EHOOPrÁHH^ECRAa XHMH3, 2015, moM 41, № 2, c. 218-226
SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL FUSED THIAZOLO[3,2-A]PYRIMIDINES AS POTENTIAL ANALGESIC AND ANTI-INFLAMMATORY AGENTS
© 2015 Nagy M. Khalifa", b, *, Mohamed A. Al-Omar", Abd El-Galil E. Amr", c, Ayman R. Baiuomy^, e, and Rehab F. Abdel-Rahmand
aPharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh, 11451 Saudi Arabia bDepartment of Therapeutical Chemistry, Pharmaceutical and Drug Industries Division, National Research Centre, Cairo, Dokki, 12622 Egypt cApplied Organic Chemistry Department, National Research Centre, Cairo, Dokki, 12622 Egypt d Department of Pharmacology, National Research Centre, Cairo, Dokki, 12622 Egypt e College of Medicine and Medical Sciences, Taif University, Saudi Arabia Received February 17, 2014; in final form, July 23, 2014
Some novel bicyclic thiazolopyrimidine derivatives bearing various substituents have been synthesized through one-pot three-component method. Structures of the target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their analgesic and anti-inflammatory activities and revealed pronounced anti-inflammatory activity greater than that of indomethacin (reference drug).
Keywords: thiazolopyrimidine, Biginelli compounds, anti-inflammatory, analgesic. DOI: 10.7868/S0132342315020098
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic agents, primarily for the treatment of pain and inflammation in arthritis. However, long-term clinical usage of NSAIDs is associated with significant side effects including gastrointestinal lesions, bleeding and nephrotoxicity [1—3]. NSAID-induced gastropathy is estimated to affect up to half of chronic NSAID users, with major world health implications . Therefore the discovery of new safer anti-inflammatory drugs represents a challenging goal for such a research area. In recent years, fused pyrimidine and their derivatives have shown diverse biological activities. Among them, thiazolopyrimidines have attracted considerable interest due to their remarkable pharmacological properties. These compounds were designed and synthesized as potent and selective anticancer [5—8], anti-inflammatory [9—11], antihypertensive , human cytomegalovirus inhibitory [13, 14], TRPV1 inhibitory , antimicrobial [16, 17], antiviral , antioxidant [19, 20], analgesic , anti-HSV-1 , CDC25 phosphatase inhibitory , acetylcholinesterase inhibitory , and calcium channel blocking  agents. In view of the therapeutic importance of thia-
5 Corresponding author (e-mail: firstname.lastname@example.org).
zolopyrimidines, we were interested to prepare some novel substituted thiazolopyrimidine derivatives aiming at developing more active anti-inflammatory agents devoid of the undesirable side effects associated with classical NSAIDs.
RESULTS AND DISCUSSION
The synthetic strategies adopted for the synthesis of the final compounds are depicted in Scheme 1. The starting compound 2,3,4,4a-tetrahydro-4-methyl-4-(pyridin-2-yl)-2-tWoxo-1#-indeno[1,2-d]pyrimidin-5-one (IV) was synthesized by acid catalyzed condensation of 2-acetyl pyridine (I), thiourea (II), and 1,3-in-danedione (III) in ethanol, by a modification of the Biginelli reaction . Thioxopyrimidine derivative (IV) was condensed with monochloroacetic acid in a mixture of acetic acid/acetic anhydride in the presence of anhydrous sodium acetate to yield the corresponding thiazolopyrimidine (V), which was condensed with aromatic aldehydes, namely, benzaldehyde, p-fluo-robenzaldehyde, p-cyanobenzaldehyde, p-toulalde-hyde, p-nitrobenzaldehyde, p-anisaldehyde, p-N,N-dimethylaminobenzaldehyde, p-isopropylbenzalde-hyde, 4-bromobenzaldehyde, p-hydroxybenzaldehyde, m-fluorobenzaldehyde, o-nitrobenzaldehyde, 3,5-dichlorobenzaldehyde, 3,5-dimethoxybenzaldehyde, and 3,4,5-trimethoxybenzaldehyde, in the presence of
Table 1. Central analgesic activity of compounds (IV, V, Via, VIb, VId, Vlf, Vlh, VIn, VII) in mice
0 min 30 min 60 min 90 min
Group Reaction reaction protection reaction protection reaction protection
time (s) time (s) (%) time (sec) (%) time (s) (%)
Control 12.7 ± 1.04 12.8 ± 0.91 = 0 14.5 ± 0.45 + 0 14.6 ± 0.58 = 0
(IV) 10.9 ± 0.70 12.9 ± 0.63 = 0.7 14.9 ± 0.34= 2.7 20.5 ± 0.63 = 40.4
(V) 11.7 ± 0.33 21.3 ± 1.74* = 66.4 23.0 ± 2.18* = 58.6 27.6 ± 0.98* = 89.0
(VIa) 10.2 ± 0.91 13.4 ± 0.38 = 4.6 15.4 ± 0.61 = 6.2 20.1 ± 1.78 = 37.6
(VIb) 10.5 ± 0.91 15.7 ± 1.00 = 22.6 19.1 ± 0.72 = 31.7 21.9 ± 1.00* = 50.0
(VId) 10.0 ± 0.57 12.9 ± 0.72 = 0.7 15.1 ± 0.57= 4.1 19.0 ± 0.78 = 30.1
(VIf) 11.8 ± 0.82 17.9 ± 1.11* = 39.8 21.4 ± 1.78* = 47.5 26.0 ± 2.20* = 78.0
(VIh) 10.8 ± 0.58 18.0 ± 1.30* = 40.6 22.3 ± 2.10* = 53.7 28.8 ± 2.67* = 97.2
(VIn) 11.2 ± 0.61 18.2 ± 1.25* = 42.1 23.0 ± 1.17* = 58.6 28.8 ± 2.58 * = 97.2
(VII) 12.3 ± 0.76 16.2 ± 1.08 = 26.5 20.3 ± 1.79* = 40.0 24.6 ± 2.18* = 68.4
Tramadol 10.8 ± 0.53 29.6 ± 1.57* 131.2 33.0 ± 1.00* 127.5 40.1 ± 2.28* 174.6
Values represent the mean ± S.E. of five mice for each group. * P < 0.05: statistically significant from control (Dunnett's test). = P < 0.05: statistically significant from tramadol (Dunnett's test).
All drugs were dissolved in DMSO (20 mg/kg), except tramadol (40 mg/kg), and given orally.
anhydrous sodium acetate and glacial acetic acid/acetic anhydride to yield the target arylmethylenethiazolopy-rimidine derivatives (VIa—o), respectively. However, the latter compounds were also prepared directly from (IV) by the action of chloroacetic acid, aromatic aldehydes, and anhydrous sodium acetate in the presence of an acetic acid/acetic anhydride. In addition, the reaction of thioxopyrimidine (IV) with 2-bromoacetophenone afforded the target 3-phenyl 2#-thiazolo[3,2-a]pyri-midine derivative (VII) in good yield (Scheme 1). All the postulated structures were supported by spectral and elemental analysis data.
The tested compounds were shown to produce variable analgesic activity in the hot plate and writhing assays in mice. In the hot-plate test, all the tested compounds and tramadol significantly prolonged the response time against the thermal stimulus as compared to the control after 30, 60, and 90 min of administration (Table 1). The central analgesic potencies of the tested compounds after 90 min, as compared to tramadol, arranged in descending order, were 97.2, 97.2, 89.0, 78.0, 68.4, 50.0, 40.4, 37.6, and 30.1% for compounds^), (VIn), (V), (VIf), (VII), (VIb), (IV), (VIa), and(VId), respectively. The selected compounds were evaluated for their possible anti-inflammatory effects in a rat model of carrageenan-induced paw edema. Table 3 shows the effect of selected compounds (IV—VII) on carrageenan-induced paw edema in rats in comparison to indomethacin as a reference drug. Intra-plantar injection of carrageenan in rats led to increase in paw volume denoting edema in the control non-treated group (Table 3). It was noticed that all compounds in oral doses of 20 mg/kg significantly decreased the paw edema rate all over the four hours in comparison to the control non-treated group. The an-
ti-inflammatory potencies of selected compounds were calculated by comparing their inhibition rate at different time intervals with those obtained from animals receiving indomethacin, as standard anti-inflammatory drug. Administration of indomethacin significantly decreased the carrageenan-induced edema starting from the first hour and was persistent until the end of the experiment. The inhibitory effect of indomethacin on paw edema was 32.78, 26.35, 29.02, and
Table 2. Peripheral analgesic activity of the tested compounds (IV, V, VIa, VIb, VId, VIf, VIh, VIn, VII) in mice
Group No. of writhes/20 min Protection (%)
Control 80.8 ± 4.47 = -
(IV) 24.8 ± 1.02* 69.31
(V) 39.6 ± 3.14* = 50.99
(VIa) 36.2 ± 2.58* = 55.20
(VIb) 44.8 ± 2.85* = 44.55
(VId) 29.2 ± 2.50* = 63.86
(VIf) 26.2 + 1.32* 67.57
(VIh) 23.6 + 2.16* 70.79
(VIn) 38.8 + 1.77* = 51.98
(VII) 26.4 + 2.46* 67.33
Acetyl 17.4 + 1.57* 78.47
Values represent the mean ± S.E. of five mice for each group.
* P < 0.05: statistically significant from control (Dunnett's test). = P < 0.05: statistically significant from acetyl salicylic acid (Dunnett's test).
All drugs were dissolved in DMSO (20 mg/kg), except acetyl salicylic acid (dissolved in DW, 150 mg/kg) and given orally.
27.45% after 1, 2, 3, and 4 h, respectively. It was noticed that anti-inflammatory potency of compound (I) was greater than that of indomethacin all over the experimental period (121.1, 219.2, 190.5, and 182.8). It is
noteworthy to mention that the derivatives (IV), (V), (VIa), (VId), (VIf), (VIh), (VIn), and (VII) showed anti-inflammatory potency after 4 h greater than that of indomethacin.
=j R4- / -Ri
/ R3 R2 (VIa- o)
a, R1 = H R2 = H R3 = H; R4 = H
b, R1 = H R2 = H R3 = F; R4 = H
c, R1 = H R2 = H R3 = CN; R4 = H
d, R1 = H R2 = H R3 = CH3; R4 = H
e, R1 = H R2 = H R3 = NO2; R4 = H
f, R1 = H; R2 = H R3 = OCH3; R4 = H
g, R1 = H; R2 = H R3 = N(CH3)2; R4 = H
h, R1 = H; R2 = H R3 = CH(CH3)2; R4 = H
i, R1 = H; R2 = H R3 = Br; R4 = H
j, R1 = H; R2 = H R3 = OH; R4 = H
k, R1 = H; R2 = F; R3 = H; R4 = H
l, R1 = NO2 R2 = H; R3 = H; R4 = H
m, R1 = H; R2 = Cl; R3 = H; R4 = Cl
n, R1 = H; R2 = OCH3; R3 = H; R4 = OCH
o, R1 = H; R2 = OCH3; R3 = OCH3; R4 = OCH
Scheme 1. Synthetic route for compounds (IV—VII).
Table 3. Anti-inflammatory activity of the tested compounds (IV, V, VIa, VIb, VId, VIf, VIh, VIn, VII) against carrageenan-induced paw edema in rats
Group 1 hour 2 hours 3 hours 4 hours
edema (%) potency (%) edema (%) potency (%) edema (%) potency (%) edema (%) potency (%)
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