Journal of Chemical and Pharmaceutical Research, 2015, 7(11):332-340
Research Article ISSN : 0975-7384 CODEN(USA) : JCPRC5
Eco-friendly and efficiently synthesis, anti-inflammatory activity of 4-tosyloxyphenylpyrans via multi-component reaction under
ultrasonic irradiation and room temperature conditions
Ahmed Khodairy
a, Shaaban K. Mohamed
b*, Ali M. Ali
a, M. T. El-Wassimy
aand Nagwa Sayed Ahmed
caDepartment of Chemistry, Faculty of Science, Sohag University, Egypt
bManchester Metropolitan University, Manchester M1 5GD, England, and Chemistry Department, Faculty of Science, Minia University, El-Minia, Egypt
cDepartment of Biochemistry, Faculty of Medicine, Sohag University, Egypt
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ABSTRACT
A series of new 4-tosyloxyphenylpyranderivatives 3-11 were efficiently synthesized via one-pot, multicomponent reaction (MCRs) of 4-tosyloxybenzaldehyde 1, malononitrile and some ketonic reagents through green chemistry protocols using Ultrasonic irradiation technique or stirring in water at room temperature. All products were obtained in excellent yield, pure at low cost processing and short time. The structure of all compounds was characterized by spectral and elemental analysis. Anti-inflammatory activity screening for all compounds was determined in vivo by the acute carrageenan-induced paw oedema standard method in rats. In general, the newly synthesized compounds 4,10 and 11showed the best anti-inflammatory activity compared to Indomethacin and Celecoxib (reference standards).The newly synthesized compounds were assessed via PASS software and showed high probability of Cystinylamino peptidase inhibitor, Anti-ischemic, Neurodegenerative diseases treatment and Cerebra.
Keywords: Multicomponent reaction, Ultrasonic irradiation, 4-Tosyloxyphenylpyran, Anti-inflammatory activity and PASS.
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INTRODUCTION
Recently there is a growing demand for the development of organic reactions in ecofriendly media. Synthetic manipulations have to be made to minimize the use of hazardous chemicals by replacing the traditional organic solvents in reactions and their subsequent workup with other non-toxic solvents. There is need to replace toxic solvents by green in industrial processes huge amount of solvent get wasted. Green chemistry techniques continue to grow in importance and alternative processes aim to conserve resources and reduce costs. Water is an abundant and environmentally benign solvent. The use of water as a promising solvent for organic reactions has received considerable attention in the area of organic synthesis owing to its green credentials [1-3]. So, replacement of conventional solvents with water, which is harmless to health and is available in large quantities, is an interesting basic approach along this line [4-6].In recent years, the focus on green chemistry using environmentally benign reagents and conditions is one of the most fascinating developments in the synthesis of widely used organic compounds.
Over last two decades, sonichemical methods have become widely used in organic synthesis [7-9]. Nowadays, many of organic reactions can be carried out in a higher yield, shorter reaction time and milder conditions under ultrasound [10-14].Multi-component reactions (MCRs) have emerged as a powerful tool for the construction of
novel and complex molecular structures due to their advantages over conventional multi-step synthesis. The major advantages of MCRs include lower costs, shorter reaction times, high atom-economy and energy savings from the avoidance of time consuming and expensive purification processes. It is established that MCRs are generally much more environmentally friendly and offer rapid access to large compound libraries with diverse functionalities [15- 17].
4H-Pyrans form the structural unit of a series of natural products [18] which have shown biologically activities such as antimicrobial[19], anti-inflammatory[20], anticancer[21],cytotoxic [22], anti-HIV [23], antimalarial[24], anti- hyperglycemic, and antidyslpidemic [25]. In addition, 4H-pyran moiety form the basis for a number of drugs are in used in the treatment of various ailments, such as hypertension, asthma, ischemia, and urinary incontinence [26].
Incorporating pyrans moiety with the mentioned newly synthesized heterocyclic derivative may enhance the potential biological activities of the synthesized compounds. In the light of this context and following to our on- going study in synthesis potential heterocyclic bio-active molecules, we report in this study a simple, rapid and high yielding one pot three component reaction protocol for the synthesis of 4-tosyloxyphenylpyranderivatives using ultrasonic irradiation and room temperature conditions in presence of a Lewis base catalyst.
EXPERIMENTAL SECTION
All melting points were recorded on Melt-Temp II melting point apparatus. IR spectra were measured as KBr pellets on a Shimadzu DR-8001 spectrometer. 1H NMR and 13C NMR spectra were recorded on a Bruker at 400 MHz using TMS as an internal reference and DMSO-d6 as a solvent. The elemental analyses were carried out on a Perkin- Elmer 240C Micro analyzer. The ultrasonic irradiation was performed by using a Bransonultrasonic cleaner bath, model 1510, AC input 115 V, output 50 W, 1.9 liters with a mechanical timer (60 min with continuous hold). All compounds were checked for their purity on TLC plates.
Synthesis of 4-tosyloxybenzylidenemalononitrile (2)
A mixture of 4-tosyloxybenzaldehyde 1(0.002 mol, 0.55 g) and malononitrile (0.002 mol, 0.13ml), was dissolved in5 ml ethanol in presence of one drop of NH4OH and then shaking for 5 minutes. The product was filtered off, washed with small amount of water, dried and crystallized from acetone. M. p. 146oC (144oC)27
General procedure for preparation of compounds 3 – 11.
Method A:
A mixture of 4-tosyloxybenzaldehyde1(0.002 mol, 0.55 g), malononitrile (0.002 mol, 0.13ml), and ketonic reagants (0.002 mol) namely; acetylaceton ( 0.21 ml), ethyl acetoacetate( 0.26 ml), benzoylacetone (0.3gm), ethybenzoylcetate(0.34 ml), cyclopentanone ( 0.18 ml), cyclohexanone (0.21 ml), 1,3-cyclohexandione ( 0.22 gm), dimidone ( 0.28 gm)or cycloheptanone ( 0.24 ml) was placed in a conical (50ml) and 10 ml of 0.5M NaCl solution was added. The mixture was exposed to ultrasonic irradiation for the appropriate time as indicated in Table 1. The progress of the reaction was monitored by TLC until the reaction was completed. The product was filtered off, washed with small amounts of water and crystallized from acetone.
Method B:
A mixture of compound 1(0.002 mol, 0.55 g), malononitrile (0.002 mol, 0.13ml) and ketonic reagents (0.002 mol) was stirred in a small amount of ethanol (5 mL) and 5 drops of NH4OH at room temperature for 3-5 minutes. After completion of the reaction (monitored by TLC), the product was filtered off, washed with alittle amounts of water (10 mL) then ethanol (5 mL) and crystallized from acetone.
Method C:
A mixture of 4-tosyloxybenzylidenemalononitrile2(0.001 mol, 0.324 g), and ketonic reagents(0.001 mol) was refluxed in ethanol in presence of drops of TEA for 3-5 h, (TLC monitoring). The reaction mixture was allowed to cool to room temperature and the precipitate was filtered off and crystallized from acetone.
4-(3-Acetyl-6-amino-5-cyano-2-methyl-4H-pyran-4-yl)phenyl-4-methylbenzene sulfonate (3):
Mp. 192-193 oC; IR (KBr) cm-1 3344, 3225 (NH2), 2190(C≡N),1660 (C=O), 1368, 1176 (SO2) cm-1; 1H NMR (DMSO-d6): 7.73 (d, 2H, J = 8.1 Hz, Ar-H), 7.47 (d, 2H, J = 8.0 Hz, Ar-H), 7.20 (d, 2H, J = 8.1 Hz, Ar-H), 7.02 (d, 2H, J = 8.0 Hz, Ar-H), 6.77 (s, 2H,NH2, D2O exchangeable),4.47 (s, 1H, CH-pyran); 2.43 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.04 (s, 3H, CH3);13C NMR: δ 194.21, 159.35, 137.16,136.62, 132.56,132.14,130.61, 130.23, 128.84, 128.03, 121.15, 118.15, 112.48, 58.14, 36.47, 27.42, 21.11, 18.14: Anal. Calcd. for C22H20N2O5S (424.48): C (62.25%), H(4.75%), N (6.60%), S(7.55%)Found: C (62.22%), H(4.63%), N (6.57%), S(7.61%).
Ethyl-6-amino-5-cyano-2-methyl-4-(4-(tosyloxy)phenyl)-4H-pyran-3-carboxylate (4):
Mp. 183-184oC; IR (KBr) cm-1 3322, 3201 (NH2), 2188(C≡N),1708 (C=O), 1394, 1198 (SO2) cm-1; 1H NMR (DMSO-d6): 7.72 (d, 2H, J = 7.8 Hz, Ar-H), 7.46 (d, 2H, J = 8.0 Hz, Ar-H), 7.15 (d, 2H, J = 7.8 Hz, Ar-H), 6.99 (d, 2H, J = 8.0 Hz, Ar-H), 6.87(s, 2H,NH2, D2O exchangeable),4.30 (s, 1H, CH-pyran); 4.05-3.95 (q, 2H, CH2), 2.43 (s, 3H, CH3), 2.30 (s, 3H, CH3), 1.01-0.96 (t, 3H, CH3);13C NMR: δ165.70, 158.88, 157.43, 148.23, 146.15, 144.58, 132.12, 130.61,129.22,128.55, 122.38,119.88, 107.24, 60.57, 57.49, 38.90, 21.60, 18.59, 14.10: Anal. Calcd. for C23H22N2O6S (454.49): C (60.78%), H (4.88%), N (6.16%), S (7.06%)Found: C (60.59%), H (4.91%), N (6.21%), S (7.11).
4-(2-Amino-5-benzoyl-3-cyano-6-methyl-4H-pyran-4-yl)phenyl-4-methylbenzene sulfonate (5):
Mp. 204-205oC; IR (KBr) cm-1 3320, 3266 (NH2), 2192(C≡N),1677 (C=O), 1368, 1197 (SO2) cm-1; 1H NMR (DMSO-d6): 7.57-7.52 (m, 5H, Ar-H), 7.47 (d, 2H, J = 8.0 Hz, Ar-H), 7.35 (d, 2H, J = 8.0 Hz, Ar-H), 7.12-7.04(m, 4H, Ar-H), 6.92(s, 2H,NH2, D2O exchangeable),4.46 (s, 1H, CH-pyran); 2.40 (s, 3H, CH3), 1.37 (s, 3H, CH3): 13C NMR: δ191.27, 158.11, 156.24, 147.96,139.07, 138.54, 136.54, 134.13, 132.84, 132.61,130.74,130.43, 128.83, 126.42, 121.19,119.81, 105.09, 58.12, 37.41, 21.87, 18.71:Anal. Calcd. for C27H22N2O5S (486.53): C(66.65%), H(4.56%), N(5.76%), S(6.59%)Found:(66.41%), H(4.59%), N(5.89%), S(6.43%)
Ethyl-6-amino-5-cyano-2-phenyl-4-(4-(tosyloxy)phenyl)-4H-pyran-3-carboxylate (6):
Mp. 186-187oC; IR (KBr) cm-1 3384, 3263 (NH2), 2212 (C≡N),1714 (C=O), 1367, 1156 (SO2) cm-1; 1H NMR (DMSO-d6): 7.85-7.76 (m, 5H, Ar-H), 7.67 (d, 2H, J = 7.9 Hz, Ar-H), 7.55 (d, 2H, J = 7.9 Hz, Ar-H), 7.35-7.27 (m, 4H, Ar-H), 6.90(s, 2H,NH2, D2O exchangeable),4.41 (s, 1H, CH-pyran); 4.07-3.99 (q, 2H, CH2), 2.47 (s, 3H, CH3), 1.12-1.06 (t, 3H, CH3);13CNMR: δ164.68, 158.19,154.16, 147.31, 138.98, 136.87,132.98, 132.91,130.99, 130.91,130.51, 128.91, 127.08, 126.01, 121.71, 119.11, 109.12, 61.25, 58.19, 37.12, 21.04, 14.29:Anal. Calcd. for C28H24N2O6S (516.56): C(65.10%), H(4.68%), N(5.42%), S(6.21%) Found:C(65.19), H(4.76%), N(5.38%), S(6.34%).
4-(2-Amino-3-cyano-4,5,6,7-tetrahydrocyclopenta[b]pyran-4-yl)phenyl-4-methyl benzenesulfonate (7):
Mp. 191-192 oC; IR (KBr) cm-1 3329, 3246 (NH2), 2216(C≡N),1369, 1153(SO2) cm-1; 1H NMR (DMSO-d6): 7.75 (d, 2H , J = 8.0 Hz, Ar-H),7.47 (d, 2H, J = 8.1 Hz, Ar-H), 7.18 (d, 2H, J = 8.1 Hz, Ar-H), 7.05 (d, 2H, J = 8.0 Hz, Ar-H), 6.90(s, 2H,NH2, D2O exchangeable),4.39 (s, 1H, CH-pyran); 2.41 (s, 3H, CH3), 1.99-1.95 (m, 4H, CH2) 1.90- 1.84 (m, 2H, CH2): 13C NMR: δ158.04, 148.19, 147.04, 137.91,134.07,132.18, 130.71,130.33, 126.61, 121.08, 119.17, 107.73, 55.22,40.51, 31.12, 27.31, 21.19, 18.22 Anal. Calcd. for C22H20N2O4S (408.47)C (64.69%), H(4.94%), N(6.86%), S(7.85%)Found:C (64.46%), H(4.83%), N(6.72%), S(7.90%).
4-(2-Amino-3-cyano-5,6,7,8-tetrahydro-4H-chromen-4-yl)phenyl-4-methylbenzenesulfonate (8):
Mp. 180-181oC; IR (KBr) cm-1 3350, 3243 (NH2), 2215 (C≡N), 1369-1175 (SO2) cm-1; 1H NMR (DMSO-d6): 7.71 (d, 2H, J = 8.1 Hz, Ar-H), 7.45 (d, 2H, J = 8.0 Hz, Ar-H), 7.05 (d, 2H, J = 8.1 Hz, Ar-H), 6.96 (d, 2H, J = 8.0 Hz, Ar-H), 6.92 (s, 2H,NH2, D2O exchangeable), 4.23 (s, 1H, CH-pyran), 2.48 (s, 3H, CH3): 2.01-1.97 (m, 4H, CH2), 1.63-159 (m, 2H, CH2), 1.56-1.29 (m, 2H, CH2): 13C NMR: δ 160.01, 146.07,144.10, 137.91,134.42,132.04, 130.61, 130.13, 126.81, 120.01, 118.99,110.11, 53.79, 37.96, 26.27, 22.41, 22.31, 22.04, 20.97: Anal. Calcd. for C23H22N2O4S (422.49) C(65.38%), H(5.25%), N(6.63%), S(7.59%)Found: C(65.32%), H(5.17%) ,N(6.58%), S(7.41%).
4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)phenyl-4-methyl benzenesulfonate(9):
Mp. 223-224 oC; IR (KBr) cm-1 3329, 3258 (NH2), 2197 (C≡N),1682 (C=O), 1362, 1155 (SO2) cm-1; 1H NMR (DMSO-d6): 7.76 (d, 2H, J = 8 Hz, Ar-H), 7.49 (d, 2H, J = 8.0 Hz, Ar-H), 7.19 (d, 2H, J = 8 Hz, Ar-H), 7.02(s, 2H,NH2, D2O exchangeable),6.97 (d, 2H, J = 8.0 Hz, Ar-H), 4.20 (s, 1H, CH-pyran), 2.61-2.58 (m, 2H, CH2), 2.44 (s, 3H, CH3): 2.27-2.23 (m, 2H, CH2), 1.95-1.91 (m, 2H, CH2): 13C NMR: δ 196.30, 165.20, 158.95, 148.02, 146.17, 144.37, 132.31, 130.71, 129.14, 128.51, 122.28, 120.01, 113.81, 58.25, 36.74, 35.39, 26.95, 21.64, 20.18: Anal.
Calcd. forC23H20N2O5S (436.48);C(63.29%), H(4.62%), N(6.42%), S(7.35%) Found: C(63.38%), H(4.25%), N(6.63%), S(7.59%).
4-(2-Amino-3-cyano-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)phenyl-4-methylbenzene sulfonate (10):
Mp. 237-238oC; IR (KBr) cm-1 3330, 3271 (NH2), 2185 (C≡N),1671 (C=O), 1370-1151 (SO2) cm-1; 1H NMR (DMSO-d6): 7.73 (d, 2H, J = 8.0 Hz, Ar-H), 7.46 (d, 2H, J = 7.8 Hz, Ar-H), 7.18 (d, 2H, J = 8.0 Hz, Ar-H), 7.03 (s, 2H,NH2, D2O exchangeable), 6.97 (d, 2H, J = 8.0 Hz, Ar-H), 4.21 (s, 1H, CH-pyran), 2.42 (s, 3H, CH3), 2.27 (s, 2H, CH2), 2.23 (s, 2H, CH2), 1.04(s, 3H, CH3), 0.93(s,3H,CH3):13CNMR:δ196.05, 163.09, 159.05, 148.03,146.15, 144.16,132.17,130.64,130.14, 129.16, 128.52, 122.32,118.12,112.88, 58.26, 50.41,35.50, 32.23, 28.76,27.29, 21.63:
Anal. Calcd. forC25H24N2O5S (464.48) C(64.64%), H(5.21%), N(6.03%), S(6.90%) Found: C(64.71%), H(5.29%), N(6.11%), S(6.59%).
4-(2-Amino-3-cyano-4,5,6,7,8,9-hexahydrocyclohepta[b]pyran-4-yl)phenyl-4-methyl benzenesulfonate (11):
Mp. 217-218oC; IR (KBr) cm-1 3352, 3263 (NH2), 2210 (C≡N), 1378-1192 (SO2) cm-1; 1H NMR (DMSO-d6): 7.70 (d, 2H, J = 7.8 Hz, Ar-H), 7.41 (d, 2H, J = 7.9 Hz, Ar-H), 7.12 (d, 2H, J = 7.8Hz, Ar-H), 7.05 (d, 2H, J = 7.9 Hz, Ar-H), 6.96(s, 2H,NH2, D2O exchangeable),4.22 (s, 1H, CH-pyran), 2.36 (s, 3H, CH3),1.87- 183(m, 4H, CH2),142- 1.34 (m, 2H, CH2): 1.30-127 (m,4H, CH2): 13C NMR: δ 158.03, 146.22,144.11, 138.55, 134.17, 132.15, 130.41, 130.12,126.81,121.08, 119.01, 109.43, 55.07, 39.79, 32.61,31.13,28.18,26.95, 24.64, 20.76Anal. Calcd. for C24H24N2O4S (436.52)C(66.03%), H(5.54%) N(6.42%) S(7.35%)Found: C(66.21%), H(5.35%), N(6.51%), S(7.31%).
RESULTS AND DISCUSSION
The parent compound 4-tosyloxybenzaldehyde 1 was simply prepared via the reaction of 4-tosylechloride with 4- hydroxybenzaldahyde [27]. Sonication of 4-tosyloxybenzaldehyde 1withmalononitrile and ketonic reagents; namely;
acetylacetone, ethyl acetoacetate, benzoylacetone and ethybenzoylacetate in one-pot, three component process under ultra-sonic waves in presence of 10 ml distilled water and 0.5% NaCl solution within few minutes (11-15 min) afforded 4-tosyloxyphenyl pyran derivatives3-6(Scheme 1).
The same compounds 3-6 were obtained on treating of1 with malononitrile and the same ketonic reagents in one- pot, three component process under stirring for few minutes in a little amount of ethanol and few drops ammonia solution at room temperature (Scheme 1).
Scheme 1
Synthesis of pyran derivatives in different media
Excellent yield were obtained in both methods (83-90%) within short time (3-15 minutes) and problems associated with toxic solvent use (cost, safety, and pollution) were avoided compared to the conventional protocol. The optimized results are summarized in Table 1.
We became interested to see if compounds 3-6 can be obtained by tradition method and compare the products obtained by this way in terms of yield and time to those green chemistry obtained. 4- Tosyloxybenzylidinemalononitile [27] 2was subjected to react with the same ketonic reagents in refluxing ethanol in presence of TEA (Scheme 1). The same products 3-6 were obtained in moderate yield (63-78 %) in longer reaction time (3-5h), Table 1.
Scheme 2
The structure of these products is established on the basis of IR, 1H-NMR, 13C NMR, spectral data and elemental analyses.
IR spectra of compounds 3-6 revealed the appearance of new carbonyl groups at 1660,1667acetyl, 1708, 1714ester, CN groups in range 2212-2188 cm-1, in addition to two bands at 3384-3201 cm-1assigned for NH2 groups.1H NMR (δ- DMSO-d6) spectra showed, beside the expected aromatic protons signals, a new singlet signal in the region δ 4.30- 4.47 ppm consistent with the pyran-CH, beside a singlet signal corresponding to NH2 groups in the region δ 6.92- 6.77 ppm which disappeared on deuteriation. Furthermore, 1H NMR (δ -DMSO-d6) of compounds 4, 6 showed quartet and triplet signals in the region δ 4.07- 3.95 and δ 1.12-0.96 ppm for CH2 and CH3 of the ester groups, respectively.13CNMR spectra and elemental analyses of compounds 3-6 provided the structure of pyran rings, For example the 13C NMR spectrum of compound 4 showed the appearance of a new signals at at δ 21.60, 18.59, 14.10 ppm due to three ( CH) groups, a new signal at 165.70 ppm due to the CO group, beside the expected aromatic and
pyran signals. Elemental analyses of compounds 3-6approved the structure of pyran rings (cf. experimental).
By analogy, when compound 1 was allowed to react with malononitrile, and some respective cyclic ketones namely; cyclopentanone, cyclohexanone, 1,3-cyclohexandione, dimidoneor cycloheptanoneunder ultrasonic irradiation technique in presence of 0.5% NaCl or stirring in ethanol in presence of ammonium hydroxide solution afforded the corresponding fused pyran derivatives 7-11, respectively ( Scheme 2). Excellent yields were recorded in short time(yield, 84-92%, 3-15 min). On the other hand, the same compounds 7-11 were obtained onthe treatment of compound 2 with same cyclic ketones under refluxing ethanol in presence of TEA. Moderate yields were obtained but on longer times (yield, 64-71%, 3-5 h).The optimized results are summarized in Table 1.
The structure of products 7-11was characterized on the basis of IR, 1H-NMR, 13C NMR spectral data and elemental analyses. The IR spectra of compounds 7-11 showed two absorption bands at 3352-3220 cm-1 due to NH2 groups, a new absorption band in the range 2236-2197 cm-1 due to cyano groups and a new absorbation bands at 1682, 1671 cm-1 due to CO group in compounds 9, 10.
The 1H NMR (δ DMSO-d6) spectra of compounds7-11showed, beside the expected aromatic protons resonances, a new singlet signals in the region δ 7.03– 6.90 ppm consistent with the NH2 groups which disappeared on deuteriation, beside a singlet signal corresponding to pyran-CH in the region δ 4.39-4.20 ppm, Furthermore, 13C NMR spectra of compounds 9,10 showed the appearance of the C=O groups in the region δ 196.05, 196.30 ppm.
Elemental analyses of compounds 7-11confirmed the structure of pyran rings (cf. experimental).
Synthesis of different fused pyran derivatives in different media
The reaction mechanism of products is proposed to involve Knoevenagel condensation of 4-tosyloxybenzaldehyde 1, Michael addition of active methylene to double bond, followed by cyclization and tautomerization (Scheme 3).
Scheme 3 Reaction mechanism of compound 8
Table 1. Comparison of the reaction time and yield for synthesis of pyran derivatives in different media Ultra Sonic wave/ H2O/ NaCl Stirrer at r.t. in EtOH/ NH4OH
Conventional method/ EtOH/ TEA Comp. No.
Time (min) Yield %
Time (min) Yield %
Time (h) Yield %
12 84
3 86
4 68
3
15 87
5 93
3 78
4
11 90
3 89
5 71
5
12 83
4 84
3 63
6
13 85
4 89
5 67
7
11 91
5 92
3 71
8
15 88
3 91
5 66
9
12 86
3 88
4 71
10
15 84
5 85
5 64
11
From the recorded results in table 1, it is clear that the consumed time and yield of products when green chemistry protocols have been employed are much better compared with that of conventional procedure. It is worth mentioning that the green chemistry procedure is considered as environ-friendly and economically method compared with the conventional procedure for synthesis of 4-tosyloxyphenylpyran derivatives.
3- Anti-inflammatory activity
Anti-inflammatory activity screening for all compounds was determined in vivo by the acute carrageenan-induced paw oedema standard method in rats [28-30]. Adult albino rats of either sex (pregnant female animals were excluded) weighing 160-190 g were examined. Rats were fasted overnight, then on the next day (day of experiment), animals were uniformly hydrated by giving 3 mL of water per rat orally. Indomethacin and Celecoxib (reference standards) and the tested compounds (100 mg/kg body weight) were suspended in saline solution by the aid of few drops of Tween 80 (to improve wettebility of particles) and given orally one hour before induction of inflammation. The control group was given saline solution containing few drops of Tween 80. Carrageenan paw oedema was induced according to a modified method of Winter et al., [28] by subcutaneous injection of 1% solution of carrageenan in saline (0.1 ml/rat) into the subplanter region of the right hind paw of rats. The thickness of rat paw was measured by mercury digital micrometer at different time intervals, at zero time and after one, two and three hours of carrageenan injection. The oedema was determined from the difference between the thickness of injected and non-injected paws. Data were collected, checked, revised and analyzed. Quantitative variables from normal distribution were expressed as means ± SE "standard error". The significant difference between groups was tested by using one-way ANOVA followed by post hoc test at p < 0.05 and p< 0.01. Table 2.
Table 2: Anti-inflammatory activity of the tested compounds using carrageenan-induced paw oedema in rats
% inhibition of oedema ± SE
Comp. No. 1 hr 2hr 3hr
Control 0.00 0.00 0.00
Indomethacin 31.5 ± 2.32 40.1 ± 2.91 60.8 ± 3.15 Celecoxib 31.43 ± 2.87 45.75 ± 3.41 63.78 ± 3.30
3 25.3 ±3.031** 34.17 ± 2.708** 48.7 ± 2.261**
4 26.44 ±3.028** 44.02 ± 3.133** 58.18 ±2.94**
5 19.127 ± 3.572* 26.9 ±3.099* 42.79 ± 3.172*
6 16.86 ± 1.456** 22.9 ±4.099* 36.41 ±3.704**
7 21.19 ± 2.471* 30.73 ±3.01* 41.42 ± 2.955*
8 29.092.957** 39.128 ± 3.47** 41.71 ± 3.704**
9 26.86 ± 1.556** 37.25 ± 1.327** 50.1 ± 1.255**
10 29.86 ± 1.556** 39.43 ± 2.396* 54.23 ±1.179**
11 26.86 ± 1.856** 35.25 ± 1.227* 52.8 ± 1.165**
The pyran derivative 4, and the hydro-pyranes 10 and 11 have showed the best anti-inflammatory activities compared to the standard references Indomethacin and Celecoxibl.
4-Biological activity predicted by PASS
The biological activity spectra of new compounds were obtained by PASS software. The predictions were carried out based on analysis of training set containing about 46,000 drugs and biologically active compounds. This set consider as reference compounds for known chemical compounds as well as different biological activities. It estimates the probability of the molecule to be active (Pa) and inactive (Pi) for each type of activity from the biological activity spectrum. Interpretation of prediction results is based on consideration of Pa values [31, 32]. 1. Pa
> 0.7: the chance of finding activity experimentally is high; in many cases the compound may be a close analogue of known pharmaceutical agents.2. 0.5 < Pa <0.7: the chance of finding activity experimentally is less; the compound is not so similar to known pharmaceutical agents.3. Pa < 0.5: the chance of finding activity experimentally is even
less; the compound has only a low similarity to the compounds from the training set. Activity (Pa) and inactivity (Pi) percent of new compounds, which have Pa more than 0.500, are represented in table 2.
Table 2: Biological activities of compounds 3-11 predicted by PASS Compound
No. Activities Pa Pi
3 Cystinyl aminopeptidase inhibitor Catalase stimulant
0.572 0.572
0.004 0.003 4 Antiischemic, cerebra
Cystinyl aminopeptidase inhibitor
0.760 0.608
0.019 0.004 5
Cystinyl aminopeptidase inhibitor Catalase stimulant
Antidiabetic (type 2)
0.588 0.569 0.466
0.004 0.002 0.012 6
Cystinyl aminopeptidase inhibito Catalase stimulant
Potassium channel large-conductance Ca-activated activator Chemosensitizer
Apoptosis agonist
0.683 0.562 0.529 0.504 0.504
0.003 0.002 0.003 0.019 0.040 7
Cystinyl aminopeptidase inhibitor Catalase stimulant
Apoptosis agonist
Potassium channel large-conductance Ca-ctivated activator Neurotransmitter uptake inhibitor
0.745 0.654 0.564 0.524 0.557
0.002 0.002 0.031 0.003 0.042
8
Cystinyl aminopeptidase inhibitor Catalase stimulant
Apoptosis agonist
Potassium channel large-conductance Ca-activated activator Neurotransmitter uptake inhibitor
0.745 0.654 0.564 0.524 0.557
0.002 0.002 0.031 0.003 0.042
9
Cystinyl aminopeptidase inhibitor
Excitatory amino acid transporter 1 inhibitor Catalase stimulant
Apoptosis agonist Antiarthritic
Neurodegenerative diseases treatment
0.722 0.649 0.628 0.602 0.556 0.517
0.002 0.001 0.002 0.026 0.036 0.028 10
Neurodegenerative diseases treatment Cystinyl aminopeptidase inhibitor Catalase stimulant
Apoptosis agonist
0.707 0.704 0.608 0.617
0.003 0.007 0.002 0.024 11
Cystinyl aminopeptidase inhibitor Catalase stimulant
Apoptosis agonist
Potassium channel large-conductance Ca-activated activator Neurotransmitter uptake inhibitor
0.745 0.654 0.564 0.524 0.557
0.002 0.002 0.031 0.003 0.042
The data in table 2demonstrate that the most frequently predicted types of biological activities are Cystinyl aminopeptidase inhibitor, excitatory amino acid transporter 1 inhibitor, Antiischemic, cerebra, Catalase stimulant, Potassium channel large conductance Ca-activated activator and Apoptosis agonist.
From this assessment, compound 4 showed the highest potential bio-active molecule as an anti-ischemic, while compound10 is the more predicted molecule for neurodegenerative diseases treatment. Compounds 7-11were predicted to be the highest cystinyl aminopeptidase inhibitor, while 7,8,11 are predicted to be the highest catalase stimulant.
CONCLUSION
In conclusion, we report in this study a new green chemistry protocol can be used as a facile and very fast technique for synthesis of 4-tosyloxyphenylpyran derivatives in different media. The reaction involves a three component condensation, and the products were obtained with high purity and higher yields compared to the conventional methods. The pyran 4 and the two hydrpyrans 10 and 11 have showed a remarkable anti-inflammatory activity and high potential bio-active molecules.
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