for the first time from gall stones nearly two centuries ago by Chevreul [1,2]. This sterol is an important component of mammalian cell membranes; it is also present in significant concentrations in the brain and nervous tissue [3,4,5,6]. Cholesterol is the biosynthetic precursor of steroid hormones, bile acids, vitamin D and lipoproteins [7,8,9]. Like the functions of cholesterol in mammals, ergosterol is necessary to support the life of fungi. It serves two main purposes: a bulk membrane function and a sparking function. Ergosterol is a biological precursor to vitamin D2 (ergocalciferol) [10,11,12].

All sterols are crystalline compounds with a secondary hydroxyl group in the position C(3) of the steroid skeleton, one or two double bonds and differently modified side chains. Rings A/B of the steroid skeleton may have trans geometry (the allo series) or cis (the normal series). Sterols have the hydroxy group on the C(3) position forming a number of β-sterols with respect to the average plane of the ring. By contrast bile acids have hydroxy groups on the C(3) position which prefer the α orientation [13,14,15,16,17].

Bile acids are major metabolites of cholesterol, being end products of its metabolism in the liver [18,19]. They are isolated from the bile of higher animals, where they are found as sodium salts of peptide conjugates with glycine and taurine. The most important are the primary bile acids, e.g., chenodeoxycholic acid and cholic acid, which are successively transformed into secondary bile acids such as ursodeoxycholic, deoxycholic and lithocholic acids [20,21,22]. Bile acids (e.g., lithocholic, deoxycholic and cholic) are very interesting because they display a large, rigid, and curved skeleton. Moreover, they possess chemically different polar hydroxy groups (3α, 3α,7α and 3α,7α,12α) and amphiphilic properties. Modifications of the functional groups of sterol molecules allow one to obtain systems with high pharmacological activity [23].

Quaternary alkylammonium salts play an important role in the living organisms and many functions of prokaryotic and eukaryotic cells have been shown to be alkylammonium salts dependent [24,25]. These compounds also exhibit excellent antimicrobial activity, and therefore they are used as antiseptics, bactericides and fungicides, as well as therapeutic agents. In general, quaternary alkylammonium salts with good antimicrobial activities contain one or two alkyl chains with lengths in the C8–C14 range. For the applications as softeners and hair conditioning agents hydrocarbon chain lengths between C16 and C18 are used [26,27,28]. Phthalimides, and N-substituted phthalimides are also an important class of compounds because of their biological activities as antimicrobial agents [29,30]. It has recently been shown that tetrachlorophthalimide derivatives are good α-glucosidase inhibitors [31]. The use of microbiocides of the same type for a long time may cause an increase of resistance of microorganisms to the chemicals used, which is a very serious and dangerous problem. Antimicrobial resistance of bacteria comprises a wide variety of biochemical mechanisms and processes that allow microorganisms to grow in the presence of microbiocides [32,33,34]. There are many ways to overcome the risk of an increasing resistance of microorganisms, however the best one is a periodically application of new microbiocides with modified structures [35,36]. Therefore, connections of sterols and bile acids with various amines or polyamines appears to be an unusually interesting potential approach to such new structures [37,38,39,40].

2. Results and Discussion

In the present work, the synthesis and physicochemical properties of some new quaternary N,N-dimethyl-3-phthalimidopropylammonium conjugates of sterols (ergosteryl 3β-bromoacetate (4), cholesteryl 3β-bromoacetate (5), dihydrocholesteryl 3β-bromoacetate (6)) and derivatives of bile acids (methyl litocholate 3α-bromoacetate (13), methyl deoxycholate 3α-bromoacetate (14) and methyl cholate 3α-bromoacetate (15)) with N,N-dimethyl-3-phthalimidopropylamine in acetonitrile are investigated.

New quaternary 3-phthalimidopropylammonium conjugates of steroids were obtained by reaction of ergosterol (1), cholesterol (2), cholestanol (5α-cholestan-3β-ol, 3), and bile acids 1012 with bromoacetic acid bromide to give 46 and 1315. The 3β-bromoacetates of sterols and 3α-bromoacetates of bile acids, as well as N,N-dimethyl-3-phthalimidopropylamine were prepared according to the literature procedures [41,42]. The structure of products was confirmed by 1H-NMR, 13C-NMR, and FT-IR analysis, as well as ESI-MS and MALDI. The syntheses of conjugates 7–9 and 1618 are shown in Scheme 1.

Scheme 1. Synthesis of quaternary phthalimidopropylammonium conjugates of sterols 79 (a) and bile acids 1618 (b).
Scheme 1. Synthesis of quaternary phthalimidopropylammonium conjugates of sterols 79 (a) and bile acids 1618 (b).
Molecules 19 04212 g010 1024

Potential pharmacological activities of the synthesized compounds have been determined on the basis of computer-aided drug discovery approach with in silico Prediction of Activity Spectra for Substances (PASSs) program. It is based on a robust analysis of the structure-activity relationship in a heterogeneous training set currently including about 60,000 biologically active compounds from different chemical series with about 4,500 types of biological activities. Since only the structural formula of the chemical compound is necessary to obtain a PASS prediction, this approach can be used at the earliest stages of investigation. There are many examples of the successful use of the PASS approach leading to new pharmacological agents [43,44,45,46,47]. The PASS software is useful for the study of biological activity of secondary metabolites. We have selected the types of activities that were predicted for a potential compound with the highest probability (focal activities). If predicted activity is higher than 0.7 (PA > 0.7), the substance is very likely to exhibit the activity in experiment and the chance of the substance being the analogue of a known pharmaceutical agent is also high. If predicted activity is between 0.5 and 0.7 (0.5 < PA < 0.7), the substance is unlikely to exhibit the activity in experiment and the similarity to known pharmaceutical substance is very limited.

The structures of all synthesized compounds were determined from their 1H- and 13C-NMR, FT-IR and ESI-MS spectra. Moreover, PM5 calculations and B3LYP ab initio methods were performed for all compounds. Additionally, analyses of the biological prediction activity spectra for the new esters prepared herein are good examples of in silico studies of chemical compounds. We also selected the types of activity that were predicted for a potential compound with the highest probability (focal activities) (Table 1). According to these data the most frequently predicted types of biological activity are: inhibitors glyceryl-ether monooxygenase, acylcarnitine hydrolase, alkylacetylglycerophosphatase, plasmanylethanolamine desaturase, N-(acyl)ethanolamine deacylase and protein-disulfide reductase.

Table 1. “Probability to be Active” (PA) values for the predicted biological activity of 79 and 1618.
Table 1. “Probability to be Active” (PA) values for the predicted biological activity of 79 and 1618.
Focal Predicted Activity (PA > 0.80)Compounds
Glyceryl-ether mono-oxygenase inhibitor0.870.910.930.930.940.95
Acylcarnitine hydrolase inhibitor--0.810.830.910.94
Alkylacetylglycerophosphatase inhibitor---0.820.900.86
Plasmanylethanolamine desaturase inhibitor----0.710.78
CYP3A4 substrate----0.700.73
N-(acyl)ethanolamine-deacylase inhibitor----0.730.76
Protein-disulfide reductase inhibitor--0.72-0.75-
Alkenylglycerophosphocholine hydrolase inhibitor----0.80-
Oxidoreductase inhibitor0.870.77----
Alcohol O-acetyl-transferase inhibitor0.88-----
DELTA14-sterol reductase inhibitor-0.73----
Alkylacetylglycerophosphatase inhibitor--0.84---
Glucan endo-1,3-β-D-glucosidase inhibitor----0.73-
D-lactaldehyde dehydrogenase inhibitor-----0.74

The 1H-NMR spectra of compounds 79 show characteristic multiplets in the range 4.96–4.48 ppm assigned to the C3α–H protons of the sterol skeleton. Similarly, compounds 1618 exhibit multiplets in the range 4.92–4.55 ppm which are assigned to the C3β–H protons of the bile acid skeleton (Figure 1). A proton singlet at 0.83 ppm for 7 and singlets in the range of 0.68–0.64 ppm for other conjugates are assigned to CH3–18. The other singlets ranging from 1.04–0.79 ppm, 0.91 ppm and 0.89 ppm are assigned to CH3–19 for 79, 17 and 18, respectively. In the case of compound 16 signal of the CH3–19 group and CH3–21 group form the multiplet. The characteristic doublets of CH3–21, with the exception of conjugate 16, are observed at 0.98–0.90 ppm and are assigned to conjugates 710, 17 and 18.

Figure 1. 1H-NMR spectra in the region (8.0–3.5 ppm) of the most characteristic signals of conjugates 8 (a) and 18 (b).
Figure 1. 1H-NMR spectra in the region (8.0–3.5 ppm) of the most characteristic signals of conjugates 8 (a) and 18 (b).
Molecules 19 04212 g001 1024

The characteristic doublets of the ergosterol-substituted derivatives are observed at 1.01 ppm for CH3–28 group and 0.84 ppm for CH3–27 and CH3–26 groups, respectively. The 1H-NMR spectra of conjugates 8 and 9 show doublets at 0.87 and doublet of doublets at 0.86 ppm of the C(26) and C(27) methyl group. In the 1H-NMR spectra of sterol conjugates 79 and bile acid conjugates 1618 a signal of protons of the COCH2N+ group in the range 5.35–4.55 ppm is observed. The peaks of six methyl protons of the N+(CH3)2 and two methylene protons of the N+CH2 appear as singlets and multiplets or broad singlets in the range 3.69–3.61 ppm and 4.96–3.87 ppm, respectively. Two methylene protons of attached to the phthalimide ring–N–CH2 group are seen as a broad singlets in the 3.83–3.82 ppm range.

The 13C-NMR spectra of conjugates 79 and 1618 in CDCl3 show characteristic signals at 15.80 ppm (7), 12.66–11.79 ppm (8, 9, 1618), and 19.19–17.25 ppm (7, 8, 1618), 12.18 ppm (9) which are assigned to CH3–18 and CH3–19, respectively. Carbon atoms of the CH3–21 group for all conjugates give signals in the ranges 22.55–18.621 ppm. Characteristic shifts of methyl groups present in the sterol side chain (CH3–26 and CH3–27) are positioned in the range 22.76–19.94 ppm and 22.52–19.61 ppm, respectively. The carbon atoms of the CO2CH3 unit resonated in the range of 174.77–174.72 ppm and 52.49–51.45 ppm, assigned to CO2 and CH3, respectively.

Two important signals for C(1')=O and C(3)–O lie at 164.25–163.87 ppm and 77.97–74.87 ppm, respectively. The spectra of all conjugates show two diagnostic signals associated with CH2 atoms in N+–C(2')H2–CO and N+–C(4')H2 groups. The carbon atoms of the first group are observed at 62.25–60.67 ppm and carbon atoms of the second group lie at 61.50–61.05 ppm for 8, 9 and 1618 and 57.03 ppm for 7, respectively. The carbon atoms of N+(CH3)2 group appear in the range of 53.16–51.42 ppm. The carbon atoms of (C(7')=O)2N–C(6')H2 group resonate in the range of 168.34–168.09 ppm and 62.25–60.67 ppm assigned to C(7')=O and C(6')H2, respectively.

The proton chemical shift assignments of N,N-dimethyl-(3β-acetate-cholest-5-ene)-3-phthal-imidopropylammonium bromide (8) (Table 2) are based on 2D COSY experiments, in which the proton-proton connectivity is observed through the off-diagonal peaks in the counter plot.

Table 2. Chemical shifts (δ, ppm) in D2O and calculating GIAO nuclear magnetic shielding tensors (σcal) for N,N-dimethyl-(3β-acetate-cholest-5-ene)-3-phthalimido- propylammonium bromide (8). The predicted GIAO chemical shifts were computed from the linear equation δexp = a + b σcalc with a and b determined from the fit the experimental data.
Table 2. Chemical shifts (δ, ppm) in D2O and calculating GIAO nuclear magnetic shielding tensors (σcal) for N,N-dimethyl-(3β-acetate-cholest-5-ene)-3-phthalimido- propylammonium bromide (8). The predicted GIAO chemical shifts were computed from the linear equation δexp = a + b σcalc with a and b determined from the fit the experimental data.
δexp.δcalcσcalc δexp.δcalcσcalc
a a--294.9163--31.4274-
b b---1.3593---0.9606-
r2 c--0.9831--0.9443-

a intercept; b slope; c correlation coefficient.

The relations between the experimental 1H- and 13C-NMR chemical shifts (δexp) and the Gauge-Independent Atomic Orbitals (GIAO) isotropic magnetic shielding tensors (σcalc) for 8 are shown in Figure 2. Both correlations are linear, described by the equation: δexp. = a + bσcalc. The a and b parameters are given in Table 2. The very good correlation coefficients (r2 = 0.9379) for 1H and (r2 = 0.9984) for 13C correlations of N,N-di-methyl-(3β-acetate-cholest-5-ene)-3-phthalimidopropyl-ammonium bromide confirm the optimized geometry of 8.

Figure 2. Experimental chemical shifts (δexp.) for N,N-dimethyl-(3β-acetate-cholest-5-ene)-3-phthalimidopropylammonium bromide (8) vs. isotropic magnetic shielding constants (σcalc) from the GIAO/B3LYP/6-31G(d,p) calculations; (a) carbons-13 and (b) protons.
Figure 2. Experimental chemical shifts (δexp.) for N,N-dimethyl-(3β-acetate-cholest-5-ene)-3-phthalimidopropylammonium bromide (8) vs. isotropic magnetic shielding constants (σcalc) from the GIAO/B3LYP/6-31G(d,p) calculations; (a) carbons-13 and (b) protons.
Molecules 19 04212 g002 1024

The correlation between the experimental chemical shifts and calculated isotropic screening constants are better for carbon atoms than for protons. The protons are located on the periphery of the molecule and thus they are exposed to stronger interactions with solvent than carbon atoms, which are more hidden inside of structure. The differences between the exact values of the calculated and experimental shifts for protons are probably due to the fact that the shifts are calculated for single molecules in gas phase, whereas experimental values are due to the condensed phase. For this reason the agreement between the experimental and the calculated data for protons are worse than for carbons.

PM5 semiempirical calculations were performed using the WinMopac 2003 program and B3LYP calculation are performed using the GAUSSIAN 03 program package with the 6-31G(d,p) basis set. The final heat of formation (HOF) and energies for the sterols 13, bile acids 1012 as well as their conjugates 79 and 1618 is presented in Table 3. Representative conjugates of sterol 7 and bile acid 18 are shown in Figure 3.

Table 3. Heat of formation (HOF) [kcal/mol] and energy [a.u.] of sterols (13), bile acids (1012) and their conjugates (79, 1618).
Table 3. Heat of formation (HOF) [kcal/mol] and energy [a.u.] of sterols (13), bile acids (1012) and their conjugates (79, 1618).
CompoundHeat of FormationΔHOF EnergyΔEnergy
[kcal/mol][kcal/mol] [a.u.][a.u.]

ΔHOF = HOFconjugates (79) – HOFsterols (13); ΔHOF = HOFconjugates (16-18) – HOFbile acids (1012); ΔEnergy = Energyconjugates (79) – Energysterols (13); ΔEnergy = Energyconjugates (1618) – Energybile acids (1012).

Figure 3. Molecular models of representative compounds 7 and 18 calculated by the PM5 method.
Figure 3. Molecular models of representative compounds 7 and 18 calculated by the PM5 method.
Molecules 19 04212 g003 1024

The lowest values of HOF for sterols are observed for cholestanol 3 and its conjugate 9, where there are no double bonds which stabilize the molecule and hinder its reactivity, in contrast to conjugates of ergosterol 7 and cholesterol 8 where the double bonds increase the reactivity of the molecule, thereby increasing values of HOF. The HOF relationship for methyl esters of bile acids 1012 and their corresponding conjugates 1618 can be explained in a similar manner. In this case, the number of hydroxyl groups in the steroid skeleton lowers the value of the determinant of HOF. This spatial arrangement of bile acids can facilitate the formation of stable host-guest complexes. These complexes may be stabilized by hydrogen bonding or electrostatic interactions that arise from the number of hydroxyl groups in the bile acid molecule. Similar correlations have been observed using the B3LYP method.

The spatial arrangement and interaction of the conjugates 7 and 18 are shown in Figure 4. The final heat of formation is –1249.429 kcal/mol for 7 and –1358.893 kcal/mol for 18 and the distances between the quaternary nitrogen and the anion bromide are 4.34 Å and 4.33 Å, respectively. Compensation charges occurs only through intermolecular electrostatic interaction. This is a very good confirmation of the conclusion that interactions reduce HOF. The dipole moments and selected geometry parameters were calculated at the PM5 and B3LYP /6-31G(d,p) level of theory are presented in Table 4.

Figure 4. Molecular models of conjugates 7 and 18 calculated by the PM5 method.
Figure 4. Molecular models of conjugates 7 and 18 calculated by the PM5 method.
Molecules 19 04212 g004 1024
Table 4. Calculated structural parameters (B3LYP\6-31G(d,p), PM5) for sterol conjugates 79 as well as bile acid conjugates 1618.
Table 4. Calculated structural parameters (B3LYP\6-31G(d,p), PM5) for sterol conjugates 79 as well as bile acid conjugates 1618.
Dipole moments (Debye)9.08178.97258.85338.95788.48977.7646
Bond lengths [Å]
Bond angles [°]
Torsion angles [°]
Hydrogen bonds and short contacts lengths
Distances [Å]
Angles [deg]

The calculated bond lengths and bond angles for 79 and 1618 optimized by the PM5 and B3LYP methods are quite similar, however the bond lengths N(2)-C(2') and N(2)-C(4') are different. Also the torsion angles calculated by the PM5 and B3LYP methods are slightly different, especially the C(5')-C(4')-N(2)-C(2') angle for fatty acid conjugates 1618. This shows a crucial role of electrostatic interaction between oppositely charged groups in the structure of the investigated compounds (Table 4). Hydrogen bonds and short contact lengths distances are shorter for compounds calculated by B3LYP method. These data prove that in the gas phase the type of quantum chemical methods used play an important role in the molecular structure of ionic compounds. The solid-state IR spectra of sterols and bile acids conjugates are shown in Figure 5 and Figure 6, respectively.

Figure 5. FT-IR spectra of sterol conjugates 7 (red) and 8 (blue) in the 3,100–400 cm−1 region.
Figure 5. FT-IR spectra of sterol conjugates 7 (red) and 8 (blue) in the 3,100–400 cm−1 region.
Molecules 19 04212 g005 1024
Figure 6. FT-IR spectra of bile acid conjugates 16 (blue), 17 (red), 18 (black) in the 3100–400 cm−1 region
Figure 6. FT-IR spectra of bile acid conjugates 16 (blue), 17 (red), 18 (black) in the 3100–400 cm−1 region
Molecules 19 04212 g006 1024

The FT-IR spectra of conjugates show characteristic bands at 1,775–1,772 cm−1 which are due to the asymmetric carbonyl group νasC=O stretching vibrations in a phthalimide moiety (Figure 5, Figure 6, Figure 7 and Figure 8) [48,49]. The symmetric νsC=O stretching vibration appears in the FT-IR spectrum as an intense and broad nonsymmetrical band at 1,716–1,699 cm−1 suggesting the small nonequivalence of carbonyl groups in the phthalimide moiety. Moreover strong characteristic bands in the region 1,251–1,240 cm−1 are present, which are assigned to the ν(C–O).

Figure 7. FT-IR spectra of bile acid conjugates in the carbonyl group region 16 (blue), 17 (red), 18 (black).
Figure 7. FT-IR spectra of bile acid conjugates in the carbonyl group region 16 (blue), 17 (red), 18 (black).
Molecules 19 04212 g007 1024
Figure 8. Spectrum of N,N-dimethyl-(3β-acetate-5β-cholestan)-3-phthalimidopropyl-ammonium bromide (9); (a) FT-IR (b) calculated scaled FT-IR spectrum.
Figure 8. Spectrum of N,N-dimethyl-(3β-acetate-5β-cholestan)-3-phthalimidopropyl-ammonium bromide (9); (a) FT-IR (b) calculated scaled FT-IR spectrum.
Molecules 19 04212 g008 1024

The FT-IR spectra of bile acid conjugates (Figure 7, blue line) shows characteristic vibration bands of νasC=O and νsC=O in a phthalimide moiety at 1,773 cm−1 and at 1,712 and 1,699 cm−1, respectively. In this case the νasC=O and νsC=O bands are more nonsymmetrical in comparison to the carbonyl bands of 17 and 18. The nonequivalence of νasC=O in the FT-IR spectrum is observed for N,N-bis-(phthalimidopropyl)-N-propylamine [50]. In contrast to the above examples, in N,N-dimethyl-3-phthalimidopropylammonium hydrochloride monohydrate and N-n-butyltetrachlorophthalimide no split of the carbonyl bands in FT-IR spectra were observed, in spite of the different interactions of each carbonyl group in the supramolecular structure [51,52]. The ν(COO) stretching vibrations of carboxy groups are observed at 1,747–1,736 cm−1 (Figure 7).

The room-temperature solid-state FT-IR and the calculated spectrum of 9 are shown in Figure 8. The band frequencies, relative intensities and their assignments in the 4,000–400 cm−1 range are listed in Table 5. For convenience of comparison, the band intensities for the calculated spectrum are scaled.

Table 5. Observed and calculated B3LYP/6-31G(d,p) vibrational frequencies and infrared intensities for N,N-dimethyl-(3β-acetate-5β-cholestan)-3-phthalimidopropylammonium bromide (9).
Table 5. Observed and calculated B3LYP/6-31G(d,p) vibrational frequencies and infrared intensities for N,N-dimethyl-(3β-acetate-5β-cholestan)-3-phthalimidopropylammonium bromide (9).
IRIRcalc.IRcalc.scaledINTProposed Assignment
1,454m1,5811,5052.76nCC, βCH2
1,445 m1,5771,50214.1βasCH3
1,375 m1,4301,35915.7βsCH3
1,364 m1,4241,353178nCO
1,335 w1,4061,3363.82nCC
1,313 w1,3791,31018.5nCN
1,285 w1,3611,29210.4nCC
1,272 w1,3431,27534.6nCC, βCH2
1,251 m1,3311,26382.7nCO
1228 m1,2901,22417.7βCH2
1,209 s1,2681,202232nCC
1,188 m1,2511,18610.8nCC
1,176 m1,2361,1724.70nCC
1,150 w1,2251,16111.5nCN
1,142 w1,2171,153135nCN
1,132 w1,2141,150141βCH
1,108 w1,2021,13825.0nCN
1,089 w1,1921,128169nCN
1,074 w1,179-10.6γCH2
1,044 w1,1411,11614.3γCH2
1,037 w1,1241,0793.42γCH2
1,026 w1,1061,0633.28δCH2
1,017 m1,0981,0455.41βCH2
1,001 m1,0741,03732.5γCH2
978 w1,0471,01413.0βCCC
964 w1,0259883.87βCO
950 w1,01696713.6γCH2
935 w9989583.96βCH2
927 w96694143.5γCH2
904 w96390925.0γCH2
897 w9209076.08βCCC
887 w9019072.12βCCC
860 vw8958652.04tring
842 vw8798475.89nCC
802 vw8678253.62βCCC
787 vw81381413.5βCCC
720 m76476111.0βCCC
710 vw7517141.86βCNC
692 vw7467018.70βring
663 vw6986943.00γCH
636 vw6596120.13γCH
625 vw65761028.5γCH
605 vw6506033.71βring
600 vw6255796.76βNCC
545 vw61056515.1γCC
531 w5665227.31βCCC
512 vw55150814.9tring
498 vw54049712.4tring
482 vw51547210.3γCCC
438 vw4694281.23Lattice mode
419 vw43439411.4Lattice mode
409 vw4093709.39Lattice mode
-3863485.04Lattice mode
-34530822.0Lattice mode
-32929257.4Lattice mode
-2822473.62Lattice mode
-25722310.3Lattice mode
-2051725.27Lattice mode
-1771451.08Lattice mode
-102721.63Lattice mode
-56282.59Lattice mode

The abbreviations are: s: strong; m: medium; w: weak; vw; very weak; ν: stretching; β: in plane bending; δ: deformation; w: wagging; γ: out of plane bending and τ: twisting.

The DFT harmonic vibrational wavenumbers are usually higher than the experimental values. However, in this case the overall agreement between the experimental and calculated frequencies for (9) is very good (Figure 9).

Figure 9. Correlation between the experimental and calculated wavenumbers (cm−1) for (9); νscaled = -26.3525 + 0.9689νcalc., r2 = 0.9973.
Figure 9. Correlation between the experimental and calculated wavenumbers (cm−1) for (9); νscaled = -26.3525 + 0.9689νcalc., r2 = 0.9973.
Molecules 19 04212 g009 1024

Any discrepancy noted between the observed and calculated frequency may be due to the fact that the calculations have been done for a single molecule in the gaseous state contrary to the experimental spectrum recorded in the presence of intermolecular interactions. The scaling procedure, as recommended by Palafox was used [53,54]. The scaled IR spectrum is shown in Figure 8b and the predicted frequencies are listed in Table 3 as νscaleq. Scaling of the harmonic vibrational frequencies reproduce the experimental solid-state FT-IR frequencies with the r.m.s. error of 38.1 cm−1. The vibrational band assignments of 9 were made using Gauss-View molecular visualization program [55].

3. Experimental

3.1. General

The NMR spectra were measured with a Varian Mercury 300 MHz NMR spectrometer (Oxford, UK), operating at 300.07 and 75.4614 for 1H and 13C, respectively. Typical conditions for the proton spectra were: pulse width 32°, acquisition time 5 s, FT size 32 K and digital resolution 0.3 Hz per point, and for the carbon spectra pulse width 60°, FT size 60 K and digital resolution 0.6 Hz per point, the number of scans varied from 1200 to 10,000 per spectrum. The 13C and 1H chemical shifts were measured in CDCl3 relative to an internal standard of TMS. Infrared spectra were recorded in the KBr pellets using a FT-IR Bruker IFS 66 spectrometer (Karlsruhe, Germany). The ESI (electron spray ionization) mass spectra were recorded on a Waters/Micromass (Manchester, UK) ZQ mass spectrometer equipped with a Harvard Apparatus (Saint Laurent, QC, Canada), syringe pump. The sample solutions were prepared in methanol at the concentration of approximately 10−5 M. The standard ESI-MS mass spectra were recorded at the cone voltage 110 V. The MALDI (matrix-assisted laser desorption/ionization) mass spectra were recorded on a Waters Maldi Q-Tof Premiere. The sample solutions were prepared in methanol at the concentration of approximately 10−5 M. The matrix was 2,5-dihydroxybenzoic acid (gentisic acid) and the standard was β-cyclodextrin (m/z 1157.3218). PM5 semiempirical calculations were performed using the WinMopac 2003 program [56,57,58]. The calculations were performed using the GAUSSIAN 03 program package [59] at the B3LYP [60,61,62] levels of theory with the 6-31G(d,p) basis set [63]. The NMR isotropic shielding constants were calculated using the standard Gauge-Independent Atomic Orbital (GIAO) approach of Gaussian 03 [64,65].

3.2. Synthesis

The appropriate 3β-bromoacetate of sterols or 3α-bromoacetate of bile acids (0.20 mmol) were dissolved in CH3CN (6 mL) under reflux. Then N,N-dimethyl-3-phthalimidopropylamine (0.24 mmol) was added and the mixture heated under reflux for 3 h. The precipitate was filtered and crystallized from CH3CN-EtOH (90:1), to give white solids.

N,N-Dimethyl-(3β-acetate-ergosta-5,7,22-triene)-3-phthalimidopropylammonium bromide (7): white solid (76%), m.p. 185–187 °C. 1H-NMR: δH 7.85 (bs, 2H, Ar–H), 7.75 (bs, 2H, Ar–H), 5.35 (s, 2H, COCH2N+), 5.31–5.12 (m, 4H, 6, 7, 22, 23–H), 4.96–4.58 (m, 3H, 3α–H, N+CH2), 3.82 (bs, 2H, CH2–N–phthalimide ring), 3.69 (s, 6H, N+(CH3)2), 1.04 (s, 3H, CH3–19), 1.01 (d, J = 6,0 Hz, 3H, CH3–28), 0.93 (d, J = 6.7 Hz, 3H, CH3–21), 0.84 (d, J = 6.7 Hz, 6H, CH3–26 and CH3–27), 0.83 (s, 3H, CH3–18). 13C-NMR: δC 168.17 (C-7'), 163.98 (C-1'), 140.11 (C-8), 139.96 (C-5), 135.43 (C-22), 134.32, 132.08 (C-23), 131.81, 123.57, 118.11 (C-6), 118.03 (C-7), 74.87 (C-3), 62.40, 61.67, 60.67 (C-2'), 57.03 (C-4'), 53.16 (C-3'), 44.76, 42.79, 40.80, 40.72, 38.86, 36.82, 36.65, 36.44, 36.40, 34.93, 34.03, 33.81, 33.05, 27.58, 27.45, 26.43, 25.10, 25.04, 22.81, 21.77 (C-21), 20.96 (C-19), 19.94, 19.61, 18.28, 18.20, 17.63, 15.80 (C-18). FT-IR (KBr) νmax: 2957, 2871, 1773, 1740, 1713, 1466, 1437, 1396, 1365,1250, 1208, 1044, 926. ESI-MS (m/z): 670 (100%) [C43H61N2O4]+. MALDI-MS (m/z): 669.9. HRMS: calcd 669.5678 for C43H61N2O4; found 669.5630.

N,N-Dimethyl-(3β-acetate-cholest-5-ene)-3-phthalimidopropylammonium bromide (8): white solid (82%), m.p. 199–200 °C. 1H-NMR: δH 7.85–7.80 (m, 2H, Ar–H), 7.76–7.70 (m, 2H, Ar–H), 5.35 (d, J = 4.9 Hz, 1H, 6–H), 4.80 (bs, 2H, COCH2N+), 4.69–4.48 (m, 1H, 3α–H), 4.00–3.89 (m, 2H, N+CH2), 3.83 (bs, 2H, CH2–N–phthalimide ring), 3.66 (s, 6H, N+(CH3)2), 0.99 (s, 3H, CH3–19), 0.92 (d, J = 6.4 Hz, 3H, CH3–21), 0.87 (dd, J = 6.6, 1.4 Hz, 6H, CH3–26 and CH3–27), 0.68 (s, 1H, CH3–18). 13C-NMR: δC 168.12 (C-7'), 163.90 (C-1'), 138.76 (C-5), 134.22, 131.72, 123.49, 123.33 (C-6), 76.57 (C-3), 62.05 (C-2'), 61.05 (C-4'), 56.60, 56.06, 52.38 (C-3'), 49.93, 42.24, 39.62, 39.44, 37.63, 36.75, 36.44, 36.11, 35.71, 34.63, 31.84, 31.72, 29.64, 28.15, 27.95, 27.42, 24.21, 23.76, 22.76, 22.50, 20.95, 19.19 (C-19), 18.65 (C-21), 11.79 (C-18). FT-IR (KBr) νmax: 2943, 2868, 1774, 1737, 1713, 1467, 1637, 1395, 1364, 1252, 1210, 1089, 925. ESI-MS (m/z): 660 (100%) [C42H63N2O4]+. MALDI-MS (m/z): 659.9. HRMS: calcd 659.5812 for C42H63N2O4; found 659.5802.

N,N-Dimethyl-(3β-acetate-5β-cholestan)-3-phthalimidopropylammonium bromide (9): white solid (83%), m.p. 191–192 °C. 1H-NMR: δH 7.83 (d, J = 3.90 Hz, 2H, Ar–H), 7.74 (m, 2H, Ar–H), 4.88–4.55 (m, 3H, COCH2N+, 3α–H), 3.92 (bs, 2H, N+CH2), 3.83 (bs, 2H, CH2–N–phthalimide ring), 3.61 (s, 6H, N+(CH3)2), 0.90 (d, J = 6.5 Hz, 3H, CH3-21), 0.86 (dd, J = 6.7, 1.9 Hz, 6H, CH3–26 and CH3–27), 0.79 (s, 3H, CH3–19), 0.65 (s, 1H, CH3–18). 13C-NMR: δC 168.18 (C-7'), 163.89 (C-1'), 134.26, 131.74, 123.51, 76.68 (C-3), 62.25 (C-2'), 61.27 (C-4'), 56.34, 56.21, 54.10, 52.51 (C-3'), 44.62, 42.52, 39.90, 39.45, 36.56, 36.11, 35.74, 35.34, 34.65, 33.55, 31.90, 29.65, 28.44, 28.18, 27.96, 27.13, 24.14, 23.79, 22.78, 22.56, 22.52, 21.15, 18.62 (C-21), 12.18 (C-19), 12.02 (C-18). FT-IR (KBr) νmax: 2952, 2867, 1770, 1742, 1712, 1467, 1445, 1396, 1375, 1251, 1089, 927. ESI-MS (m/z): 661 (100%) [C42H65N2O4]+. MALDI-MS (m/z): 661.5. HRMS: calcd 661.5905 for C42H65N2O4; found 661.5917.

N,N-Dimethyl-(methyl litocholate)-3-phthalimidopropylammonium bromide (16): white solid (96%), m.p. 104–105 °C. 1H-NMR: δH 7.86–7.82 (m, 2H, Ar–H), 7.77–7.73 (m, 2H, Ar–H), 4.84–4.67 (m, 3H, 3β–H, COCH2N+), 3.92 (bs, 2H, N+CH2), 3.83 (bs, 2H, CH2–N–phthalimide ring), 3.66 (s, 9H, CO2CH3 and N+(CH3)2), 0.91 (m, 6H, CH3–19 and CH3–21), 0.64 (s, 3H, CH3–18). 13C-NMR: δC 174.72 (C-24), 168.09 (C-7'), 163.87 (C-1'), 134.24, 131.73, 123.45, 77.97 (C-3), 62.11 (C-2'), 61.14 (C-4'), 56.15, 55.79, 52.49 (C-3'), 51.42 (C-25), 43.04, 42.64, 41.89, 40.23, 39.89, 35.68, 35.28, 35.02, 34.81, 34.61, 34.45, 31.76, 31.00, 30.93, 28.10, 26.84, 26.23, 26.13, 24.09, 23.16, 22.53, 20.76 (C-21), 18.21 (C-19), 11.97 (C-18). FT-IR (KBr) νmax: 2937, 2867, 1773, 1746, 1737, 1712, 1698, 1466, 1438, 1404, 1378, 1210, 1088, 930. ESI-MS (m/z): 664 (100%) [C40H59N2O6]+. MALDI-MS (m/z): 663.5. HRMS: calcd 663.5361 for C40H59N2O6; found 663.5396.

N,N-Dimethyl-(methyl deoxycholate)-3-phthalimidopropylammonium bromide (17): white solid (90%), m.p. 170–172 °C. 1H-NMR: δH 7.87–7.83 (m, 2H, Ar–H), 7.76–7.72 (m, 2H, Ar–H), 4.92–4.67 (m, 3H, 3β–H, COCH2N+), 3.98 (s, 1H, 12β–H), 3.96–3.87 (m, 2H, CH2–N+), 3.82 (bs, 2H, CH2–N–phthalimide ring), 3.63 (s, 9H, CO2CH3 and N+(CH3)2), 0.98 (d, J = 5.7 Hz, 3H, CH3–21), 0.91 (s, 3H, CH3–19), 0.66 (s, 3H, CH3–18). 13C-NMR: δC 174.75 (C-24), 168.30 (C-7'), 164.00 (C-1'), 134.26, 131.76, 123.55, 77.66 (C-3), 72.81 (C-12), 62.07 (C-2'), 61.39 (C-4'), 52.55 (C-3'), 51.45 (C-25), 48.04, 47.08, 46.40, 41.81, 35.86, 35.13, 34.71, 34.03, 33.37, 31.62, 31.07, 30.90, 28.61, 27.41, 26.77, 26.09, 25.97, 23.62, 22.87, 22.55 (C-21), 17.26 (C-19), 12.66 (C-18). FT-IR (KBr) νmax: 2955, 2870, 1774, 1736, 1716, 1485, 1466, 1405, 1393, 1201, 1091, 967. ESI-MS (m/z): 680 (100%) [C40H59N2O7]+. MALDI-MS (m/z): 679.5. HRMS: calcd 679.5358 for C40H59N2O7; found 679.5341.

N,N-Dimethyl-(methyl cholate)-3-phthalimidopropylammonium bromide (18): white solid (85%), m.p. 204–205 °C. 1H-NMR: δH 7.86–7.83 (m, 2H, Ar–H), 7.76–7.69 (m, 2H, Ar–H), 4.95 (s, 2H, COCH2N+), 4.66–4.55 (m, 1H, 3β–H), 3.97 (bs, 1H, 12β–H), 3.92–3.89 (m, 2H, CH2–N+), 3.82 (bs, 2H, CH2–N–phthalimide ring), 3.80 (bs, 1H, 7β–H), 3.63 (s, 3H, CO2CH3,), 3.62 (s, 6H, N+(CH3)2), 0.97 (d, J = 5.8 Hz, 3H, CH3–21), 0.89 (s, 3H, CH3–19), 0.66 (s, 3H, CH3–18). 13C-NMR: δC 174.77 (C-24), 168.34 (C-7'), 164.25 (C-1'), 134.19, 131.78, 123.49, 76.57 (C-3), 72.62 (C-12), 67.75 (C-7), 61.86 (C-2'), 61.50 (C-4'), 52.50 (C-3'), 51.41 (C-25), 46.95, 46.35, 41.89, 41.22, 39.54, 35.26, 34.86, 34.66, 34.37, 31.13, 30.91, 28.37, 27.45, 26.68, 26.30, 23.13, 22.55, 22.32 (C-21), 17.25 (C-19), 12.47 (C-18). FT-IR (KBr) νmax: 2938, 2870, 1772, 1739, 1711, 1468, 1437, 1399, 1370, 1208, 1073, 953. ESI-MS (m/z): 696 (100%) [C40H59N2O8]+. MALDI-MS (m/z): 695.5. HRMS: calcd 695.5192 for C40H59N2O8; found 695.5242.

4. Conclusions

In conclusion, six new quaternary N,N-dimethyl-3-phthalimidopropylammonium conjugates of sterols (compounds 79) and bile acids (compounds 1618) were prepared by the reactions of ergosteryl 3β-bromoacetate, cholesteryl 3β-bromoacetate, dihydrocholesteryl 3β-bromoacetate as well as methyl litocholate 3α-bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate, with N,N-dimethyl-3-phthalimidopropylamine in acetonitrile. These new compounds were characterized by spectroscopic and molecular structure methods. The obtained conjugates may find applications in molecular recognition and in pharmacology, especially as compounds with a high antimicrobial activity.


This work was supported by the funds from Adam Mickiewicz University, Faculty of Chemistry.

Author Contributions

The listed authors contributed to this work as described in the following. Bogumił Brycki gave the concepts of work, interpreted the results and prepared the manuscript. Hanna Koenig carried out of the synthetic work, interpreted the results and cooperated in the preparation of the manuscript. Tomasz Pospieszny performed semiempirical calculations and Prediction of Activity Spectra for Substances (PASS). Iwona Kowalczyk performed quantum chemical calculations. All authors contributed with valuable discussions and scientific input and approved the final version.

Conflicts of Interest

The authors declare no conflict of interest.


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  • Sample Availability: Samples of the compounds 49 and 1318 are available from the authors.
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