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Synthesis and Anti-inflammatory Study of Novel N-substituted Hydroacridine- 1,8-diones and Bis-hexahydroacridine-1,8-dione Derivatives | OMICS International
ISSN: 2161-0444
Medicinal Chemistry

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Synthesis and Anti-inflammatory Study of Novel N-substituted Hydroacridine- 1,8-diones and Bis-hexahydroacridine-1,8-dione Derivatives

Omyma A Abd-Allah1*, Antar A Abdelhamid1 and Shaaban K Mohamed2,3

1Department of Chemistry, Faculty of Science, Sohag University, Sohag, Egypt

2Chemistry and Environmental Division, Manchester Metropolitan University, Manchester M1 5GD, England

3Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt

*Corresponding Author:
Omyma A. Abd-Allah
Department of Chemistry
Faculty of Science, Sohag University
Sohag, Egypt
Tel: 00201069087871
Fax:
002093460115
E-mail: [email protected]

Received date: October 20, 2015; Accepted date: November 05, 2015; Published date: November 10, 2015

Citation: Abd-Allah OA, Abdelhamid AA, Mohamed SK (2015) Synthesis and Anti-inflammatory Study of Novel N-substituted Hydro-acridine-1,8-diones and Bis-hexahydroacridine-1,8-dione Derivatives. Med chem S2:004. doi: 10.4172/2161-0444.1000004

Copyright: © 2015 Abd-Allah OA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

We report in this study the synthesis of some new N-substituted hexahydro- acridine-1,8-dione compounds including some new N- 2-hydroxypropylhexahydro- acridine-1,8-diones and their tosylatedoctahydroacridine-1,8-dione derivatives in addition to some bis-hexahydroacridine-1,8-diones via a one pot reaction technique. Moreover, in vivo anti-inflammatory evaluation for some newly synthesized compounds has been investigated. The highly alkylated bishydroacridine- 1,8-dione 5f showed a higher anti- inflammatory potency more than the non-alkylated and the standard employed indomethacin. The structure of all new products has been characterized by IR, 1H-NMR and 13C-NMR.

Keywords

Acridines; Bis-acridine; Hexahydroacridinones; Antiinflammatory agents

Introduction

Large number of natural and synthetic acridine scaffold compounds exhibit broad spectrum of biological and physical properties [1-5]. Although many researchers have devoted their studies on synthesis of acridine compounds and their pharmaceutical applications as antitumor [6-9], bacterial [10], malarial [11] and inflammatory agents [12]. Acridinediones, in particular, have been identified asanti-malarial and -tumor agents [13-15]. Hexahydroacridine-1,8-dione derivatives are also reported to possess important properties such as high fluorescence efficiency [16]. As a consequence, the interest of organic chemists in the synthesis or structure modifications of hydroacridinone derivatives remains high. It has also been discovered that the introduction of a substituted group to the nitrogen atom of hexahydroacridine-1,8- diones leads to enhance the fluorescence activity [17,18]. Recently, Hubschwerlen et al. found that the introduction of a cyclopropyl group to the nitrogen atom of the pyridine ring results in a wide spectrum of anti-bacterial activities [19]. However, the introduction of a 2-hydroxypropyl or tosylated propyl groups to the nitrogen atom has not been reported yet.

On other hand, many studies showed that dimerization of acridine compounds enhance their biological activities. They were first developed as tumorostatic agents compared to those of the respective mono acridines [20-22]. Synthesis of such dimeric ligands, have been employed to improve the local concentration of the bioactive species and to avoid the cellular efflux mechanisms associated with multi drug resistance to the respective monomeric counter parts [23,24]. Bis-acridines have also demonstrated bioactivity in mice infected with Plasmodium berghei [22] and in vitro against Plasmodium falciparum and try panosomatid parasites [25]. Such aforementioned facts inspired us to synthesis and investigate the anti-inflammatory potency of some new N-substituted hydroacridine-1,8-diones and their dimer derivatives.

Experimental

All melting points are uncorrected and were determined by Kofeler melting point apparatus. IR (cm-1) spectra were recorded (KBr disc) on a Shimadzu DR-8001 spectrophotometer. 1H-NMR and 13C-NMR (DMSO-d6 or CDCl3) spectra were recorded at 400 MHz on a Varian Mercury- 300 BB at Sohag University, the chemical shift is expressed in δ value (ppm) using TMS as an internal reference.

Synthesis of hexahydroacridine-1,8-diones (3a-f)

General procedure: A mixture of (2 mmol) of the 1,3-cyclohexanedione (2a), (1 mmol) of salicylaldehyde or 5-bromosalicylaldehyde (1a,b), a mixture of (2 mmol) of the 3,3,6,6-tetramethyl-1,3-cyclohexanedione (2b), (1 mmol) of salicylaldehyde or 5-bromosalicylaldehyde (1a,b) or a mixture of 3,6-diphenyl-1,3-cyclohexanedione (2c), (1 mmol) of 5-bromosalicylaldehyde or 3-bromo-5-chlorosalicylaldehyde (1b,c),(1 mmol, 0.08 mL) of 1-aminopropan-2-ol in (20 mL) ethanol and a catalytic amount of triethylamine was refluxed and monitored by TLC till completion after 5 hrs. The excess of solvent was evaporated under reduced pressure, and the obtained solid was collected by filtration and crystallized from ethanol to afford the corresponding products of hexahydroacridine-1,8-diones 3a-f respectively (Scheme 1).

9-(2-hydroxyphenyl)-10-(2-hydroxypropyl)-3, 4, 6, 7, 9, 10-hexahydroacridine-1,8-(2H,5H)-dione (3a): Yellow crystals, m.p 228°C. IR: (KBr,υ max, cm-1), 3397(OH), 3062(CH aromatic), 2935-2874(CH aliphatic), 1627(C=O).1H-NMR (DMSO-d6):(δH), 10(s,1H,OH-phenolic), 9.0-6.7(m, J=4.5,6H, aromatic), 5.3-5.0 (m, J=7.2, 1H, CH3-CHN), 5.1(s, 1H, OH alcoholic), 4.2(s,1H, ArCH), 3.8, 3.6(t, J=8.0, 4H, 2CH2C=O cyclic),2.30–2.0(d,1H, N-CH2- alcoholic), 2.2(t, J=8.0, 4H, 2=CH2 cyclic), 2.0-1.9(m, J=8.0, 4H, 2CH2-CH2-CH2), 1.3(d, J=7.2, 3H, CH3).13C-NMR(DMSO-d6): (δC), 187(2C=O), 158(2C=C hydropyridine ring), 137(C-OH phenolic), 129.6, 129.3 (2C-CH hydropyridine), 128.1, 127.9, 126.7, 126.1, 125.5, 123,118.9(C-Ar),109(CH-Ar), 65.9 (C-OH alc.), 58(CH2-N), 51, 36.5,30, 27.6, 25.9, 21.6, 21.1, 20.3 (6 CH2 + CH3).

9-(5-bromo-2-hydroxyphenyl)-10-(2-hydroxypropyl)- 3,4,6,7,9,10-hexahydro- acridine-1,8(2H,5H)-dione (3b): Yellow crystal, m.p 218°C. IR: (KBr, υmax, cm-1), 3419(OH), 3005(CH aromatic), 2966-2947(CH aliphatic), 1630(C=O), 616(C-Br);1HNMR( DMSO-d6): (δH), 10(s, 1H, OH phenolic), 7.12-7(d, J=4.0, 2H, aromatic),6.66 (s,1H, aromatic), 4.97-4.93(d, J=4.5, 2H, NCH2), 3.83- 3.81 (m, J=4.5, 1H, CH3CH-), 3,35(s,1H, ArCH),3.13-3.08(t, J=7.2, 2H, CH2C=O cyclic),2.93-2.89(m, J=7.2, 2H, CH2-CH2-CH2), 2.5(s, OH, alcoholic), 2.63-2.62(m, J=7.2, 2H, CH2CH2C=O), 2.01-1.99 (t, J=7.2, 4H,=CH2CH2), 1.15-1.16(d, J=4.5, 3H, CH3); 13C-NMR(DMSOd 6):(δC), 198, 197.3(2 C=O), 156, 153 (2C=C hydropyridine ring), 153(Br-C), 135.3 (CH-OH phenolic), 131, 130, 119,114.3, 114,111(6C Ar), 66.8(CH-OH alc), 51(CH2-N), 36.18, 36.05(2 CH2-CO), 26, 21 (4 CH2 cyclic), 19(CH3).

9-(2-hydroxyphenyl)-10-(2-hydroxypropyl)-3,3,6,6- tetramethyl-3,4,6,7,9,10-hexa- hydroacridine-1,8(2H,5H)-dione (3c): Yellow crystals, m.p 170°C. IR : (KBr, υ max, cm-1), 3420(OH), 3055(CH aromatic), 2952, 2870(CH aliphatic), 1635(C=O), 1601(C=C),620(C-Br).1H-NMR(DMSO-d6):(δH),10.5(s,1H, OH phenolic, D2O exchangeable), 8.5-6.84(m, 3H,aromatic), 5.2 (s, 1H, OH-alcoholic D2O exchangeable),5.06 (s, 1H, CH-Ar),3.6 (m, J=4.0, 1H, CH-CH3), 2.51 (s, 4H, 2CH2-C=O),2.44 (d, J=7.2, 2H, CH2- OH), 2.30(s,4H,2=CH2),1.19,1.02,0.92,0.88 (m, 15H, 5CH3).13CNMR( DMSO-d6):(δC), 196.2 (2C=O), 164.5(2C=C hydropyridine ring), 149.5(C-OH phenolic),135, 133.9,131.17,130.6, 129.2,120.7 (6 C-Ar),119.6, 117.6 (2C-CH hydropyridinr ring), 66.01, 65.6(2CH2- CO), 51.2(CH-OH alc), 40.62 (CH2-N), 32.3, 31.9(2CH2 cyclic), 29.68, 28.2, 26.7, 25.5, 18.77( 5CH3).

9-(5-bromo-2-hydroxyphenyl)-10-(2-hydroxypropyl)-3,3,6,6- tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (3d): Yellow crystal, m.p 144°C. IR: (KBr, υ max, cm-1), 3420(OH), 3055(CH aromatic), 2965(CH aliphatic), 1630(C=O), 1600(C=C).1H-NMR (DMSO-d6):(δH), 10.94(s,1H, OH-phenolic, D2O exchangeable)),7.10- 6.93(m, 4H, aromatic),5.2(s,1H,CH-Ar), 5.06 (m, J=8.0, 1H, HOCH- CH2-N), 3.37(s,1H, OH D2O exchangeable), 2.56-2.51(d, J=8.0, 2H, N-CH2-CHOH), 2.36(s,2H, 2CH2-C=O), 2.32(s,2H, 2CH2-C=O), 2.26 (s, 2H,=C-CH2),2.22 (s, 2H,=C-CH2),1.05(s, 3H, CH3),0.99(s, 6H, 2CH3), 0.89(s,6H, 2CH3).13C-NMR(DMSO-d6): (C), 196.2(2C=O), 165.19(C-OH aromatic), 150.1, 128.8, 127.3,126.09, 124.62(5C aromatic + 2C(CH3)2), 115.7(2NC=C), 111.24 (2 NC=C), 102(CH-Ar), 50(2CH2 for 2CH2-C=O), 40(CH2 for CH2-N),32.5(CH-OH), 32(2C 2=C-CH2), 29.6, 28.4, 26.6( 5CH3).

9-(5-bromo-2-hydroxyphenyl)-10-(2-hydroxypropyl)-3,6- diphenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (3e): Yellow crystal, m.p 253°C. IR: (KBr, υmax, cm-1), 3418(OH), 3027 (CH aromatic), 2967-2892 (CH aliphatic),1625(C=O),699(C-Br).1H-NMR (DMSO-d6):(δH), 11.2 (s, 1H, OH-phenolic),8.3-6.8(m,13H,13CH aromatic), 4.54(s,1H,Ar-CH=), 3.65 (m, J=4.0, H, CH3CHCH2N), 3.58(d, J=4.0, 2H,NCH2), 3.55-3.51(m, J=7.2, 2H, 2PhCH), 2.5(s,1H,OH alc.), 2.41-2.39(t, J=7.2, 4H, 2 CH2C=O), 1.79-1.77(d, J=7.2, 4H, 2 CH2CHPh), 1.39(d, J=4.0, 3H, CH3).13C-NMR(DMSO-d6): (δC), 199.8, 191.8 (2 C=O), 175 (2C=Chydropyridine ring), 170(C-OH phenolic), 156.4, 155.5(2Ph-C), 144.7, 139.9, 138.6, 132, 131, 129, 127.2,127.1(8C, 2Ph), 121, 118, 110.9(C-Ar), 110.8(C-Br), 44(2CH-Ph), 42(CHOH), 40(CH2-N),33,15,29.7(4CH2 cyclic),22 (CH3).

9-(3-bromo-5-chloro-2-hydroxyphenyl)-10-(2-hydroxypropyl)- 3,6-diphenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (3f): Yellow crystal, m.p 235°C. IR: (KBr,υ max, cm-1), 3437(OH), 3014(CH aromatic), 2987-2990 (CH aliphatic), 1645(C=O),750(CCl), 640(C-Br). 1H-NMR (DMSO-d6): (δH), 11(s, 1H, OH-phenolic), 8.3-7.0 (m, 12H, aromatic),6.86-6.83(m, J=8.0, 2H, 2PhCH), 4.5(s,1H, CH-Ar), 3.6(m, J=7.6, 1H, CH3CHOH),3.4(s, 1H, OH-alcoholic), 2.3(t, J=8.0, 4H, 2 CH2C=O in cyclohexanone), 1.7(d, J=7.6, 2H,NCH2),1.3(d,J=8.0, 4H, 2 CH2CH in cyclohexanone), 0.8(d, J=7.6, 3H, CH3).13CNMR (DMSO-d6): (δC), 175,170(2C=O),157.8, 156(2Ph-C), 147 (C=C hydropyridine ring), 140 (C-OH phenolic),139.1, 131.7(C-Cl, C-Br respectively),129.8,129.5, 127.7, 127.5, 119.9, 119.7, 119.1 (ArCH cyclic), 116.8 (2C-CH hydropyridine ring), 44(CHOH),30.1 (CH2- N),22.6(NCH2),19.2(2CH2 cyclic),18.3(CH3).

Preparation of (3a) from the corresponding xanthenone (7) (see Scheme 2)

To a solution of 9-(2-hydroxyphenyl)-3,4,5,6,7,9-hexahydro- 1H-xanthene-1,8(2H)-dione(7)[26](0.248 g, 0.0008 mol) in (20 ml) ethanol,1-aminopropan-2-ol (0.0625 ml, 0.0008 mol) and catalytic amount of triethylamine were added. The reaction mixture was refluxed for 3 hrs and allowed to cool at room temperature. The solid product was collected by filtration and crystallized from ethanol as yellow crystals, m.p. 228°C.

Synthesis of tosylatedhexahydroacridinediones (4a-d)

General procedure: A solution of (1 mmol) of the hexahydroacridine-1,8-dione derivatives 3a-d, (1 mmol) of tosyl chloride and a catalytic amount of triethylamine in (20 mL) ethanol was refluxed and monitored by TLC till completion after 3 hrs. The reaction mixture was allowed to cool down to room temperature and the obtained solid product was collected by filtration, dried under vacuum and crystallized from the appropriate solvent to afford the corresponding tosylatedacridinediones4a-d respectively.

1- (9- (2-hydroxypheny l ) -1,8-dioxo-1,2,3,4,5,6,7,8- octahydroacridin-10(9H)-yl)propan-2-yl 4-methylbenzenesulfonate (4a): Yellow fine powder, m.p. 154°C. IR: (KBr, υ max, cm-1), 3008(CH aromatic), 2950–2924(CH aliphatic), 1639(C=O), 1183(O=S=O).1HNMR (DMSO-d6):(δH),7.5(m, 9H, Ar), 5.01 (m, J=4.4, 1H, CH-O tosylate), 3.5(s,1H, CH-Ar), 3.1(t, J=4.4, 4H,2CH2-Otosyl), 2.7, 2.5 (t, J=8.0, 4H, 2CH2C=O),2.29-2.27(t, J=8.0, 4H, 2=C-CH2), 1.82,1.81(m, J=8.0, 4H, 2 CH2CH2CH2C=O), 1.21, 1.19(s,6H,2CH3 of tosyl),1.18(d, m, J=4.4, 3H, CH3).13C-NMR(DMSO-d6):(C), 197.3, 196.4(4C=O), 166.9 (2C=C cyclic hydropyridine ring), 149.2 (C-OH phenolic),146.4 (C-SO2 tosyl), 133.7(C-CH3 tolyl), 130.8, 128.7, 128.4, 128.2, 127.8, 125.9, 125.1(C-CAr), 123(CH-N), 116 (CH-Ar), 56.4(CH2-O alc.), 46,36.8(2CH2-C=O cyclic), 28, 27.6(2CH2=C), 21.6,20.9 (2C-C), 20.4, 19,9(2 CH3).

1-(9-(5-bromo-2-hydroxyphenyl)-1,8-dioxo-1,2,3,4,5,6,7,8- octahydroacridin-10(9H)-yl)propan-2-yl 4-methylbenzenesulfonate (4b): Yellow fine powder, mp. 1920C. IR: (KBr, υ max, cm-1), 3402(OH), 3005(CH aromatic), 2950-2881(CH aliphatic), 1638(C=O), 1180(O=S=O). 1H-NMR (DMSO-d6): (δH), 9.5(s, 1H, OH-phenolic), 7.6-6.9(m, 6H, Ar), 5.0(m, m, J=4.2, 1H, CH-O tosylate), 3.0 (s, 3H, CH3 of tosyl), 2.9-2.8(m, J=4.2, 1H, CH-tosylate),2.3-2.2(t, 2H, CH2C=O), 2.0-1.9(t, J=7.2, 2H, CH2CH2CH2), 1.84-,8(t, J=7.2, 4H,=CCH 2),1.9-1.8(d, d, J=4.2, 2H, NCH2CH), 1.2-1.0(d, J=4.2, 3H, CH3).13CNMR( DMSO-d6):(δC),207,197.3(2C=O), 167.9(2=C-N cyclic), 150 (C-OH phenolic),146.4(C-SO2 tosyl), 139, 130, 129.7, 128.5, 125, 122.1,120,115(C-C Ar), 111(C-Br),100, 58(CH-O alc.), 45.8(2CH2- C=O),32(CH2-N), 28,25.6 (2CH2=C), 21.1,23(2 CH2-CH2-CH2), 23, 19.01(CH3 alc., CH3 tolyl respectively).

1-(9-(2-hydroxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo- 1,2,3,4,5,6,7,8-octahydro- acridin-10(9H)-yl)propan-2-yl 4-methylbenzenesulfonate (4c): Yellow fine powder, m.p 1000C. IR: (KBr,υ max, cm-1), 3300(OH arm), 3008(CH arm), 2975, 2870(CH aliphatic), 1696(C=O), 1177(O=S=O). 1H-NMR (DMSO-d6): (δH), 10(s,1H, OH aromatic), 7.78-6.93(m, 8H, CH aromatic), 5.26 (s,1H, CHAr), 5.04(m, d, J=2.6, 1H, CH-O tosylate), 2.42–2.32(t, J=2.6, 2H, CH2-O tosyl), 2.27 (t, J=4.8, 4H, 2CH2C=O), 2.24- 2.29(t, J=4.8, 4H, 2=C-CH2), 2.1 (s, 3H, CH3 of tosyl ) 1.1,0.93, 0.85 (s, 15H, 5CH3). 13C-NMR (DMSO-d6):(δC), 197.3,188.3 (2C=O), 166, 149.9,136.5,133.1,130.8,129.4, 128.7, 127.6, 125.8, 125.6, 124.8,118.6, 116.8, 31, 29.4(12C aromatic + 2C=C + 2C-(CH3)2 respectively),115.9(CH-N), 111(CH-Ar), 50.6 (CH2-O), 50.4, 46.7, 41, 40.8, 28 (4CH2), 26.9, 26.4,25.4, 21.5,21, 20.9(6 CH3).

1-(9-(5-bromo-2-hydroxyphenyl)-3,3,6,6-tetramethyl-1,8- dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)propan-2-yl 4-methylbenzenesulfonate (4d): Yellow fine powder, m.p 1600C. IR: (KBr, υ max, cm-1), 3008(CH aromatic), 2950, 2924, 2886, 2856(CH aliphatic), 1638 (C=O), 1178 (O=S=O), 660(C-Br). 1H-NMR (DMSO-d6): (δH), 8.03-6.88(m, 11H, CH-Ar), 5.06 (m, J=6.8, 1H, CH-O tosylate), 2.83(s, 2H,CH2-C=O), 2.51 (s, 6H, CH3 of alc., CH3 of tosyl), 2.38-2.33(m, J=6.8, 1H, CH-N), 2.25 (d, J=6.8, 2H, CH2-O tosyl), 2.08(s, 4H, 2=C-CH2), 1.03,0.96 (s, 12H, 4CH3), 0.87(s,3H,CH3). 13C-NMR (DMSO-d6):(δC), 197.3,196.2(2C=O), 165.7, 164.6 (2=CN dihydropyridine ring),163(C-OH phenolic), 149.4, 148.4, 146.6, 133.4, 131.1, 130.9, 129.8, 128.07, 126.2, 119.3 (C-C Ar), 118.9(CBr), 108.8(2=C-CH hydropyridine ring), 56.4(CH2-O propyl), 51.1,50.5(2C-CO), 42.1, 41.3(2C-C), 29.4, 28.8, 28.3,27.6 (4CH3 cyclic), 25.8(CH3-tosyl), 19.9 (CH3-propyl).

Synthesis of bis-hexahydroacridine-1,8-diones (5a,b,e,f) and bis-Schiff bases (6a,b)

General procedure: A mixture of (4 mmol) of the 1,3-cyclohexanedione derivatives 2a-c (448 mg of 2a, 560 mg of 2b or 752 mg of 2c),(2 mmol) of salicylaldehyde1a (244 mg) or its derivative 1b (402 mg) and a catalytic amount of triethylamine was refluxed for 3 hrs. Ethylenediamine (60 mg, 1mmol) was added to the reaction mixture with further reflux for another 3 hours. The mixture was allowed to cool down to the ambient temperature, and the resulting solid product was collected by filtration, dried under vacuum and crystallized from ethanol to afford the pure products of the corresponding bis-hexahydroacridine-1,8-diones 5a,b,e,f (Scheme 1). In some cases, when we tried to repeat the reaction but at a shorter time with cyclohexane-1,3-dione 2a and also with the dimedone2b, we isolated the corresponding bis-Schiff bases 6a,b instead.

10,10'-(ethane-1,2-diyl)bis(9-(2-hydroxyphenyl)-3,4,6,7,9,10- hexahydroacridine-1,8(2H,5H)-dione) (5a): Yellow fine powder, m.p 213C. IR: (KBr, υ max, cm-1), 3387(OH), 3035(CH aromatic), 2911-2863 (CH aliphatic), 1640(C=O).1H-NMR (DMSO-d6) :(δH), 9.93(s, 2H, 2OH-phenolic), 7.8-6.90(m, 8H, 8CH aromatic), 5.4(s, 2H, 2Ar-CH), 3.27-2.95(t, J=7.4, 8H, 4 CH2C=O), 2.10-2.00(t, J=8.0, 4H, NCH2CH2N), 1.89-1.83(t, J=7.4, 8H, 4C=C-CH2), 1.76-1.70(m, J=7.4, 8H, CH2CH2CH2C=O). 13C-NMR (DMSO-d6): (δC), 200.08, 195.01(4C=O), 163 (4 C=C-CH2), 153 (2C-OH phenolic), 126.5, 125.9, 124.4, 123.5, 122.2, 121.4, 119.1(C-C Ar), 113(4=C-N), 100 (2CH cyclic), 59.2 (2 CH2, NCH2CH2N), 51, 39, 37, 35(4CH2, 4CH2C=O), 29.2, 28.3, 26.7, 25.2(4CH2, CH2CH2CH2C=O cyclic), 19.9, 18.5, 17.2, 16.8(4CH2, CH2CH2C=O cyclic).

10,10'-(ethane-1,2-diyl)bis(9-(5-bromo-2-hydroxyphenyl)- 3,4,6,7,9,10-hexahydro- acridine-1,8(2H,5H)-dione) (5b): Yellow fine powder, m.p 223°C. IR: (KBr, υ max,cm-1), 3437(OH), 3076(CH aromatic), 2941-2885(CH aliphatic), 1639 (C=O), 725(C-Br). 1H-NMR (DMSO-d6): (δH), 10.3(s, 2H, 2OH-phenolic), 7.1-6.93(m, 8H, 8CH aromatic), 5.1(s, 2H, 2Ar-CH), 2.57-2.51(t, J=7.8, 8H, 4 CH2C=O), 2.15-2.24(t, J=4.6, 4H, NCH2CH2N), 1.92-1.86 (t, J=7.8, 8H, 4C=CCH2), 1.85-1.73 (m, J=7.8, 8H, CH2CH2CH2C=O). 13C-NMR (DMSO-d6):(δC), 204.6, 196.4(4C=O), 167, 150(4C aromatic), 128.8, 128.3, 127.4, 127.2, 126, 121.8(8CH aromatic), 119.8(4NC=C),115(4NC=C),101(2CH cyclic), 56.4 (2CH2, NCH2CH2N),48, 37,36, 34 (4CH2, 4CH2C=O), 27.7,27, 25.8, 24(4CH2, CH2CH2CH2C=O cyclic), 20.8,20.7,20.2, 19(4CH2, CH2CH2C=O cyclic).

10,10'-(ethane-1,2-diyl)bis(9-(2-hydroxyphenyl)-3,3,6,6- tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione) (5e): Yellow fine powder, m.p 250°C. IR: (KBr, υ max, cm-1), 3443 (OH-phenolic), 3100 (CH aromatic), 2951-2883(CH aliphatic), 1630(C=O). 1H-NMR(DMSO-d6): (δH), 9.4 (2OH phenolic), 7.3-6.8 (m, 6H, aromatic), 5(s, 2H, 2CHAr), 4.9(HO-C=, D2O exchangable), 2.5(s, 4H, 2CH=C-OH), 2.25-2.15( t, J=8.0, 4H,NCH2CH2N), 2.1(s, 8H, 4C=CCH2), 1.0(s, 24H, 8CH3). 13C-NMR (DMSO-d6):(δC),196.1(4 C=O), 164.9 (2C-Br, aromatic), 149.4 (2C–OH, aromatic), 131, 130, 128 (6CH, aromatic), 118(4 NC=C), 115(4NC=C),110(2CH– C,aromatic),56(4C,C-CH3),50.8(2CH2, NCH2CH2N), 40.6 (4CH2, 4CH2C=O cyclic), 32(=C-CH2), 29, 28, 26, 25 (8CH3).

10,10'-(ethane-1,2-diyl)bis(9-(5-bromo-2-hydroxyphenyl)- 3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)- dione) (5f): Yellow fine powder, m.p 225°C. IR: (KBr, υ max, cm-1), 3443 (OH-phenolic), 3100 (CH arm), 2951-2883(CH aliphatic), 1630(C=O). 1H-NMR(DMSO-d6): (δH), 9.4 (2 OH phenolic),7.3-6.8 (m, 6H, aromatic), 5 (s, 2H, 2CHAr), 4.9(HO-C=, D2O exchangable), 2.5(s, 4H, 2CH=C-OH), 2.25-2.15 (t, J=8.0, 4H, NCH2CH2N), 2.1 (s, 8H, 4C=CCH2), 1.0 (s, 24H, 8CH3). 13C-NMR (DMSO-d6):(δC), 196.1(4C=O), 164.9 (2C-Br, arm), 149.4(2C–OH, aromatic), 131,130, 128 (6CH, aromatic), 118(4NC=C), 115(4NC=C), 110 (2CH– C,aromatic), 56(4C,C-CH3), 50.8(2CH2, NCH2CH2N), 40.6 (4CH2, 4CH2C=O cyclic),32(=C-CH2), 29, 28, 26, 25 (8CH3).

(3Z,3'E)-3,3'-(ethane-1,2-diylbis(azanylylidene)) dicyclohexanone (6a): IR: 2889-2818(CH2 aliphatic), 1638(C=O), 1602(C=N).1H-NMR (DMSO-d6): (δH), 3.45(s, 4H, 2=C-CH2C=O), 3.3(t, J=6.4, 4H, 2CH2-C=N cyclic) 2.70-2.73(t, J=8.0, 4H, N-CH2- CH2-N), 2.26-2.4 (m, J=6.4, 8H, 4CH2 cyclic). 13C-NMR (DMSO-d6) : (δC), 210 (2C=O), 165 (2C=N), 65(2N-CH2), 40, 43(2CH2-CO-CH2), 35(2CH2-C=N), 20 (2CH2 cyclic).

(5Z, 5'E)-5, 5'-(ethane-1,2-diylbis(azanylylidene))bis(3,3- dimethylcyclohexanone) (6b):

IR: 2900-2828(CH2aliphatic), 1640(C=O), 1610(C=N).1HNMR( DMSO-d6): (δH), 3.15 (s, 4H, 2=C-CH2C=O), 1.38-1.34(t, J=8.0, 4H, N-CH2-CH2-N), 2.16(s, 2H,=C-CH2-C(CH3)2), 1.97 (s, 4H, 2O=CCH 2-C(CH3)2), 0.99-0.97 (s, 12H, 4CH3).

Results and Discussion

Heating a solution of cyclohexane-1,3-dione 2a, 5,5-dimethylcyclohexane-1,3-dione 2b or 5-phenylcyclohexane- 1,3-dione 2c with salcylaldehyde 1a, 5-bromo-salcylaldehyde 1b, or 5-bromo-3-chlorosalcylaldehyde 1c and 1-amiopropan-2-ol afforded the corresponding six derivatives of hexahydroacridinones 3a-f (Scheme 1).

medicinal-chemistry-hydroacridinediones

Scheme 1: Synthesis of a new series of hydroacridinediones 3a-f and 4a-d and new bis-hexahydroacridinediones 5a,b,e,f.

The molecular structure of the products 3a-f was elucidated from their IR, 1H- NMR and 13C-NMR spectra. The IR spectrum of these products in KBr showed broad bands at 3397-3421cm-1 assigned for both of phenolic and alcoholic OH groups, and strong bands ranged from 1630-1648cm-1 related to carbonyl groups. Broad bands characteristic of stretching the aliphatic CH3 and CH2 groups have been also observed at 2874-2965 cm-1. The 1H-NMR spectrum of 3a-f showed clearly the presence of phenolic OH at δ=10-10.9 ppm and alcoholic OH at δ=3.2-3.5 ppm. Singlet sharp peaks at δ=1.05, 0.99, 0.89 ppm were attributed to the alcoholic CH3 and the four methyl groups of dimedone scaffold respectively in 3d. The other two clear singlet peaks were observed at δ=3.6 and 5.06 ppm assigned for the CH of the hydro pyridine ring and the CH of the isopropanol group respectively. The 13C-NMR spectrum of 3a-f supported the presence of carbonyl at the range δ=199-196 ppm, and aliphatic carbon signals appeared in the regular region (see experimental). Moreover, compound 3a has been further confirmed by refluxing the corresponding xanthenone 7 [26] with amino-iso-propanol (Scheme 2). The spectral data of the authentic product was identical with 3a.

medicinal-chemistry-corresponding-xanthenone

Scheme 2: Synthesis of 3a via direct reaction of the corresponding xanthenone 7 with isopropanol amine.

The alcoholic group in 3a-d has been tosylated by tosyl chloride in TEA to afford the corresponding tosylatedoctahydro-acridine- 1,8-diones 4a-d via elimination of HCl. IR spectra showed a clear characteristic peak at 1177 (in 4c), 1178 (in 4d), 1180(in 4b) and 1183cm-1(in 4a) for (O=S=O) group. The 1H-NMR supported the presence of a multiplet peaks at δ=5-5.06 ppm assigned for the CH-O tosylate and a singlet peak for the CH3 tolyl has been observed at the range δ=2.5-2.9 ppm. Furthermore 13C-NMR confirmed the existence carbonyl at average δ=197 ppm. Two clear peaks have been also observed at δ=19 and 22 ppm attributed to the CH3 tolyl and CH3 propyl groups respectively.

Gratifyingly, the symmetry function in the structures of the new products 5a,b,e,f (Scheme 1) has been unambiguously confirmed by both 1H-NMR and 13C-NMR spectra. The 13C resonance of the two carbon atoms of the ethyl linkage have been observed in all compounds 5a,b,e,f at the average δ=50-56 ppm and the 1H-NMR confirmed the four proton resonance of the ethyl linkage as a symmetrical triplet peak between δ=2.0-2.5 ppm. Moreover 13C-NMR confirmed the existence of the peaks of four carbonyl groups between δ=204-196 ppm for all compounds 5a,b,e,f.

The formation of N-hydroxypropyl-hexahydroacridine-1,8-diones 3a-f and the bis-hexahydroacridine-1,8-dione derivatives 5a,b,e,f can be rationalized as depicted in Scheme 3. An initial nucleophilic attack by the unstable imine 9 on the electrophilic C=C of the arylidene 8, where the two electron withdrawing carbonyl groups facilitate this reaction to form the intermediate 10 which undergoes an intramolecular arrangement to form the corresponding hydroxyloctahydroacridinediones 10. Elimination a molecule of water from 10 affords the formation of 3a-f. As a result, this synthesis allows much wider substrate scope and provides a general and practical access to 3aj. Similarly bis-hexahydroacridine-1,8-diones 5a,b,e,f can be justified by formation of the stable bis-imines 6 which we have succeeded to isolate two of these isomers 6a,b and characterized their structures (see experimental). The two nucleophilic centers labeled by the pair of electrons of the bis-imine nitrogen atoms could attack two folds of the arylidenes 8 to form the intermediate 12 which in turn could be stabilized to give the corresponding bis-hydroxy-octahydroacridine- 1,8-diones 13. Elimination of two water molecules from 13 gives ultimately the corresponding bis-hexahydroacridine-1,8-diones 5a,b,e,f (Scheme 3).

medicinal-chemistry-Reaction-mechanism

Scheme 3: Reaction mechanism of formation of the hydroacridienediones 3a-f, 4a-f and the bis-hydroacredenediones 5a-f.

Anti-inflammatory activity

Carrageenan-induced paw oedema standard method in rats: Anti-inflammatory activity screening for the chosen compounds 3c, 5a, 5b and 5f was determined in vivo by the acute carrageenan-induced paw oedema standard method in rats [27]. Adult albino rats of either sex (pregnant female animals were excluded) weighing 160-190 g were divided into 6 groups of 6 animals each. To reduce the variability of oedema response, 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 (reference standard) and the tested compounds (20 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. [27,28] 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 three, four and five 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 [29] at p<0.05 and p<0.01.

The results of the anti-inflammatory activity were expressed as percentage inhibition of oedema thickness in treated animals in comparison with the control group according to the following equation (Table 1, Figure 1).

  % of Oedema Inhibition
Compound 1hours 2hours 3hours 4hours 5hours
Control 0.00 0.00 0.00 0.00 0.00
Indomethacin 15.06 ± 2.1 27.39 ± 0.39 28.76 ± 0.2 41.09 ± 3.2 54.79 ±1.4
5a 12.33 ± 1** 23.28 ±1.2** 26.02 ± 1.2** 8.22 ± 2.7** 5.47 ± 0.91**
5b 6.85 ± 0.79** 12.33 ± 1.2** 26.03 ± 3.2 30.13 ± 0.8** 39.7 2 ± 2.8**
5f 15.06 ± 0.85** 24.66 ± 0.85** 28.76 ± 0.61** 41.09 ± 1.2** 57.53 ± 2.1**
3c 2.74 ± 1.6** 13.7 ± 1.4 20.55 ± 1.2** 20.37 ± 0.83** 36.73 ± 1.7**

Table 1: Anti-inflammatory activity of the tested compounds using carrageenan-induced paw oedema in rats.

image

Where VR represents the mean right paw thickness, VL represents the mean left paw thickness, (VR–VL)control represents the mean increase in paw thickness in the control group of rats and (VR–VL)treated represents the mean increase in paw thickness in rats treated with the tested compounds [30-34].

Discussion

The anti-inflammatory activity of four representative synthesized compounds (5a,b,f and 3c) was determined by the carrageenan induced paw oedema standard method in rats [27,28]. Generally, it has been observed from the obtained results, (Table 1, Figure 1), that all the tested compounds show considerable anti-inflammatory activity. In addition, compounds 5f exhibit better anti-inflammatory properties (57.53 % inhibition of oedema) than that of the used reference standard indomethacin (54.9 % inhibition of oedema).

medicinal-chemistry-tested-compounds

Figure 1: % Inhibition of oedema of the tested compounds 3c and 5a,b,f.

The effect of substituents on the anti-inflammatory potency has been considered by comparing the activity of the bis-hydroacridine derivatives5a,b and 5f. The compound 5bshowed higher antiinflammatory potency (39.72) compared to 5.47 for 5a. This might attributed to the existence of the halogen atom. On other hand, we found the bis-hydroacridinedione5f bearing 8 alkyl groups exhibits even better anti-inflammatory potency than 5b. The N-substituted alcohol of the mono-hydroacridinedione3c showed more effectiveness as an anti-inflammatory agent compare to the bis-hydroacridine- dione5a. In general, we concluded that bis-hydroaccridinediones bearing more electron donating alkyl groups showed high anti-inflammatory effect than the standard indomethacin. This means that the electron donating alkyl groups in hydroacridines could enhance their anti-inflammatory activity.

Conclusion

Synthesis of 9-(2-hydroxyphenyl)-10-(2-hydroxypropyl)- 3,4,6,7,9,10-hexahydro- acridine-1,8(2H,5H)-diones 3a-f and 10,10'-(ethane-1,2-diyl)bis-(9-(2-hydroxy phenyl) -3,4,6,7,9,10-hexahydro- acridine-1,8-(2H,5H)-diones 5a,b,e,f are performed efficiently in a one pot reaction technique and described as a new class of antiinflammatory agents. These agents showed (particularly 5f) an antiinflammatory potency higher than the standard drug indomethacin.

Acknowledgements

The authors would like to express their gratitude to Sohage University and Manchester Metropolitan University for supporting and facilitating this study. The authors have declared no conflict of interest.

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