Synthesis of Biologically Potent Quinoline Linked Ureides Possessing Azetidin-2-one / Thiazolidin-4-one / Tetrazole Moieties

 

Madhu G. 1*, B. Santosh Kumar3,  K.N. Jayaveera2, L.K. Ravindranath3

1Department of Chemistry, Aditya College of Engineering, Madanapalle, A.P., India.

2Department of Chemistry, JNTUA College of Engineering, Anantapuram, A.P., India.

3Department of Chemistry, S.K .University, Anantapuram, A.P., India.

*Corresponding Author E-mail: madhugchem@gmail.com

 

ABSTRACT:

Purpose: The article is aimed to synthesize, characterize and screen the biological activity of a series of N-(((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)methyl)substitutedcarboxamide (4a-e) / N-(((5-(4-oxo-2-(4-(trifluoromethyl)phenyl) thiazolidin-3-yl)quinolin-8-yl)oxy)methyl)substitutedcarboxamide (5a-e) / N-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl)substituted-1-carboxamide (6a-e). Methods: The newly synthesized compounds were characterized by elemental analysis and IR, 1H-NMR, 13C NMR and Mass spectral data.  The antimicrobial activity of the novel compounds was screened by agar disc diffusion method.

Results: 4b, 4c, 5b, 6b and 6c have shown better antibacterial and anti fungal activity than other compounds of the series.

 

KEYWORDS: Quinoline, ureides, azetidin-2one, thiazolidin-4-one, tetrazole.

 

INTRODUCTION:

Ureido derivatives are one of the oldest classes of bioactives, widely used as anti-infective agents. Many of them exhibit antibacterial1-4, antimicrobial5-6, anti-viral activities7-9.  Azetidin-2-ones are very important class of compounds possessing wide range of biological activities such as antimicrobial10,11, pesticidal12, antitumor13, antitubercular14, anticancer15, cytotoxic16-18, enzyme inhibitors19, elastase inhibitors20 and cholesterol absorption inhibitors21.  4-thiazolidinones moiety is associated with variety of biological activities including antifungal22, anti-inflammatory23, anticonvulsant24, antitubercular25, antihistaminic26. Tetrazoles and its derivatives are used for biological activities such as anti-inflammatory27, antibacterial28, antifungal29, analgesic30, anticonvulsant31, anticancer32 and antihypertensive33 activities.

 

Hence it was thought worthwhile to synthesise some new congeners of ureides by incorporating the quinoline, azetidin-2-one, thiazolidin-4-one and tetrazole moieties in a single molecular frame work.

 

EXPERIMENTAL:

Melting points were determined on open capillaries using a cintex melting point apparatus. T.L.C analyses were performed on precoatedsilicagel (E-Merck Kieselgel 60F254) plates and visualisation was done by exposing to iodine vapour. Solvents were purified by standard procedures before use. IR Spectra were recorded in KBr on Perkin-Elmer Spectrum BX series FT-IR spectrometer. 1H-NMR spectrum were recorded on DRX 300MHz Bruker spectrometers using TMS as internal standard (chemical shifts in δ ppm). 13C-NMR Spectra were recorded on a Brucker 75MHz spectrometer. Mass spectra were scanned on a varian MATCH-7 at 70ev. Elemental analysis was carried out on a carlo erba 106 and Perkin-Elmer Analyser. All the chemicals used in the present investigation were purchased from Sigma-aldrich, India.


 

Comp

a

b

c

d

e

X-

 

 

 

 

 

 

Reagents and Conditions:

(i) THF / MeOH / H2O in 1:1:1 ratio, 2N NaOH, reflux, 6-7h. (ii) Isobutyl chloroformate, acetone, TEA, Aq NaN3, -150C, 20-30 minutes  (iii) Benzene, reflux, 16h.

 

General procedure for the synthesis of acids by esters hydrolysis (2a-c)

 

In the present investigation the required synthons ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl) quinolin-8-yl)oxy)acetate(1a) / Ethyl-2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)acetate(1b) / Ethyl-2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)acetate (1c) used were prepared by procedure reported in the literature34-35.

 

To a solution of one equivalent Ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl) azetidin-1-yl)quinolin-8-yl)oxy)acetate (1a) / 2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl) thiazolidin-3-yl)quinolin-8-yl)oxy)acetate(1b) / Ethyl-2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)acetate (1c) in solvent mixture tetrahydrofuran / MeOH / H2O(1:1:1) ratio, aqueous NaOH (2N) was added and reflux for 6h. The progress of the reaction was monitored by TLC. After completion, solvent was evaporated under vacuum to give crude residue. The residue was washed with ethyl acetate to remove impurities. The residue was acidified with 1N HCl up to pH-2 to give solid suspension, which was filtered under vacuum to give crude solid. The crude was purified by column chromatography (60-120 mesh- silca gel, Eluent: 70% ethylacetate- pet ether) to afford acid compound 2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)aceticacid(2a) /  2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)aceticacid (2b) / 2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)aceticacid (2c).

 

2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) aceticacid(2a)

1H NMR (300MHz, DMSO-d6): δppm 4.8 (s, 2H, -O-CH2), 5.16 (d, 1H, -CH-C6H4CF3), 5.44 (d, 1H, -CH–Cl), 7.12-8.8 (m, 9H, Ar-H), 10.54 (s, 1H, -OH). IR (KBr) spectra cm-1: 3100 (-O-H), 1690 (-C=O), 1620 (-C=N), 1320 (-C-O), 677 (-C-Cl).

 

2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)aceticacid (2b)

1H NMR (300MHz, DMSO-d6): δppm 3.85 (d, 1H, -Ha), 3.97 (d, 1H, -Hb), 4.58 (s, 2H, -O-CH2), 6.44 (s, 1H, -CH-C6H4CF3), 7.25-8.8 (m, 9H of C6H4 and C9H5 of quinoline), 10.10 (s, 1H, -OH). IR (KBr) spectra cm-1: 3180 (-O-H), 1705 (-C=O), 1610 (-C=N), 1310 (-C-O), 1188 (C-S).

 

2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)aceticacid (2c)

1H NMR (300MHz, DMSO-d6): δppm 4.58 (s, 2H,-O-CH2), 7.25-8.8 (m, 10H Ar-H), 10.15(s, 1H, -OH). IR (KBr) spectra cm-1: 3160 (-O-H), 2107 (azide), 1698 (-C=O), 1620 (-C=N), 1310 (C-O), 1157 (tetrazole).

 

Synthesis of azides from acid derivatives (3a-c)

A mixture of 2-((5-(3-chloro-2-oxo-4-phenylazetidin-1-yl)quinolin-8-yl)oxy)aceticacid(2a) / 2-((5-(4-oxo-2-(4-(trifluoromethyl) phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)aceticacid (2b) / 2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)aceticacid (2c) in acetone, tri ethyl amine (3eq) was added and stirred at -15°C for 20 minutes. To the reaction mixture isobutyl chloroformate (1.1 eq) was added and stirred for 30 min. To the above reaction mixture aq NaN3(3 eq)  was added and stirred for 20 min at 0°C. The progress of the reaction was monitored by TLC with acetone:ethylacetate (6:4) solvent mixture as an eluent. After completion of the reaction, the reaction mixture was poured in ice cold water (20 mL), extracted with 10 mL diethyl ether (5 times). The organic layer was separated, washed with water, brine, dried over anhydrous Na2SO4.The dried organic layer was filtered and evaporated under vacuum to give crude oil. The crude oil was purified by column chromatography by using (60-120) mesh silicagel. The 10% Ethylacetate- pet ether solvent mixture was used as eluent. After the evaporation of the solvent under vacuum, it affords pure 2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetylazide(3a) / 2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)acetylazide (3b) / 2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)acetylazide (3c).

 

2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) acetylazide (3a)

1H NMR (300MHz, DMSO-d6): δppm 4.82 (s, 2H, -O-CH2), 5.12 (d, 1H, -CH-C6H4CF3), 5.48 (d, 1H, -CH–Cl), 7.2-8.7 (m, 9H, Ar-H). IR (KBr) spectra cm-1: 2118 (-azide), 1690 (-C=O), 1620 (-C=N).

 

2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)acetylazide (3b)

1H NMR (300MHz, DMSO-d6): δppm 3.85 (d, 1H, -Ha), 3.99 (d, 1H, -Hb), 4.88 (s, 2H, -O-CH2), 6.48 (s, 1H, -CH-C6H4CF3), 7.25-8.8 (m, 9H of C6H4 and C9H5 of quinoline). IR (KBr) spectra cm-1: 2120 (-azide), 1698 (-C=O), 1620 (-C=N), 1188 (C-S).

 

2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)acetylazide (3c)

1H NMR (300MHz, DMSO-d6): δppm 4.98 (s, 2H,-O-CH2), 7.25-8.8 (m, 9H Ar-H). IR (KBr) spectra cm-1: 2125 (azide), 1698 (-C=O), 1620 (-C=N).

 

Procedure for the synthesis of ureides (4a-e, 5a-e, 6a-e)

To a mixture of acid azide (3a/3b/3c) (1eq), in benzene, amine (X) (1 eq) in benzene was added and refluxed for 16h. The progress of the reaction was monitored by TLC with acetone:ethyl acetate (6:4). After completion of the reaction, solvent was evaporated under vacuum to give crude residue, purified by column chromatography (60-120 mesh silica gel, Eluent: 80% EtOAc- petether) to give corresponding ureides 4a-e / 5a-e / 6a-e respectively.

 

N-(((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) methyl)piperidine-1-carboxamide (4a)

1H NMR (300MHz, DMSO-d6): δppm 1.30–1.59 [m, 6H (CH2)3 of piperidine ring], 2. 10 (t, 4H, –CH2–N–CH2 of piperidine ring), 4.9(s, 2H,-O-CH2), 5.14(d,1H,-CH of azetidin attached to phenyl ring), 5.48(d,1H,-CH of azetidin attached to –Cl), 7.3-8.8(m,9H, C6H4 Ar-H), 9.6(s, 1H, -NH).  13C NMR (CDCl3) (δppm) = 49, 24, 62, 69, 77 (aliphatic C), 107, 116, 120, 122, 125, 127, 130, 139  (ar-C), 146 (ar-C-O), 162(-C=O), 155 (NH-CO-N). IR (KBr) spectra cm-1 3186(-NH), 3041 (ar-H str), 1724(CO-NH), 1684 (-C=O), 1610 (-C=N). MS, m/z : (M+, 532.15, M+2, 534.42).

 

N-(((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) methyl)morpholine-4-carboxamide (4b)

1H NMR (300MHz, DMSO-d6): δppm 3.54 (t, 4H, –CH2–O–CH2 of morpholine ring), 2.45 (t, 4H, –CH2–N–CH2 of morpholine ring), 5.06(s,2H,-O-CH2), 5.08(d,1H,-CH of azetidin attached to phenyl ring), 5.48(d,1H,-CH of azetidin attached to –Cl), 7.3-8.7(m,9H, C6H4 and C9H5 of quinoline ring), 9.7(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 47, 62, 66, 69, 78 (aliphatic C), 108, 116, 120, 126, 130, 133, 139 (ar-C), 146 (ar-C-O)   161(-C=O), 158 (NH-CO-N). IR (KBr) spectra cm-1 3183(-NH), 3040 (ar-H str), 1694(CO-NH), 1682 (-C=O), 1614 (-C=N). MS, m/z : (M+, 534.91, M+2, 536.85).

 

N-(((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) methyl)thiomorpholine-4-carboxamide (4c)

1H NMR (300MHz, DMSO-d6): δppm 3.53 (t, 4H, –CH2–S–CH2 of thiomorpholine ring), 2.62 (t, 4H, –CH2–N–CH2 of thiomorpholine ring), 5.02(s,2H,-O-CH2), 5.12(d,1H,-CH of azetidin attached to phenyl ring), 5.48(d,1H,-CH of azetidin attached to –Cl), 7.3-8.7 (m,9H, C6H4 and C9H5 of quinoline ring), 9.65(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 26, 51, 62, 68, 78 (aliphatic C), 107, 116, 120, 123, 125, 128, 130,133, (Ar-C), 146 (ar-C-O), 163(-C=O), 157(NH-CO-N). IR (KBr) spectra cm-1 3186(-NH), 3042 (ar-H str), 1696(CO-NH), 1688 (-C=O), 1612 (-C=N). MS, m/z : (M+, 550.11, M+2, 552.09).

 

N-(((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) methyl)-4-methylpiperazine-1-carboxamide (4d)

1H NMR (300MHz, DMSO-d6): δppm 2.22(s,3H,-N-CH3 of piperizine ring), 2.32 (t, 4H, –CH2–N(CH3)–CH2), 2.46(t,4H, , –CH2–N–CH2of piperizine ring), 4.98(s,2H,-O-CH2), 5.12(d,1H,-CH of azetidin attached to phenyl ring), 5.52(d,1H,-CH of azetidin attached to –Cl), 7.4-8.7 (m,9H, C6H4 and C9H5 of quinoline ring), 9.62(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 26, 47, 52, 62, 69 (aliphatic-C), 107, 116, 120, 125, 130, 133, 138 (ar-C), 146 (ar-C-O), 162 (-C=O), 157(NH-CO-N). IR (KBr) spectra cm-1 3188(-NH), 3041 (ar-H str), 1698(CO-NH), 1684 (-C=O), 1618 (-C=N). MS, m/z : (M+, 547.36, M+2, 549.19 ).

 

1-(((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)methyl) -3-phenylurea (4e)

1H NMR (300MHz, DMSO-d6): δppm 4.88(s,2H,-O-CH2), 5.15(d,1H,-CH of azetidin attached to phenyl ring), 5.43(d,1H,-CH of azetidin attached to –Cl), 7.2-8.7 (m,14H, C6H4, C6H5 and C9H5 of quinoline ring), 9.7(s, 2H, two -NH). 13C NMR (CDCl3) (δppm) = 62, 68, 77 (aliphatic C), 107, 116, 120, 125, 128, 130, 133, 139 (ar-C), 146 (ar-C-O), 162(-C=O), 154 (NH-CO-N). IR (KBr) spectra cm-1 3183(-NH), 3045 (ar-H str), 1698(CO-NH), 1686 (-C=O), 1610 (-C=N). MS, m/z : (M+, 540.92, M+2, 542.54).

 

N-(((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)methyl) piperidine-1-carboxamide (5a)

1H NMR (300MHz, DMSO-d6): δppm 1.32–1.52 [m, 6H (CH2)3 of piperidine ring], 2. 12 (t, 4H, –CH2–N–CH2 of piperidine ring), 3.85(d,1H, Ha of -CH2 of Thiazolidinone), 3.94(d,1H, Hb of -CH2 of Thiazolidinone),5.22(s,2H,-O-CH2), 6.40 (s,1H,-CH of Thiazolidin attached to phenyl ring), 7.2-8.7 (m,9H, C6H4 and C9H5 of quinoline ring), 9.62(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 25, 33, 49, 73, 77 (aliphatic C), 108, 117, 120, 123, 125, 129, 129, 130, 135, 140 (ar-C), 147 (ar-C-O), 172 (-C=O), 155 (NH-CO-N). IR (KBr) spectra cm-1 3190 (-NH), 3040 (ar-H str), 1694 (-CO-NH), 1688 (-C=O), 1613(C=N), 1188 (-C-S). MS, m/z : (M+, 530.16).

 

N-(((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)methyl) morpholine-4-carboxamide (5b)

1H NMR (300MHz, DMSO-d6): δppm 2.42(t, 4H, –CH2–N–CH2 of morpholine ring),3.50 (t, 4H, –CH2–O–CH2 of morpholine ring), 3.80(d,1H, Ha of -CH2 of Thiazolidinone), 3.92(d,1H, Hb of -CH2 of Thiazolidinone), 5.30(s,2H,-O-CH2), 6.44(s,1H,-CH of Thiazolidin attached to phenyl ring), 7.3-8.7 (m, 9H, C6H4 and C9H5 of quinoline ring), 9.7(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 26, 33, 50, 73, 78(aliphatic-C), 107, 116, 120, 123, 125, 130, 134, 142 (Ar-C), 173 (-C=O), 157 (NH-CO-N). IR (KBr) spectra cm-1 3183 (-NH), 3042 (ar-H str), 1696 (-CO-NH), 1688 (-C=O), 1614(C=N), 1185(-C-S). MS, m/z : (M+, 532.53).

 

N-(((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)methyl) thiomorpholine-4-carboxamide (5c)

1H NMR (300MHz, DMSO-d6): δppm 2.72 (t, 4H, –CH2–N–CH2 of thiomorpholine ring), 3.50 (t, 4H, –CH2–S–CH2 of thiomorpholine ring), 3.80(d,1H, Ha of -CH2 of Thiazolidinone), 3.96(d,1H, Hb of -CH2 of Thiazolidinone), 5.20(s,2H,-O-CH2), 6.48(s,1H,-CH of Thiazolidin attached to phenyl ring), 7.2-8.8(m, 9H, C6H4 and C9H5 of quinoline ring), 9.68(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 26, 33, 50, 73, 78 (aliphatic-C), 107, 116, 120, 123, 125, 129, 131, 139, 142 (Ar-C), 171(C=O), 158 (NH-CO-N). IR (KBr) spectra cm-1 3188 (-NH), 3040 (ar-H str), 1698 (-CO-NH), 1684 (-C=O), 1618(C=N), 1168 (-C-S). MS, m/z : (M+, 548.42).

 

4-methyl-N-(((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy) methyl)piperazine-1-carboxamide (5d)

1H NMR (300MHz, DMSO-d6): δppm 2.20(s,3H,-N-CH3 of piperizine ring), 2.38 (t, 4H, –CH2–N(CH3)–CH2), 2.52 (t, 4H, N–CH2–N–CH2of piperizine ring), 3.85(d,1H, Ha of -CH2 of Thiazolidinone), 4.06(d,1H, Ha of -CH2 of Thiazolidinone), 5.3(s,2H,-O-CH2), 6.40(s,1H,-CH of Thiazolidin attached to phenyl ring), 7.2-8.7(m, 9H, C6H4 and C9H5 of quinoline ring), 9.52(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 33, 46, 511, 73, 76(aliphatic-C), 106, 118, 122, 125, 129, 131, 133, 138 (ar-C), 172 (-C=O), 157 (NH-CO-N). IR (KBr) spectra cm-1 3185 (-NH), 3040 (ar-H str), 1696 (-CO-NH), 1688 (-C=O), 1620(C=N), 1158 (-C-S). MS, m/z : (M+, 545.64).

 

1-(((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)methyl)-3-phenylurea (5e)

1H NMR (300MHz, DMSO-d6): δppm 3.80(d,1H, Ha of -CH2 of Thiazolidinone), 3.96(d,1H, Hb of -CH2 of Thiazolidinone), 5.20(s,2H,-O-CH2), 6.42(s,1H,-CH of Thiazolidin attached to phenyl ring), 7.3-8.8(m, 14H, C6H4, C6H5 of phenyl and C9H5 of quinoline ring), 9.64(s, 2H, two -NH). 13C NMR (CDCl3) (δppm) = 33, 73(aliphatic-C), 107, 116, 120, 124, 129, 130, 133,139, 142 (ar-C), 171 (-C=O), 154 (NH-CO-N). IR (KBr) spectra cm-1 3188 (-NH), 3046 (ar-H str), 1695 (-CO-NH), 1680 (-C=O), 1622(C=N), 1162 (-C-S). MS, m/z : (M+, 538.13).

 

N-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl)piperidine-1-carboxamide (6a)

1H NMR (300MHz, DMSO-d6): δppm 1.32–1.52 [m, 6H (CH2)3 of piperidine ring], 2. 12 (t, 4H, –CH2–N–CH2 of piperidine ring), 5.28(s,2H,-O-CH2), 7.1-8.8 (m,9H, C6H4 and C9H5 of quinoline ring), 9.62(s, 1H, -NH).  13C NMR (CDCl3) (δppm) 25, 49, 78 (aliphatic-C), 107, 117, 121, 126, 131, 133(ar-C), 164 (tetrazole-C), 156 (NH-CO-N-).


IR (KBr) spectra cm-1 3188 (-N-H str), 3048 (ar-H str), 2115 (azide), 1613 (-C=N) and 1158 (tetrazole). MS, m/z : (M+, 497.18).

 

N-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl) morpholine-4-carboxamide (6b)

1H NMR (300MHz, DMSO-d6): δppm 3.50 (t, 4H, –CH2–O–CH2 of morpholine ring), 2.42(t, 4H, –CH2–N–CH2 of morpholine ring), 5.20(s,2H,-O-CH2), 7.2-8.8 (m,9H, C6H4 and C9H5 of quinoline ring), 9.57(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 47, 66, 77 (aliphatic-C), 107, 117, 121, 124, 131, 134, 138(ar-C), 164 (tetrazole-C), 158 (NH-CO-N-). IR (KBr) spectra cm-1 3180 (-N-H str), 3045 (ar-H str), 2118 (azide), 1614 (-C=N) and 1156 (tetrazole). MS, m/z : (M+, 499.27).

 

N-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl) thiomorpholine-4-carboxamide (6c)

1H NMR (300MHz, DMSO-d6): δppm 3.50 (t, 4H, –CH2–S–CH2 of thiomorpholine ring), 2.72 (t, 4H, –CH2–N–CH2 of thiomorpholine ring), 5.18(s,2H,-O-CH2), 7.18-8.82 (m,9H, C6H4 and C9H5 of quinoline ring), 9.60(s, 1H, -NH). 13C NMR (CDCl3) (δppm) = 26, 51, 78 (aliphatic-C), 107, 116, 122, 125, 131, 133, 138 (ar-C), 163 (tetrazole-C), 157 (NH-CO-N-). IR (KBr) spectra cm-1 3186 (-N-H str), 3046 (ar-H str), 2112 (azide), 1619 (-C=N) and 1158 (tetrazole). MS, m/z : (M+, 515.36).

 

4-methyl-N-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl) piperazine-1-carboxamide (6d)

1H NMR (300MHz, DMSO-d6): δppm 2.20(s,3H,-N-CH3 of piperizine ring), 2.52 (t,4H, , –CH2–N–CH2of piperizine ring), 2.38 (t, 4H, –CH2–N(CH3)–CH2), 5.18(s,2H,-O-CH2), 7.14-8.82 (m,9H, C6H4 and C9H5 of quinoline ring), 9.62(s, 1H, -NH). 13C NMR (CDCl3) (δppm) 46, 50, 52, 78 (aliphatic-C), 106, 117, 122, 125, 131, 133, 139 (ar-C), 164 (tetrazole-C), 157 (NH-CO-N-). IR (KBr) spectra cm-1 3195 (-N-H str), 3042 (ar-H str), 2110 (azide), 1612 (-C=N) and 1149 (tetrazole). MS, m/z : (M+, 512.46).

 

1-phenyl-3-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl) urea (6e)

1H NMR (300MHz, DMSO-d6): δppm 5.18(s, 2H,-O-CH2), 7.15-8.82 (m, 14H, C6H4, C6H5 and C9H5 of quinoline ring), 9.68(s, 2H, two-NH). 13C NMR (CDCl3) (δppm) = 77 (aliphatic-C), 107, 116, 122, 126, 129, 132, 134, 138 (ar-C), 163 (tetrazole-C), 154 (NH-CO-N-). IR (KBr) spectra cm-1 3190 (-N-H str), 3040 (ar-H str), 2115 (azide), 1618 (-C=N) and 1152 (tetrazole). MS, m/z : (M+, 505.47).

 

Anti- Bacterial Activity

The antibacterial activity of synthesised compounds was studied by the disc diffusion method against the following pathogenic organisms. The gram-positive bacteria screened were Staphylococcus aureus NCCS 2079 and Bacillus cereus NCCS 2106. The gram negative bacteria screened were Escherichia coli NCCS2065 and Pseudomonas aeruginosa NCCS2200.

 

The synthesised compounds were used at the concentration of 250 µg/ml and 500 µg/ml using DMSO as a solvent. The cefaclor 10µg/disc was used as a standard. (Himedia Laboratories Ltd, Mumbai).

 

The test results presented in the table-2, suggest that 4b, 4c, 5b, 6b and 6c exhibit more activity against the tested bacteria, the rest of the compounds were found to be moderate active against the tested microorganisms.

 

 

Table-1: Physical and preparation data of synthesised compounds

Comp

Yield (%)

Melting Point (0C)

Analytical data Calcd (%) Found (%)

C

H

N

3a

42

144-5

52.93 (53.01)

2.69 (2.75)

14.66 (14.72)

3b

48

122-3

53.17 (53.28)

2.89 (2.98)

14.71 (14.79)

3c

45

150-7

51.74 (51.82)

2.44 (2.52)

25.39 (25.45)

4a

68

162-3

58.53 (58.60)

4.42 (4.54)

10.39 (10.51)

4b

57

176-7

56.07 (56.13)

4.09 (4.15)

10.35 (10.47)

4c

55

138-9

54.39 (54.50)

3.94 (4.02)

10.09 (10.17)

4d

59

154-5

56.89 (56.99)

4.48 (4.60)

12.69 (12.78)

4e

52

172-3

59.88 (59.95)

3.68 (3.73)

10.28 (10.36)

5a

63

114-5

58.78 (58.86)

4.69 (4.75)

10.49 (10.56)

5b

54

142-3

56.31 (56.38)

4.26 (4.35)

10.45 (10.52)

5c

55

127-8

54.69 (54.73)

4.17 (4.23)

10.12 (10.21)

5d

45

144-5

57.18 (57.24)

4.77 (4.80)

12.78 (12.84)

5e

43

184-5

64.17 (60.22)

3.88 (3.93)

10.33 (10.40)

6a

58

136-7

57.83 (57.94)

4.37 (4.46)

19.59 (19.71)

6b

61

167-8

55.22 (55.31)

3.95 (4.04)

19.55 (19.63)

6c

54

137-8

53.48 (53.59)

3.84 (3.91)

18.95 (19.02)

6d

52

152-3

56.12 (56.25)

4.43 (4.52)

21.78 (21.86)

6e

49

175-6

69.33 (59.41)

3.46 (3.59)

19.29 (19.40)

 

 

Antifungal Activity:

The antifungal activity of synthesised compounds were studied by disc diffusion method against the organisms of Aspergillus niger NCCS1196 and Cadida albicans NCCS34471.

 

Compounds were treated at the concentrations of 100µg/ml, 250µg/ml, 500µg/ml and 1000µg/ml using DMSO as solvent. The standard used was Clotrimazole 50µg/ml against both the organisms. The test results were presented in the table-3.

 

Table–2:Antibacterial activity by disc diffusion method of Quinoline-ureides having azetidi-2-one(4a-e), thiazolidinone(5a-e) and tetrazole (6a-e)

Compound

Zone of Inhibition (mm)

Staphylococcus aureus

Bacillus cereus

Escherichia coli

Pseudomonas aeruginosa

4a

09

06

11

13

4b

14

15

15

18

4c

12

11

13

16

4d

10

08

12

14

4e

07

05

08

10

5a

08

07

09

11

5b

11

09

13

14

5c

10

08

10

12

5d

07

08

09

12

5e

06

04

07

09

6a

09

10

11

14

6b

15

17

17

18

6c

13

14

15

16

6d

11

12

13

15

6e

06

08

10

13

Cefaclor

19

22

19

20

 

Table–3: Antifungal activity by disc diffusion method for Quinoline-ureides having Azetidi-2-one(4a-e), thiazolidinone(5a-e) and tetrazole (6a-e).

Compound

Zone of Inhibition (mm)

Asperigillus niger

Candida albicans

4a

11

09

4b

17

15

4c

14

11

4d

13

10

4e

09

07

5a

10

08

5b

15

14

5c

12

09

5d

11

08

5e

06

05

6a

15

11

6b

19

17

6c

17

14

6d

16

12

6e

10

08

Clotrimazole

25-30

25-30

 

CONCLUSION:

The present investigation discovered a new class of biologically potent ureides possessing quinoline core unit bearing azetidin-2one, thiazolidin-4-one and tetrazole moieties in a single molecular frame work. These ureides exhibited promising antibacterial and antifungal activities. Hence, it can be concluded that, this new class of compounds certainly holds a greater consent in the design of new potent antibacterial and antifungal agents.

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Received on 13.06.2014         Modified on 22.06.2014

Accepted on 26.06.2014         © AJRC All right reserved

Asian J. Research Chem. 7(7): July 2014; Page 622-627