Microwave mediated synthesis of non-carboxylic analogues of ibuprofen with improved pharmacological activity

Article abstract of DOI:10.1016/j.cclet.2010.12.013

A series of 1,2,4-triazolo[3,4-b]-thiadiazoles were synthesized following microwave irradiation method and also by conventional method. Newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activities.

Full text of DOI:10.1016/j.cclet.2010.12.013

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 508–510
www.elsevier.com/locate/cclet
Microwave mediated synthesis of non-carboxylic analogues of
ibuprofen with improved pharmacological activity
a
b
K.V. Sujith a, Balakrishna Kalluraya a, , Adithya Adhikari , J. Ravikumar
*
a Department of Studies in Chemistry, Mangalore University, Mangalagangothri 574199, Karnataka, India
b Department of Pharmacology, NGSM Institute of Pharmaceutical Science, Deralakkatte 574160, Karnataka, India
Received 24 August 2010
Available online 3 March 2011
Abstract
A series of 1,2,4-triazolo[3,4-b]-thiadiazoles were synthesized following microwave irradiation method and also by conven-
tional method. Newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activities.
# 2010 Balakrishna Kalluraya. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ibuprofen; Microwave; Thiadiazole; Anti-inflammatory; Analgesic
Ibuprofen is an important class of drug belongs to NSAIDs with anti-inflammatory and analgesic activity [1]. Long
term use of NSAIDs like ibuprofen has been associated with gastrointestinal complications ranging from stomach
irritation to life-threatening GI ulceration bleeding and nephrotoxicity [2,3]. In this perspective ibuprofen has been
exploited, infactthismoleculehasa carboxylicgroupasfunctionalgroup, commontomostNSAIDswhichisresponsible
for its local irritation [4]. It has been reported that the derivatization of the carboxyl function of representative NSAIDs,
resulted in an increased anti-inflammatory activity with reduced ulcerogenic effect [5–7]. Keeping in view of these
observations and in continuation of our search for non-carboxylic derivatives of ibuprofen having improved
pharmacological activity [8] we prepared a novel series of triazolothiadiazoles. Retaining the ibuprofen core and
replacing its carboxylic group by a triazolothiadiazole moiety. Similarly the development of environmental friendly
process has become a focal point in chemical research in recent years [9,10]. Particularly the more efficient use of energy
and reduction in the amount of solvents and hazardous substance grab the attention. The microwave induced organic
reaction received considerable attention due to their simplicity and operational convenience [11–13]. So we also
developed newer eco friendly methods for the synthesis of target molecules namely triazolothiadiazole and the
microwave induced reactions were found to be more efficient than the conventional method.
Melting points were determined in open capillary tubes and are uncorrected. IR spectra were recorded by dispersing
1
the compounds in KBr pellets on a Shimadzu FT-IR 157 spectrophotometer. H NMR spectra were recorded on a
400 MHz Bruker Avance spectrometer and all the chemical shift values were reported as d. Mass spectra were recorded
on a JEOL SX-102 (FAB) mass spectrometer. Microwave reactions were performed on a godrej domestic oven, with
rotating platform tray.
* Corresponding author.
E-mail address: bkalluraya@gmail.com (B. Kalluraya).
1001-8417/$ – see front matter # 2010 Balakrishna Kalluraya. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.013

[()TD$FIG]
K.V. Sujith et al. / Chinese Chemical Letters 22 (2011) 508–510
509
a
CH3
N
N
N
N
O
H3C
R
+
N
S
R
SH
N
OH
N
CH3
CH3
NH
2
b
(1)
R = H, CH3, C2H5, C3H7, C6H5
Scheme 1. Synthetic route for compound 3. Conditions: (a) POCl3, microwave irradiation at 160 W for 5 min; (b) POCl3, reflux 16 h.
(2)
H3C
CH3
(3)
In the design of new compounds, development of hybrid molecules through the combination of different
pharmacophores in one structure may lead to compounds with increased biological activity. These observations
prompted us to synthesize new 1,2,4-triazolo[3,4-b]thiadiazoles derivatives carrying ibuprofen moiety at 6th position.
Both ibuprofen and 1,2,4-triazoles are two important pharmacophores. When they combine to form fused
triazolothiadiazole ring system, their synergism towards bio-active properties are studied.
Synthetic pathway for 3-substituted-6-[1-(4-isobutylphenyl)ethyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (3) is
summarized in Scheme 1. An equimolar mixture of substituted triazoles (2) and ibuprofen were dissolved in
phosphorus oxychloride. This mixture was then heated conventionally for about 16 h or by employing microwave
irradiation for about 5 min at 160 W. The reaction mixture was then cooled to room temperature and poured into ice
cold water and treated with saturated solution of sodium bicarbonate. It was then filtered, dried and recrystallized from
ethanol to obtain compound 3. Formation of the compounds was confirmed by spectral and analytical data [14]. Anti-
inflammatory activity was determined by the carrageenan-induced paw edema method in Wistar albino rats by using
plethysmography following the method of Winter et al. [15]. Diclofenac at an oral dose of 20 mg/kg served as the
standard drug for comparison and Ibuprofen is used as a second reference for further comparison. The compounds
showed anti-inflammatory activity ranging from 41% to 62% (Table 1), whereas standard drugs diclofenac and
ibuprofen showed 75% and 42% inhibition after 3 h, respectively. Except compound 3a all the other tested compounds
exhibited more significant anti-inflammatory activity compared to the starting compound ibuprofen. Analgesic
activities were evaluated on Swiss albino mice by hot plate method [16]. The reaction time of the animals on the hot
plate at 60 and 120 min after drug administration (10 mg/kg) are noted. A dose level of 10 mg/kg diclofenac served as
the standard drug for comparison. Compounds showed analgesic activity ranging from 39.28% to 61.84%, whereas the
standard drug diclofenac showed 79.24% and ibuprofen showed 30.04% inhibition after 2 h (Table 2). All the tested
compounds exhibited more significant analgesic activity compared to ibuprofen. Among the five compounds tested for
biological activity, compound 3c, carrying methyl group at sixth position exhibited significant anti-inflammatory and
analgesic properties.
Discovery of mild and practical routes for the synthesis of heterocycles continues to attract the attention of
researchers. To accomplish this, we employed microwave irradiation, which has been extensively used for the rapid
synthesis of a variety of heterocyclic compounds. The newly synthesized analogues of ibuprofen exhibited increased
biological potency compared to the parent drug, ibuprofen.
Table 1
Anti-inflammatory activity of ibuprofen derivatives.
Compounds (R)
Change in paw volume in mL Æ SEM (% inhibition)
1 h 2 h
3 h
Diclofenac
Ibuprofen
3a (H)
0.5 Æ 1.01 (65)
0.8 Æ 4.18 (76)
1 Æ 0.89 (75)
1.15 Æ 2.67 (18)
0.98 Æ 2.32 (30)
1.14 Æ 1.88 (19)
1.1 Æ 1.22 (22)
1.22 Æ 1.18 (13)
0.9 Æ 1.69 (36)
2.11 Æ 3.74 (36)
2.22 Æ 3.14 (32)
2 Æ 1.21 (39)
2.26 Æ 2.35 (42)
2.3 Æ 2.96 (41)
1.98 Æ 3.45 (49)
1.5 Æ 1.15 (62)
2.05 Æ 2.77 (47)
1.68 Æ 1.88 (57)
3b (CH3)
3c (C2H5)
3d (C3H7)
3e (C6H5)
1.4 Æ 2.11 (58)
1.64 Æ 1.17 (50)
1.7 Æ 1.36 (49)

510
K.V. Sujith et al. / Chinese Chemical Letters 22 (2011) 508–510
Table 2
Analgesic activity of ibuprofen derivatives.
Compounds (R)
Before treatment Æ SEM
After treatment Æ SEM (% increase in reaction time)
1 h
2 h
Diclofenac
Ibuprofen
3a (H)
2.12 Æ 0.18
2.13 Æ 0.26
1.68 Æ 0.64
1.71 Æ 0.17
1.52 Æ 0.25
1.58 Æ 0.21
1.81 Æ 0.23
3.14 Æ 0.28 (48.11)
2.61 Æ 0.38 (22.53)
2.18 Æ 0.26 (29.76)
2.2 Æ 0.58 (28.65)
2.24 Æ 0.34 (47.36)
2.04 Æ 0.50 (29.11)
2.36 Æ 0.38 (30.38)
5.92 Æ 0.21 (79.24)
2.77 Æ 0.33 (30.04)
2.34 Æ 0.12 (39.28)
2.43 Æ 0.18 (42.10)
2.46 Æ 0.22 (61.84)
2.30 Æ 0.23 (45.56)
2.72 Æ 0.18 (50.27)
3b (CH3)
3c (C2H5)
3d (C3H7)
3e (C6H5)
Acknowledgment
The authors are thankful to UGC for the financial assistance and to the Head, SAIF, CDRI, Lucknow for providing
1
mass and H NMR spectral data.
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[14] Analytical data 3a. yield: 58%; m.p. 83–86 8C; IR (KBr) g/cmÀ1: 2925 (C–H), 1510 (C N); 1H NMR (CDCl3): d 0.82 (d, 6H, J = 6.54 Hz,
(CH3)2), 1.66 (d, 3H, J = 7.12 Hz, CHCH3), 1.77–1.81 (m, 1H, CH), 2.40 (d, 2H, J = 7.20 Hz, CH2-Ar), 4.59 (q, 1H, CHCH3), 7.09 (d, 2H,
J = 8.00 Hz, ibu-Ar), 7.30 (d, 2H, J = 8.00 Hz, ibu-Ar); LC–MS (m/z): 287 (M++1). Anal. calcd. for C15H18N4S: C 63.96, H 6.71, N 18.64;
Found: C 63.89, H 6.77, N 18.59. 3b. yield: 64%; m.p. 122 8C; IR (KBr) g/cmÀ1: 2954 (C–H), 1535 (C N); 1H NMR (CDCl3): d 0.84 (d, 6H,
J = 6.57 Hz, (CH3)2), 0.90 (s, 3H, CH3), 1.69 (d, 3H, J = 7.02 Hz, CHCH3), 1.77–1.80 (m, 1H, CH), 2.43 (d, 2H, J = 7.11 Hz, CH2-Ar), 4.60 (q,
1H, CHCH3), 7.16 (d, 2H, J = 7.92 Hz, ibu-Ar), 7.31 (d, 2H, J = 7.95 Hz, ibu-Ar); LC–MS (m/z): 301 (M++1). Anal. calcd. for C16H20N4S: C
64.93, H 7.05, N 17.81; Found: C 64.87, H 7.02, N 17.78. 3c. yield: 69%; m.p. 96–98 8C; IR (KBr) g/cmÀ1: 2958 (C–H), 1561 (C N); 1H NMR
(CDCl3): d 0.91 (d, 6H, J = 6.56 Hz, (CH3)2), 1.50 (t, 3H, CH3),1.81 (d, 3H, J = 7.16 Hz, CHCH3), 1.83–1.89 (m, 1H, CH), 2.49 (d, 2H,
J = 7.20 Hz, CH2-Ar), 3.08–3.14 (q, 2H, CH2), 4.40 (q, 1H, CHCH3), 7.17 (d, 2H, J = 8.16 Hz, ibu-Ar), 7.23 (d, 2H, J = 8.12 Hz, ibu-Ar); LC–
MS (m/z): 315 (M++1). Anal. calcd. for C17H22N4S: C 65.81, H 7.36, N 17.05; Found: C 65.77, H 7.33, N 17.11. 3d. yield: 56%; m.p. 101–
103 8C; IR (KBr) g/cmÀ1: 2959 (C–H), 1488 (C N); 1H NMR (CDCl3): d 0.82 (d, 6H, J = 6.60 Hz, (CH3)2), 0.97 (t, 3H, CH3), 1.69 (d, 3H,
J = 7.08 Hz, CHCH3), 1.75–1.82 (m, 1H, CH), 1.75–1.82 (m, 2H, CH2), 2.43 (d, 2H, J = 7.17 Hz, CH2-Ar), 2.98 (t, 2H, CH2), 4.61 (q, 1H,
CHCH3), 7.17 (d, 2H, J = 8.04 Hz, ibu-Ar), 7.31 (d, 2H, J = 8.04 Hz, ibu-Ar); LC–MS (m/z): 329 (M++1). Anal. calcd. for C18H24N4S: C 69.53,
H 6.08, N 15.41; Found: C 69.58, H 6.11, N 15.45. 3e. yield: 51%; m.p. 115–118 8C; IR (KBr) g/cmÀ1: 2951 (C–H), 1578 (C N); 1H NMR
(CDCl3): d 0.92 (d, 6H, J = 6.64 Hz, (CH3)2), 1.83–1.90 (m, 1H, CH), 1.89 (d, 3H, J = 7.12 Hz, CHCH3), 2.50 (d, 2H, J = 7.16 Hz, CH2-Ar),
4.50 (q, 1H, CHCH3), 7.19 (d, 2H, J = 8.12 Hz, ibu-Ar), 7.27 (d, 2H, J = 8.08 Hz, ibu-Ar), 7.49–8.38 (m, 5H, Ar); LC–MS (m/z): 363 (M++1).
Anal. calcd. for C21H22N4S: C 70.11, H 6.39, N 14.91; Found: C 70.17, H 6.42, N 14.88.
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