Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their quantum chemical calculations

Article abstract of DOI:10.1016/j.molstruc.2016.10.087

In the present research paper corticosteroids prodrugs of hydrocortisone acetate (1) have been synthesized, which was isolated from the flowers of Allamanda Violacea. The hydrocortisone acetate (1) was hydrolyzed to hydrocortisone (2) which was subsequently converted to prednisolone (3). Both the hydrocortisone (1) and prednisolone (2) underwent Steglich esterification with naproxen and Ibuprofen yielding compounds 11, 17 dihydroxy-21-(2-(6-methoxynaphthalene-2yl) propionoxy)-pregn-4-ene-3, 20-dione (4), 11, 17-dihydroxy-21-(2-(4-isobutylphenyl) propionoxy)-pregn-4-ene-3, 20-dione (5), 21-(2-(6-methoxynaphthalene-2-yl) propionoxy) 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene (6) and 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene-21-yl-2-(4-isobutylphenyl) propanoate (7). The synthesized compounds have been characterized with the help of spectroscopic techniques like ¹H, ¹³C NMR, FT-IR spectroscopy and mass spectrometry. Density functional theory (DFT) with B3LYP functional and 6-31G (d, p) basis set has been used for the Quantum chemical calculations. The electronic properties such as frontier orbitals and band gap energies were calculated by TD-DFT approach. Intramolecular interactions have been identified by AIM (Atoms in Molecule) approach and vibrational wavenumbers have been calculated using DFT method. The reactivity and reactive site within the synthesized prodrugs have been examined with the help of reactivity descriptors. Dipole moment, polarizability and first static hyperpolarizability have been calculated to get a better insight of the properties of synthesized prodrugs. The molecular electrostatic potential (MEP) surface analysis has also been carried out.

Full text of DOI:10.1016/j.molstruc.2016.10.087

Journal of Molecular Structure xxx (2016) 1e7
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Facile synthesis of corticosteroids prodrugs from isolated
hydrocortisone acetate and their quantum chemical calculations
,
Arun Sethi a *, Ranvijay Pratap Singh a, Rohit Prakash b, Amandeep a
a Department of Chemistry, University of Lucknow, Lucknow, 226007, India
b Faculty of Chemical Sciences, Shri Ramswaroop Memorial University, Barabanki, 225003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present research paper corticosteroids prodrugs of hydrocortisone acetate (1) have been syn-
thesized, which was isolated from the flowers of Allamanda Violacea. The hydrocortisone acetate (1) was
hydrolyzed to hydrocortisone (2) which was subsequently converted to prednisolone (3). Both the hy-
drocortisone (1) and prednisolone (2) underwent Steglich esterification with naproxen and Ibuprofen
yielding compounds 11, 17 dihydroxy-21-(2-(6-methoxynaphthalene-2yl) propionoxy)-pregn-4-ene-3,
20-dione (4), 11, 17-dihydroxy-21-(2-(4-isobutylphenyl) propionoxy)-pregn-4-ene-3, 20-dione (5), 21-(2-
(6-methoxynaphthalene-2-yl) propionoxy) 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene (6) and 11,17-
di-hydroxy-3,20-diketo-pregn-1,4-diene-21-yl-2-(4-isobutylphenyl) propanoate (7). The synthesized
compounds have been characterized with the help of spectroscopic techniques like 1H, 13C NMR, FT-IR
spectroscopy and mass spectrometry. Density functional theory (DFT) with B3LYP functional and 6-
31G (d, p) basis set has been used for the Quantum chemical calculations. The electronic properties such
as frontier orbitals and band gap energies were calculated by TD-DFT approach. Intramolecular in-
teractions have been identified by AIM (Atoms in Molecule) approach and vibrational wavenumbers have
been calculated using DFT method. The reactivity and reactive site within the synthesized prodrugs have
been examined with the help of reactivity descriptors. Dipole moment, polarizability and first static
hyperpolarizability have been calculated to get a better insight of the properties of synthesized prodrugs.
The molecular electrostatic potential (MEP) surface analysis has also been carried out.
Received 30 September 2016
Received in revised form
27 October 2016
Accepted 27 October 2016
Available online xxx
Keywords:
Hydrocortisone acetate
Hydrocortisone
Prednisolone
Prodrugs
NLO
Reactivity descriptors
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
synthesized hydrocortisone C-21 mercaptobenzothiazole and C-21
mercapto derivatives of prednisolone showed significant anti-
Corticosteroids (CS) or corticoids also belong to C-21 class of
carbon compounds having a cyclopentanoperhydro-phenanthrene
(steroid) nucleus. The synthetic as well natural analogs of these
hormones have virtually affected every aspect of human physiology
and are most widely used for various inflammatory and autoim-
mune disorders. Modifications of 21-hydroxy group of corticoste-
roids by esterification with carboxylic acids have been found to
inflammatory activity [5,6].
Non steroidal anti-inflammatory drugs (NSAIDs) like naproxen
and Ibuprofen possess one or more anti-inflammatory properties
such as analgesic, anti-pyretic and edema-reducing effect [7,8]. As
most NSAID posses free carboxyl group, which damage gastroin-
testinal (GI) track. It has been reported that esterification of the
carboxylic acid moiety of NSAIDs suppress gastro-toxicity without
adversely affecting their anti-inflammatory activity [9,10] Thus, if
corticosteroids and NSAIDs are present in one moiety, then this
single moiety may possess both biological properties of cortico-
steroid and NSAIDs. Thus keeping the above factors in mind, we
synthesized corticosteroids-NSAIDs prodrug by adopting Steglich
esterification method using N, N′-Dicylcohexylcarbodiimide (DCC)
as a coupling reagent and 4-Dimethylaminopyridine (DMAP) as a
catalyst. Hydrocortisone (2) needed for the present synthetic pro-
cess was derived from hydrocortisone acetate (1), isolated from the
chloroform extract of the flowers of Allamanda Violacea [11]. The
increase its clinical utility. The C-21 esters of corticosteroids like 9a-
fluoro-prednisolone 21-acetate [1], and flu-perolone acetate [2]
were found to be active anti-inflammatory agents. The dexameth-
asone-21-isonicotinate aerosol was highly effective in treating in
bronchial asthma [3]. The C-21 derivative of hydrocortisone
exhibited potent anti-inflammatory activity [4]. The recently
* Corresponding author.
E-mail address: alkaarunsethi@rediffmail.com (A. Sethi).
http://dx.doi.org/10.1016/j.molstruc.2016.10.087
0022-2860/© 2016 Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Sethi, et al., Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their
quantum chemical calculations, Journal of Molecular Structure (2016), http://dx.doi.org/10.1016/j.molstruc.2016.10.087

2
A. Sethi et al. / Journal of Molecular Structure xxx (2016) 1e7
synthesized corticosteroid-NSAIDs prodrugs are shown in
Scheme 1.
Louis, MO) and used without further purification. Thin layer chro-
matography (TLC) was performed on silica gel G coated plates to
detect completion of reaction. Compounds were purified by column
chromatography using silica gel (60e120 mesh). 1H NMR spectra
were recorded on Bruker DRX-300 MHz spectrometer using CDCl3
and DMSO-d6 as the solvent and TMS as an internal standard,
Quantum chemical calculations have been performed by density
functional theory (DFT) using B3LYP functional and 6-31G (d, p)
basis set. Development of materials with large nonlinear optical
(NLO) property has been of great interest because of their vast
varieties of application. Energy gap between HOMO and LUMO
characterized the chemical stability and charge transfer interaction
in the molecules. Atoms in molecules (AIM) theory have been
extensively applied to classify and understand hydrogen bonding
interactions in the molecules.
Therefore, the present paper aims to give a complete description
of the chemical shifts, vibrational assignments, intramolecular in-
teractions, electronic transitions, global reactivity descriptors and
non-linear optical (NLO) features of the synthesized prodrugs.
chemical shifts were reported as
d
(ppm) and 13C NMR spectrum
was recorded on JOEL AL 300 FTNMR (75 Mz) using TMS as an in-
ternal reference. FT-IR spectra were recorded on Perkin Elmer FT-IR
spectrometer from 4500 to 400 cmꢀ1 range. The spectra were
analyzed using Spectrum™ Software suite. ESIeMS spectrum was
recorded on Agilent 6520 QeTOF mass spectrometer. Melting point
was determined using open capillary tube method and
uncorrected.
2.2. Extraction and isolation of hydrocortisone acetate (1)
2. Experimental
Extracts were prepared as reported earlier by Sethi et al. [12].
Dry chloroform extract (690 mg) of the flowers of A. violacea was
subjected to column chromatography using silica gel (60e120
mesh) and Chloroform/methanol of increasing polarity. Chloro-
form/methanol (97:3e96:4) afforded 20 fractions which contained
1 in impure form. Compound 1 (32 mg) was obtained in pure form
with repeated column chromatography using chloroform/meth-
anol of increasing polarity. m.p: 497 K, Molecular formula:
2.1. Materials and physical measurements
The whole plant of the A. violacea was collected in the month of
October 2010 from Lucknow, India. The identity of the plant was
confirmed by Dr. Tariq Hussain, Scientist and Head, Department of
Taxonomy and Herbarium, National Botanical Research Institute,
Lucknow, India where Voucher specimen, no-97108 was deposited.
All reagents for synthesis were purchased from Sigma Aldrich (St.
C
23H32O6, 1H NMR in CDCl3 at 300 MHz (ppm):
d
7.262(D, s, CDCl3),
5'
OAc
4'
21
20
O
2'
HO
19
18
12
8
17
OH
3'
11
13
14
1
16
2
9
6
15
10
7
1'
O numbering = 1', 2'.......
5
3
O
1
4
Na/MeOH
21
21
20
20
O
OH
O
OH
18
18
12
8
12
8
17
17
OH
16
HO
19
11
OH
16
HO
19
11
13
14
13
1
1
DDQ
in dioxane
2
2
9
6
14
9
6
15
10
15
10
7
7
5
3
O
5
3
2
O
3
4
4
O
O
21
21
23
25
20
23
25
20
22
O
O
22
O
O
24
32
24
32
18
18
12
8
12
17
17 OH
16
OH
HO 11
11
HO
Naproxen
DCC/DMAP
Naproxen
DCC/DMAP
19
19
26
27
26
27
13
14
13
14
1
1
16
33
33
2
2
9
6
9
6
15
8
7
10
15
10
31
30
31
30
34
28
34
28
7
5
3
O
5
3
O
4
4
29
6
4
29
O
O
O
35
O
35
24
21
23
25
21
20
23
25
20
22
O
O
22
O
O
24
18
18
12
8
12
8
17
OH
HO 11
11
17 OH
16
HO
19
19
26
27
30
29
26
27
30
13
14
13
14
Ibuprofen
DCC/DMAP
1
1
16
Ibuprofen
DCC/DMAP
29
2
3
2
9
9
6
15
10
15
10
28
31
28
31
7
7
5
O
5
3
33
O
6
4
33
4
7
32
5
32
34
34
Scheme 1. The synthesis of corticosteroids-NSAIDs prodrugs 4, 5, 6 and 7.
Please cite this article in press as: A. Sethi, et al., Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their
quantum chemical calculations, Journal of Molecular Structure (2016), http://dx.doi.org/10.1016/j.molstruc.2016.10.087

A. Sethi et al. / Journal of Molecular Structure xxx (2016) 1e7
3
d
d
d
d
1.862 (1H, m, H-1
2.534 (1H, d, H-2
2.504 (1H, m, H-6
a
b
),
),
d
2.222 (1H,m, H-1
5.690 (1H, s, H-4),
1.143 (1H, m, H-7 ),
b
),
d
d
d
2.317 (1H, m, H-2
2.271 (1H, d, H-6
2.001 (1H, m, H-7
a
a
b
),
),
),
and chloroform/methanol (98:2) as eluent yielding 5.6 mg (86.15%)
of compound 4 as white crystalline solid. m.p: 482 K, Molecular
d
b
),
d
a
formula: C35H42O7, 1H NMR in CDCl3 at 300 MHz (ppm):
d
7.260 (D,
1.013e0.976 (1H, dd, H-9, J ¼ 3.3
1.624 (3H, d, H-24, J ¼ 7.2), 3.911 (3H, s,
3.959 (1H, q, H-23, J ¼ 6.9 Hz, 7.2 Hz), 4.428e4.408 (1H,
q, J ¼ 3 Hz, H-11), 4.800 (1H, d, J ¼ 17.4, H-21A), 5.046 (1H, d,
5.676 (1H, d, H-4, J ¼ 1.2), 7.120 (1H, s, H-28),
7.149 (1H, d, H-30, J ¼ 2.7), 7.451e7.417 (1H, dd, H-26, J ¼ 1.8 Hz),
7.726 (1H,d. H-27,
2.091 (1H, m, H-8),
2.02 (1H, m, H-12
1.797 (1H, m, H-15
), 2.832 (1H, m, H-16
5.007 (1H, d, J ¼ 17.4 Hz, H-21A),
2.186 (1H, s, H-23). ESI-MS: m/z ¼ 427, 404,
d
0.999, 1.036 (1H, dd, H-9),
), 1.707 (1H, m, H-12
1.479 (1H, m, H-15
),
d
4.478 (1H, q,
s, CDCl3),
Hz), 1.446 (1H, s, H-19),
CH3-35),
d 0.961 (1H, s, H-18), d
J ¼ 2.7 Hz, H-11),
d
a
d
b
b
),
),
d
d
d
d
d
d
1.75 (1H, m, H-14),
d
a
),
d
d
d
1.479 (1H, m, H-16
a
d
b
d
0.972 (1H, s, H-18),
4.879(1H,
d
d
1.253 (1H, s, H-19),
d
d
J ¼ 17.1, H-21B),
d
d
d, J ¼ 17.4 Hz, H-21B),
d
d
d
d
386, 362, 302.
7.698 (2H, d, H-31, H-32, J ¼ 1.8 Hz),
d
J ¼ 2.4 Hz). FT-IR nmax (in cmꢀ1): 3486, 2948, 2922, 2870, 2850,
1729, 1654, 1608, 1507, 1484, 1458, 1389, 1367, 1324, 12651, 1229,
1181, 1030, 893, 858, 812, 753, 669. ESI-MS: 575, 574, 557, 539, 362,
345, 302.
2.3. Synthesis of 11, 17, 21-trihydroxy-pregn-4-ene-3, 20-dione (2)
Compound 2 was synthesized by dissolving 29 mg (0.071 mmol)
of compound (1) in 1.5 mL of methanol followed by addition of
0.3 mL of sodium methoxide as a catalyst. The mixture was kept at
room temperature for 30 min. The reaction mixture was neutral-
ized with IR 120H þ resin and filtered. Filtrate was concentrated
and compound 2 was purified with column chromatography using
Chloroform/methanol as eluent yielding 27.5 mg (94.82%) of com-
pound 2 in pure state. m.p: 490e491 K, Molecular formula:
2.6. Synthesis of 11, 17-dihydroxy-21-(2-(4-isobutylphenyl)
propionoxy)-pregn-4-ene-3, 20-dione (5)
A solution of ibuprofen 2.2 mg (0.011 mmol), DCC 2.2 mg
(0.011 mmol), DMAP 1.34 mg (0.011 mmol) and compound 2,
4.0 mg (0.011 mmol) in CHCl3 (2 mL) was stirred mechanically at
room temperature for 3e4 h and the progress of reaction was
monitored by TLC. DCU formed during the reaction was filtered off
and the filtrate washed successively with 5% HCl and water, dried
over anhydrous sodium sulphate and filtered. Filtrate obtained was
evaporated under reduced pressure and the crude product was
purified by column chromatography using ethyl acetateehexane
(2:98) as eluent yielding 4.1 mg (66.12%) of compound 5 as solid. M.
P. ¼ 489 K, Molecular formula: C34H46O6, 1H NMR (CDCl3, 300 MHz)
C
21H30O5, 1H NMR in CDCl3 at 300 MHz:
(1H, s, H-18),
1.054, 1.017 (1H, dd, H-9, J ¼ 3.3 Hz),
H-19), 3.061 (1H, broad signal, OH-21),
4.337(1H, d, J ¼ 19.8 Hz,
H-21A),
J ¼ 3 Hz, H-11),
d
7.260(D, s, CDCl3),
d 0.962
d
d
1.442 (1H, s,
d
d
d
4.686 (1H, d, J ¼ 19.8 Hz, H-21B)
d 4.468e4.499 (1H,q,
d
5.689 (1H, d, H-4, J ¼ 1.2 Hz). FT-IR nmax (in cmꢀ1):
3381.44, 2950.5, 2924.74, 2859.79, 1711.34, 1658.76, 1462.88,
1378.35, 1271.13, 1235.05, 1090.72, 1025.77, 869.07, 763.91, 743.29.
ESI-MS: 385, 362, 346, 302.
d
(ppm): 7.24 (2H, dd, H-27 &H-29, J ¼ 8.1, 2.2 Hz), 7.12 (2H, dd, H-
2.4. Synthesis of 11, 17, 21-tri-hydroxy-3, 20-diketo-pregn-1, 4-
diene (3)
26 & H-30, J ¼ 7.8, 1.5 Hz), 5.67 (1H, br s, H-4), 5.11 (1H, d, H-21A,
J ¼ 17.4 Hz) 4.91 (1H, br s, H-17), 4.78 (1H, d, H-21B, J ¼ 17.4 Hz),
4.45 (1H, br d, H-11, J ¼ 3.0 Hz), 3.88e3.80 (1H, m, H-23), 1.56 (3H,
d, CH3-24, J ¼ 7.2 Hz), 1.43 (3H, s, CH3-19), 0.96 (3H, s, CH3-18), 0.90
(6H, d, CH3-33 & CH3-34, J ¼ 6.6 Hz). 13C NMR (CDCl3, 75 MHz)
Mixture of 11,17,21-tri-hydroxy-3,20-diketo-pregn-4-ene (2)
15 mg (0.041 mmol) in 1, 4- dioxane (3 mL) was added 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) (21.0 mg, 0.092 mmol) at
room temperature and the mixture was refluxed for 4 h (progress of
reaction was monitored by TLC). The reaction mixture was cooled
down and filtered, washed with 1, 4-dioxane and concentrated to
give crude product, which was purified by column chromatography
using ethyl acetate: hexane (7:93) to yielding 12.5 mg (83.33%) of
the pure compound. The compound was identified by comparing
its data as reported in literature [13]. Melting Point: 506 K, Mo-
lecular formula: C21H28O5, 1H NMR at 300 MHz (in DMSO-d6)
d
(ppm): 204.77 (C-20), 199.8 (C-3), 174.62 (C-22 & C-5), 140.89 (C-
28), 137.52 (C-25), 129.5 (C-30 & C-26), 127.50 (C-29 & C-27), 122.2
(C-4), 89.84 (C-17), 68.48 (C-11), 68.11 (C-21), 56.50 (C-9) 52.11 (C-
14), 47.75 (C-31), 45.27 (C-13), 45.10 (C-23), 39.42 (C-12), 35.20 (C-
1), 34.84 (C-2), 34.03 (C-6), 32.93 (C-7), 32.22 (C-10), 31.58 (C-16),
30.38 (C-8), 29.92 (C-32), 23.83 (C-19), 22.62 (C-33 & 34), 21.21 (C-
15), 18.92 (C-24), 17.39 (C-18). FT-IR nmax (in cmꢀ1): 3480, 2952,
2930, 2864, 1717, 1657, 1515, 1459, 1411, 1377, 1367, 1229, 1185, 1163,
1127, 1111, 1081, 1055, 1033, 1017, 1003, 973, 943, 897, 861, 785, 743,
697, 645, 545, 523, 499, 457. ESI-MS: m/z ¼ 551, 550, 513, 225.
d
ppm: 7.29 (1H, d, H-1, J ¼ 9.9 Hz), 6.17e6.13 (1H, dd, H-2, J ¼ 1.2,
10.2 Hz), 5.91 (1H, s, H-4), 5.19 (1H, br s, H-17(OH)), 4.70e4.64 (2H,
11-OH, 22-OH), 4.52e4.44 (1H, dd, H-21A, J ¼ 6.0, 19.2 Hz), 4.26
(1H, s, H-11), 4.10e4.02 (1H, dd, H-21B, J ¼ 6.0,19.2 Hz), 1.38 (3H, s,
CH3-19), 0.76 (3H, s, CH3-18).
2.7. Synthesis of 21-(2-(6-methoxynaphthalene-2-yl) propionoxy)
11, 17-di-hydroxy-3, 20-diketo-pregn-1, 4-diene (6)
4.0 mg (0.011 mmol) of 11, 17, 21-tri-hydroxy-3, 20-diketo-
pregn-1, 4-diene (3) was dissolved in 2 mL of chloroform and then
naproxen 2.5 mg (0.011 mmol), DCC 2.2 mg (0.011 mmol) and
DMAP 1.34 mg (0.011 mmol) were added. The reaction mixture was
stirred at room temperature. The completion of reaction was
monitored with the help of thin layer chromatography (TLC). Re-
action mixture was washed with 5% HCl and water, dried over
anhydrous sodium sulphate and filtered. The organic layer was
concentrated under reduced pressure and the crude concentrated
product was purified by column-chromatography using ethyl ace-
tate: hexane (2:98) yielding 4.8 mg (73.84%) of 6 as amorphous.
m.p ¼ 462 K, Molecular formula: C35H40O7, 1H NMR at 300 MHz (in
2.5. Synthesis of 11, 17 dihydroxy-21-(2-(6-methoxynaphthalene-
2yl) propionoxy)-pregn-4-ene-3, 20-dione (4)
4.0 mg (0.011 mmol) of compound 2 (11,17,21-tri-hydroxy-3,20-
diketo-pregn-4-ene), dissolved in 2.5 mL of chloroform and 2.5 mg
(0.011 mmol) of naproxen was added followed by the addition of
1.34 mg (0.011 mmol) of DMAP and 2.2 mg (0.011 mmol) of DCC.
The reaction mixture was stirred at room temperature until reac-
tion was complete. Progress of reaction was monitored by thin layer
chromatography. N, N0 dicyclohexyl urea (DCU) formed as by
product was filtered off and the filtrate was treated with 5% HCl and
water, dried over anhydrous sodium sulphate. Chloroform was
distilled off under reduced pressure. The crude product obtained
was subjected to column chromatography for purification of syn-
thesized compound using silica gel (60e120 mesh) as absorbent
DMSO-d6)
d
ppm: 7.80 (3H, d, H-27, H-31 & H-32, J ¼ 9.6 Hz), 7.45
(1H, d, H-26, J ¼ 8.4 Hz), 7.32 (2H, d, H-30 & H-28, J ¼ 9.0 Hz), 7.17
(1H, d, H-1, J ¼ 9.0 Hz), 6.13 (1H, d, H-2, J ¼ 10.2 Hz), 5.91 (1H, s, H-
4), 5.38 4.90 (1H, br s, H-17(OH)), 5.07 (1H, d, H-21A, J ¼ 17.7 Hz),
Please cite this article in press as: A. Sethi, et al., Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their
quantum chemical calculations, Journal of Molecular Structure (2016), http://dx.doi.org/10.1016/j.molstruc.2016.10.087

4
A. Sethi et al. / Journal of Molecular Structure xxx (2016) 1e7
4.72 (1H, d, H-21B, J ¼ 17.7 Hz), 4.26 (1H, br s, H-11), 4.01 (1H, q, H-
23), 3.86 (3H, s, CH3-35), 1.52 (3H, d, H-24, J ¼ 6.9 Hz), 1.38 (3H, s,
CH3-19), 0.85 (3H, s, CH3-18), 0.88 (6H, d, CH3-33 & CH3-34, J ¼ 6.6
directly attached ester group. In the ESI-MS of compound 1, mo-
lecular ion and Mþþ Na peaks were recorded at m/z 404 and m/z
427 respectively.
Hz). IR (KBr)
n
max (cmꢀ1): 3415, 2930, 2853, 1724, 1656, 1607, 1452,
In 1H NMR spectrum of compound 2 showed two, 3 proton
1391, 1265, 1232, 1174, 1033, 888, 818. ESI-MS: m/z 572 [Mþ], m/z
574 [Mþþ2], m/z 537, m/z 324.
singlets, for angular methyl groups at d 0.962 and d 1.442 corre-
sponding to CH3-18, CH3-19 groups respectively, which are char-
acteristic of pregnane nucleus. Formation of compound 2 was
confirmed by absence of signal due to methyl protons of acetate
moiety which was present in compound 1; deacetylation of com-
pound 1 was further confirmed by the appearance of a broad signal
2.8. Synthesis of 11, 17-di-hydroxy-3, 20-diketo-pregn-1, 4-diene-
21-yl-2-(4-isobutylphenyl) propanoate (7)
4.0 mg (0.011 mmol) of prednisolone (3) was dissolved in 2 mL
of chloroform and then Ibuprofen 2.2 mg (0.011 mmol), DCC 2.2 mg
(0.011 mmol) and DMAP 1.35 mg (0.011 mmol) were added. The
reaction mixture was stirred at room temperature. The completion
of reaction was monitored with the help of thin layer chromatog-
raphy (TLC). Reaction mixture was washed with 5% HCl and water,
dried over anhydrous sodium sulphate and filtered. The organic
layer was concentrated under reduced pressure and the crude
concentrated product was purified by column-chromatography
using ethyl acetate: hexane (2:98) yielding 4.7 mg (75.80%) of 7
as crystalline powder. m.p ¼ 504 K, Molecular formula: C34H44O6,
of proton at d 3.061 due to primary hydroxyl group at C-21 position.
An upfield shifting of methylene protons of C-21 further confirmed
the structure of compound 2. These methylene protons were
observed as doublets at
well defined quartet was observed at
is due to methine proton at C-11 position. The splitting pattern of
d
4.686 (J ¼ 19.8 Hz) 4.337 (J ¼ 19.8 Hz). A
d
d
4.468 (J ¼ 3 Hz) this quartet
H-11 proton was further support the structure of compound 1
where hydroxyl group was found to be
trum of compound 2, hydrogen bonded O-H stretching was
observed from 3551.54 cmꢀ1e3145.36 cmꢀ1
centered at
3381.41 cmꢀ1. The C]O stretching frequency of carbonyl group at
C-21 position was observed at 1711.34 cmꢀ1 while
unsaturated
b-oriented. In the IR spec-
,
1H NMR at 300 MHz (in CDCl3)
dppm: 7.22 (2H, d, H-27 & H-29,
a, b
J ¼ 7.8 Hz), 7.27 (1H, d, H-1, J ¼ 9.3 Hz), 7.10 (2H, d, H-26 & H-30,
J ¼ 7.8 Hz), 6.24 (1H, dd, H-2, J ¼ 1.5, 10.2 Hz), 6.01 (1H, s, H-4), 5.01
(1H, d, H-21A, J ¼ 17.4 Hz), 4.90 (1H, br s, H-17(OH)), 4.75 (1H, d, H-
21B, J ¼ 17.4 Hz), 4.46 (1H, s, H-11), 3.82 (1H, q, H-23), 1.56 (3H, d,
CH3-24, J ¼ 7.2 Hz), 1.44 (3H, s, CH3-19), 0.97 (3H, s, CH3-18), 0.88
(6H, d, CH3-33 & CH3-34, J ¼ 6.6 Hz). 13C NMR (CDCl3, 75 MHz)
carbonyl stretching frequency corresponding to C5]C4-C3]O was
observed at 1658.76 [17], which further support the presence of
unsaturated carbonyl group. In the ESI-MS spectrum of compound
2 molecular ion was recorded as Mþ ¼ 362 with 100% abundance,
while MþþNa was also present at 385.
The double bond is well recognized in the 1H NMR spectrum of
compound 3, which besides other signals of the hydrocortisone
d
(ppm) 204.81 (C-20), 186.84 (C-3), 174.85 (C-22), 170.35 (C5),
156.53 (C-1), 140.28 (C-28), 137.47 (C-25), 129.58 (C-27 & C-29),
128.02 (C-2), 127.49 (C-26 & C-30), 122.60 (C-4), 89.83 (C-17), 70.34
(C-21), 68.32 (C-11), 55.50 (C-9), 51.51 (C-14), 47.95 (C-31), 45.26
(C-13), 45.13 (C-23), 44.29 (C-12), 39.78 (C-40), 34.74 (C-4), 34.22
(C-7), 32.19 (C-16), 31.42 (C-8), 30.37 (C-32), 24.05 (C-19), 22.61 (C-
shows two new doublet of one proton each at
6.17e6.13 (J ¼ 1.2, 10.2 Hz) for H-1 and H-2 respectively.
In the 1H NMR spectrum of 4, the downfield shifting of meth-
ylene protons as compared to compound 2 confirms that ester
group has been introduced, these methylene protons were
d
7.29 (J ¼ 9.9 Hz) and
d
33 & C-34), 21.27 (C-15), 18.89 (C-24), 17.21 (C-18). IR (KBr)
nmax
observed as one proton doublets at
d
5.046 (J ¼ 17.1 Hz) and
d
4.800
(cmꢀ1): 3461, 2933, 2870, 1722, 1657, 1615, 1513, 1453, 1409, 1366,
1263, 1239, 1114, 1058, 1040, 938, 859, 819, 737, 701, 534. ESI-MS:
m/z 548 [Mþ], m/z 531.
(J ¼ 17.4 Hz). A quartet of one proton was appeared at
d
3.959 (J ¼ 6.9
Hz, 7.2 Hz) which is due to methine proton of naproxen designated
as H-23. Six aromatic protons of naproxen moiety were well
observed from d 7.12e7.72. H-31 and H-32 protons of aromatic ring
3. Computational methods
were observed at same position as two proton doublet at
d
7.698
(J ¼ 1.8 Hz) while H-27 was observed as doublet at
d 7.726
All the calculations of synthesized compounds were carried out
with help of Gaussian 09 program package [14] using B3LYP func-
tional and 6-31G (d, p) basis set. The electronic transitions and
electronic properties such as HOMO-LUMO were computed with
the help of time-dependant DFT (TD-DFT) method. The molecular
structures were visualized with the help of Gauss View [15]. AIM
calculations were performed by AIMALL program [16].
(J ¼ 2.4 Hz). A proton doublet at 7.149 (J ¼ 2.7 Hz) was assigned to
d
H-30, while H-28 proton was observed as singlet at
26 proton of the aromatic ring was observed as double doublet at
7.451 (J ¼ 1.8 Hz). Protons of the methoxy group of naphthalene
ring were observed as sharp singlet at 3.911. A three proton
doublet was observed at
1.624 (J ¼ 7.2 Hz) this doublet is due to
d 7.120. The H-
d
d
d
methyl protons corresponds to CH3-24. In the IR-spectrum of
compound, introduction of ester group is well indicated by strong
ester C]O stretching frequency at 1729.89 cmꢀ1 [18]. Aromatic C]
C stretching vibrations were well observed at 1608.24 cmꢀ1 and
1510.30 cmꢀ1. Asymmetric deformation of methyl was observed at
1461.85 cmꢀ1 and symmetric deformation of methyls was observed
at 1377.31 cmꢀ1. C-C stretching of isopropyl group was assigned to
the band observed at 1321.64 cm-1 CH2 out of plane bending vi-
brations (wagging and twisting) were observed at 1285.56 cmꢀ1
and 1158.76 cmꢀ1 respectively. C-O stretching of ester group is
observed at 1223.71 cmꢀ1 while C3-O1 stretching vibration of ester
group was observed at 1112.37 cmꢀ1. In the ESI-MS spectrum of
compound 4, molecular ion was as well as Mþþ1 was recorded at
574 (with 100% abundance) and 575 respectively.
4. Result and discussion
4.1. 1H, 13C NMR, FT-IR spectroscopy and ESI-MS
In the 1H NMR spectrum of compound 1 two singlets of three
protons each were observed at
d 0.972 and d 1.445 which are
characteristic signals of angular methyl groups corresponding to
CH3-18, and CH3-19 respectively, of pregnanes. This signifies that
the isolated compound may be a pregnane derivative. Another
three proton singlet was observed at
d 2.186 which is also a char-
acteristic signal of methyl protons of acetate moiety this confirms
that molecule has one acetate group in the structure. Two doublets
were observed at and
d
4.879 (J ¼ 17.4 Hz) and
d
5.007(J ¼ 17.4 Hz)
In the 1H NMR spectrum of the compound 5, absence of one
which is probably due to mutually coupled protons of methylene
group which is directly attached with ester group. These protons
are most often due to methylene protons at C-21 position with
proton singlet for OH-21 at
shifting of H-21A and H-21B protons as doublets at
Hz) and
4.78 (J ¼ 17.4 Hz) (initially observed at
d
3.06 and appearance of downfield
5.11 (J ¼ 17.4
4.337 (J ¼ 19.8
d
d
d
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A. Sethi et al. / Journal of Molecular Structure xxx (2016) 1e7
5
Hz) and
along with the appearance of four aromatic protons at
dd, H-27 & H-29, J ¼ 8.1, 2.2 Hz), 7.21 (2H, dd, H-26 & H-30, J ¼ 7.8,
1.5 Hz), methine proton (H-23) at 3.88e3.80, and six proton
doublet observed at
d
4.686 (J ¼ 19.8 Hz) for H-21A and H-21B in compound 2)
(computed by TD-DFT) whereas the LUMO lying at ꢀ1.10 eV. The
energy difference between the HOMO and LUMO was obtained as
4.27 eV in the gas phase calculations. For compound 5, the HOMO
lying at ꢀ6.09 eV whereas the LUMO lying at ꢀ1.09 eV. The energy
difference between the HOMO and LUMO was obtained as 4.99 eV
in the gas phase calculations. For compound 6, the HOMO lying
at ꢀ5.45 eV whereas the LUMO lying at ꢀ1.27 eV. The energy dif-
ference between the HOMO and LUMO was obtained as 4.17 eV in
the gas phase calculations. For compound 7, HOMO whereas LUMO
lying at ꢀ6.09 and ꢀ1.27 eV respectively. The energy difference
between the HOMO and LUMO was obtained as 4.82 eV in the gas
phase calculations. Low charge separation in 6 explains eventual
charge transfer interactions within the molecule and high chemical
reactivity, which may influence the biological activity of the
molecule.
d
7.24 (2H,
d
d
d
0.90 (J ¼ 6.6 Hz) due to methyl protons of
isopropyl group corresponding to CH3-33 & CH3-34 confirmed the
esterification of compound 2 at C-21 with ibuprofen. In the 13C
NMR of the compound 5, the peak observed at
for C-21 and (C-22) (carbonyl carbon of ester group) respectively
along with the aromatic carbons at 140.89 (C-28), 137.52 (C-25),
129.5 (C-30 & C-26) and 127.50 (C-29 & C-27) confirmed the
d 68.11 and d 174.62
d
d
d
d
esterification at C-21 of the compound 2. In the IR spectrum of the
compound 5, the band at 1717 cmꢀ1 and 1229 cmꢀ1 [17,18] due to
C]O (C22]O) and CeC(]O)eO [CeC22(]O)eO] stretching of
ester along with the C]C stretching of aromatic ring at 1515 and
1459 cmꢀ1 and C-C stretching vibration (of isopropyl side chain of
Ibuprofen) at 1367 cmꢀ1 confirmed the esterification of compound
2 with ibuprofen. In the ESI-MS of the compound 5, both the mo-
lecular ion peak and protonated molecular ion peak were observed
at m/z ¼ 550 and 551 respectively.
4.3. AIM approach
In the topological theory of AIM (Atoms In Molecule), when two
atoms are chemically bonded, a bond critical point appears be-
tween them and the nature of chemical bonds and molecular
In the 1H NMR spectrum of 6, the downfield shifting of meth-
ylene protons (CH2-21) to
J ¼ 17.7 Hz) in comparison to methylene protons of 3 [
(d, J ¼ 6.0, 19.2 Hz) and 4.10e4.02 (d, J ¼ 6.0, 19.2 Hz)], confirms
d
5.07 (d, J ¼ 17.7 Hz) and
d
4.72 (d,
reactivity are described by total electronic density
r(r), and its
d
4.52e4.44
corresponding Laplacian V2r(r). Laplacian of total electronic density
is related to energetic topological parameters by a local expression
of the virial theorem at critical points [19]:
d
that the 21-OH group has been esterified. The signals for aromatic
protons of naproxen were observed at 7.80 (3H, d, H-27, H-31 & H-
32, J ¼ 9.6 Hz), 7.45 (1H, d, H-26, J ¼ 8.4 Hz), 7.32 (2H, d, H-30 & H-
28, J ¼ 9.0 Hz). In the FT-IR spectrum of 6, sharp band at 1724 cmꢀ1
[18] appears to be due to carbonyl groups at C-20 and C-22, how-
ever band at 1265 cmꢀ1 appears to be due to C-O stretching of ester
group. In the ESI-MS spectrum of 6, the molecular ion peak was
observed at m/z 572 [Mþ].
1
4
V
2r ðrÞ ¼ 2G ðrÞ þ V ðrÞ
Where, G(r) and V(r) are the kinetic and potential electron energy
densities at critical points respectively. In the characterization of
IHB (Intramolecular Hydrogen Bonding), bond critical point (BCP)
in the hydrogen bond and ring critical point (RCP) in the ring are
useful. Positive values of V2r(r)at BCP indicate that G(r) is greater
than that of V(r) and shows depletion of electronic charge along the
bond path, which is specific for closed-shell interactions such as
hydrogen bonds. However negative value of V2r(r) indicates excess
potential energy at BCP and which is specific of shared interactions,
such as covalent bonds. In the later case, electronic charge is
focused on the internuclear region and shared by two nuclei [20].
As Rozas et al. [21] explained that hydrogen bonds can be classified
In the 1H NMR spectrum of 7, the downfield shifting of methy-
lene protons (CH2-21) to
Hz) in comparison to methylene protons of 3 [(
J ¼ 6.0, 19.2 Hz) and 4.10e4.02 (d, J ¼ 6.0, 19.2 Hz)], confirms that
the 21-OH group has been esterified. The signal for aromatic pro-
d
5.01 (d, J ¼ 17.4 Hz) and
d
4.75 (d, J ¼ 17.4
d
4.52e4.44 (d,
d
tons of ibuprofen were observed at
d 7.22 (2H, d, H-27 & H-29,
J ¼ 7.8 Hz),
d
7.10 (2H, d, H-26 & H-30, J ¼ 7.8 Hz). In the 13C NMR
spectrum of 7, the observed carbon signal at d 174.85 for C22 along
with aromatics carbon at d 129.58 (C-27 & C-29), and d 127.49 (C-26
& C-30) confirm the formation of ester at C-21 position. In the FT-IR
spectrum of 7, sharp band at 1722 cmꢀ1 [18] appears to be due to
carbonyl groups at C-20 and C-22, however band at 1263 cmꢀ1
appears to be due to C-O stretching of ester group. In the ESI-MS
spectrum of 7, the molecular ion peak was observed at m/z 548
[Mþ].
as (1) Weak hydrogen bonds, when V > 0 and
2r(rBCP)
G(rBCP) þ V(rBCP) > 0; (2) Medium hydrogen bonds, when
V
2r(rBCP) > 0 and G(rBCP) þ V(rBCP) < 0; (3) Strong hydrogen
bonds, when V2r(rBCP) < 0 and G(rBCP) þ V(rBCP) < 0; Where
G(rBCP) þ V(rBCP) is also known as total electron energy density
H(rBCP). The ranges of r
(r) and V2r(r) for hydrogen bond in BCP are
0.002e0.035e/Å3 and 0.02e0.139e/Å5 respectively [22]. The nature
of IHB can be determined using ratio of ꢀG(rBCP)/V(rBCP). When
this ratio is >1, then IHB has non-covalent nature, while when this
ratio is <1, then it is partly covalent [23]. Several theoretical
methods [24,25] have been proposed to estimate hydrogen bond
energy. One of the most useful of these methods has been
explained by Espinosa et al. [26] who found that IHB energy may be
correlated with the potential electron energy density at critical
point by the expression EIHB ¼ 1/2V (rBCP). Molecular graphs of the
synthesized compounds using AIM program at B3LYP/6- 31G (d, p)
level are shown in Fig. 2. For compounds topological parameters for
bonds of interacting atoms are given in Table 1 and on the basis of
above criteria V2r (rBCP) and HBCP parameters are greater than zero,
which suggested that all the interactions are weak. The
ratio ꢀG(rBCP)/V(rBCP) of the synthesized prodrugs 4, 5, 6 and 7
were greater than unity, which suggested that hydrogen bond in-
teractions are non-covalent in nature. According to AIM calculation,
the total energy of intramolecular interaction for prodrugs 4, 5, 6
4.2. Frontier molecular orbital
The frontier orbitals, HOMO and LUMO determine the way how
the molecule interacts with other species and helps to characterize
the chemical reactivity and kinetic stability of the molecule. They
play an important role in the electric and optical properties, as well
as in the UVeVis spectra and chemical reactions. HOMO energy
determines the ability to donate an electron and LUMO energy
determines the ability to accept an electron. The energy gap be-
tween the HOMO and LUMO is very important in determining the
chemical reactivity of the molecule. A small HOMO-LUMO energy
gap implies low kinetic stability, because it is energetically favor-
able to add electrons to a low-lying LUMO and to receive electrons
from a high-lying HOMO. Thus, molecules with low frontier orbital
gap are more polarizable and associated with high chemical reac-
tivity. Fig. 1 shows the HOMO-LUMO molecular orbital diagrams for
prodrugs 4, 5, 6 and 7. For compound 4, HOMO lying at ꢀ5.38 eV
Please cite this article in press as: A. Sethi, et al., Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their
quantum chemical calculations, Journal of Molecular Structure (2016), http://dx.doi.org/10.1016/j.molstruc.2016.10.087

6
A. Sethi et al. / Journal of Molecular Structure xxx (2016) 1e7
Fig. 1. HOMO-LUMO molecular orbital diagrams for prodrugs 4, 5, 6 and 7.
Fig. 2. Molecular graphs of the synthesized compounds using AIM program at B3LYP/6- 31G (d, p) level.
Please cite this article in press as: A. Sethi, et al., Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their
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A. Sethi et al. / Journal of Molecular Structure xxx (2016) 1e7
7
Table 1
compounds, compound 7 was found to be a good electrophile
(global electrophilicity index (
) ¼ 2.81). On the basis of first
Topological parameters for bonds of interacting atoms: electron density (rBCP),
Laplacian of electron density (V2r(rBCP)), electron kinetic energy density (GBCP),
electron potential energy density (VBCP), total electron energy density (HBCP) at bond
critical point (BCP) and estimated interaction energy (Eint) for compound 4, 5, 6 and
7.
u
hyperpolarizability,
we
conclude
that
compound
4
(
b0 ¼ 5.66 ꢁ 10ꢀ30 esu) showed good attractive materials for non
linear optical (NLO) application.
Interaction
r(BCP)
V
2r(rBCP) GBCP
VBCP
HBCP
ꢀ G/V Eint
Acknowledgements
Compound 4
O2/H1B
H12B/H21A 0.048 0.017
O4/H26
H8/H18B
H11/H18B
Compound 5
O2/H1B
0.019 0.066
0.0158 ꢀ0.0151 0.0007 1.0
0.003 0.001 1.5
ꢀ0.002
ꢀ4.73
ꢀ0.62
ꢀ1.28
ꢀ1.56
ꢀ1.56
The authors are grateful for the Central Facility for Computa-
tional Research provided by Department of Chemistry, University of
Lucknow and SAIF division of CDRI, Lucknow for the spectral data.
0.006 0.023
0.009 0.039
0.009 0.037
0.0049 ꢀ0.0041 0.0008 1.1
0.007
0.007
ꢀ0.005
ꢀ0.005
0.002
0.002
1.4
1.4
0.019 0.066
0.016
0.003
0.007
0.007
ꢀ0.015
ꢀ0.001
ꢀ0.005
ꢀ0.005
0.001
0.002
0.002
0.002
1.0
3.0
1.4
1.4
ꢀ4.70
ꢀ0.31
ꢀ1.56
ꢀ1.56
Appendix A. Supplementary data
H12B/H21A 0.045 0.016
H11/H18B
H8/H18B
Compound 6
O2/H1
O4/H26
H12B/H21A 0.004 0.017
H11/H18B
H8/H18B
Compound 7
O2/H1
0.009 0.037
0.010 0.039
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.10.087.
0.021 0.073
0.066 0.025
0.017
0.005
0.003
0.007
0.007
ꢀ0.016
ꢀ0.004
ꢀ0.002
ꢀ0.004
ꢀ0.005
0.001
0.001
0.001
0.003
0.002
1.0
1.2
1.5
1.7
1.4
ꢀ5.02
ꢀ1.25
ꢀ0.62
ꢀ1.25
ꢀ1.56
Appendix A
0.008 0.037
0.009 0.039
All the spectra, optimized geometries, NLO properties, global
reactivity descriptors and MEP analysis of all compounds were
given in supplementary data.
0.020 0.072
0.017
0.003
0.007
0.007
0.006
ꢀ0.016
ꢀ0.002
ꢀ0.004
ꢀ0.005
ꢀ0.004
0.001
0.001
0.003
0.0004 1.4
0.002 1.5
1.0
1.5
1.7
ꢀ5.02
ꢀ0.62
ꢀ1.25
ꢀ1.56
ꢀ1.25
H12B/H21A 0.004 0.017
H18B/H11
H18B/H8
H19C/H8
0.008 0.037
0.010 0.040
0.008 0.033
References
r(
BCP), V2r(rBCP), GBCP, VBCP, HBCP (in a.u.); Eint (kcal/mol).
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0.184, 0.150, 0.153, 0.263 and 0.163 respectively whereas it was very
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5. Conclusion
Corticosteroids prodrugs (4, 5, 6 and 7) have been synthesized
by adopting Steglich reaction. The structures of these compounds
were well characterized with the help of 1H, 13C NMR, FT-IR spec-
troscopy and mass spectrometry. Lower charge separation in 6
explains eventual charge transfer interactions within the molecule
and high chemical reactivity. According to AIM approach, the total
energy (ꢀ9.97 kcal/mol) of intramolecular interactions for com-
pound 4 was higher than other compounds. Out of all synthesized
[28] A. Sethi, R.P. Singh, et al., J. Mol. Struct. 1125 (2016) 616e623.
Please cite this article in press as: A. Sethi, et al., Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their
quantum chemical calculations, Journal of Molecular Structure (2016), http://dx.doi.org/10.1016/j.molstruc.2016.10.087