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Synthesis and Antimicrobial Study of Pyrimidinone Substituted 4(3
Organic Chemistry: Current Research

Organic Chemistry: Current Research
Open Access

ISSN: 2161-0401

+44 1478 350008

Research Article - (2013) Volume 2, Issue 2

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Synthesis and Antimicrobial Study of Pyrimidinone Substituted 4(3H)- Quinazolinone Derivatives

Natvar A Sojitra1, Rajesh K Patel3, Ritu B Dixit2 and Bharat C Dixit1*
1Chemistry Department, V. P. & R. P. T. P. Science College, Affiliated to Sardar Patel University, Gujarat, India
2Ashok & Rita Patel Institute of Integrated Studies and Research in Biotechnology and Allied Sciences, Gujarat, India
3Department of Life Sciences, Hemchandracharya North Gujarat University, Gujarat, India
*Corresponding Author: Bharat C Dixit, Chemistry Department, V. P. & R. P. T. P. Science College, Affiliated to Sardar Patel University, VallabhVidyangar– 388 120, Anand, Gujarat, India Email:

Abstract

A series of structurally diverse and newly designed pyrimidinone substituted 4(3H)-Quinazolinone derivatives 6a–6j were synthesized in a simple and facile manner under both conventional and microwave heating conditions. Entitled compounds 6a–6j were synthesized using N-acylanthranilic acid derivatives 1a–1j and hydrazinylbenzenesulfonamide2 as a key starting materials, which under goes hierarchy of the reactions via different intermediate steps; quinazolinone derivatives 3a–3j and hydrazonoquinazolinone derivatives 5a–5j. All the synthesized compounds are in good amount of yield. The structure of entitle compounds have been evaluated on the basis of various spectroscopic techniques and analytical methods as well as, all the synthesized compounds were subjected to in vitro antibacterial activities. Some of the compounds displayed moderate to good in vitro antimicrobial activity by broth micro dilution method against pathogenic bacteria (S. aureus,B. subtilis, B. megaterium, E. coli, P. vulgaris, P. aeruginosa) species.

Keywords: Quinazolinone; Pyrimidinone; Antimicrobial activity; Microwave heating

Introduction

Heterocyclic scaffold has been under discovery due to their considerable therapeutic and medicinal importance. One of such heterocycles 2-pyrimidinone, while not naturally occurring, are receiving increased attention because of their wide-ranging biological activity like, an efficient inhibitor of DNA synthesis in E. coli, inhibitors of the enzyme cytidinedeaminase, and as metaphase inhibitors. Such pyrimidinone derivatives and the pharmaceutical acceptable salts thereof having remarkable antagonistic action against angiotensin II receptor, thereby, being useful in treating cardiovascular disease caused by binding angiotensin II to its receptor. Antitumor activity of pyrimidinones derivatives have shown statistically significant synergism with cyclophosphamide (CY) against antitumor/P388 leukemia etc. [1-7]. They have also shown anticancer [8,9], potent TF-FVIIa inhibitors [10] and inhibition of C5-cytosine DNA methyltransferases [11] activities.

In addition to that, quinazolinone and its derivatives comprise an important class of heterocyclic molecules due to their broad spectrum application in medicinal and pharmaceutical chemistry such as analgesic [12], antimicrobial and antitubercular [13,14], antitumor [15], anticancer [16], anti-inflammatory [17], anticonvulsant [18], antimalarial and antihistamine [19].

Moreover, there are many reports regarding synthesis of pyrimidinone derivatives [20,21] but no reports are available in which pyrimidinone is substituted at 3rd position of quinazolinone through hydrazono benzenesulfonamide linkage. Looking to the aforementioned literature and our ongoing research in the field of quinazolinone derivatization [22,23], we reports here synthesis of various pyrimidinone substituted quinazolinone derivatives linked through hydrazono benzenesulfonamide, of that some of the compounds showed good to moderate antimicrobial activity.

Experimental Section

Material and measurements

All the chemicals were purchased from Spectro chem. Ltd. (Mumbai, India) and were used without further purification. Solvents employed were distilled, purified and dried by standard procedures prior to use [24]. Melting points of the synthesized compounds were determined in open capillary tube method and are uncorrected. Reactions were monitored by thin-layer chromatography (TLC on alluminium plates coated with silica gel 60 F254, 0.25 mm thickness purchased from E. Merck Ltd., Mumbai-India). The mobile phase was chloroform and methanol (9:1), and detection of the components was done under UV light or explore in Iodine chamber. Infrared (IR) spectra were recorded as potassium bromide pellets using a Shimadzu 8501 Fourier transform infrared (FTIR) Spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker AVANCE II 400-MHz NMR spectrometer (Bruker Corporation, Billerica, MA, USA), with chemical shift in ppm downfield from TMS as an internal reference and DMSO-d6 used as solvent. Carbon, hydrogen and nitrogen elemental analysis were estimated by PerkinElmer 2400-II CHN elemental analyzer, USA. The electro-spray ionization mass spectra in positive mode were recorded on a Shimadzu LC-MS 2010 eV mass spectrophotometer using acetonitrile. All the microwave assisted reactions were carried out at atmospheric pressure using a multimode microwave reactor (Scientific Microwave Synthesis System, Model: Cata-R, Catalyst™ Systems, Pune-India) with attachment of glass vessel prolonged by a reflux condenser with constant stirring, whereby microwaves were generated by magnetron at a frequency of 2450 MHz having an output energy range of 140 to 700 Watts, and the temperature was monitored with an external flexible probe.

General procedure for the synthesis of 4-amino-N-(2- methyl/aryl-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide derivatives(3a-3j)

Compounds 3a–3j were prepared according to the reported method [22,23]. The possible synthetic route is given in Scheme 1.

organic-chemistry-pyrimidinone

Scheme 1: Proposed synthetic route for the preparation of pyrimidinone substituted 4(3H)-quinazolinone derivatives compound (6a-6j).

4-Amino-N-(2-methyl-4-oxoquinazolin-3(4H)-yl) benzenesulfonamide (3a)mp 217-218°C. ESI MS (m/z): 330.8 [M+H]+.

4-Amino-N-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl) benzenesulfonamide (3b)mp 187-189°C. ESI MS (m/z): 409.2, 411.3 [M]+.

4-Amino-N-(6,8-dibromo-2-methyl-4-oxoquinazolin-3(4H)-yl) benzenesulfonamide (3c) mp 212-214°C. ESI MS (m/z): 488.4, 490.4, 492.4 [M]+.

4-Amino-N-(6-nitro-4-oxo-2-phenylquinazolin-3(4H)-yl) benzenesulfonamide (3d)mp 206-209°C. ESI MS (m/z): 438.2 [M+H]+.

4-Amino-N- (4-oxo-2-phenylquinazol i n - 3 (4H) - yl) benzenesulfonamide (3e)mp 166-168°C. ESI MS (m/z): 393.4 [M+H]+.

4-Amino-N-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-yl) benzenesulfonamide (3f)mp 214-217°C. ESI MS (m/z): 471.3, 473.3 [M]+.

4-Amino-N-(6,8-dibromo-4-oxo-2-phenylquinazolin-3(4H)-yl) benzenesulfonamide (3g)mp 219-221°C. ESI MS (m/z): 548.3, 550.3, 552.3 [M]+.

4-Amino-N-[2-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl] benzenesulfonamide (3h)mp 175-179°C. ESI MS (m/z): 426.9, 428.9 [M]+.

4-Amino-N-[6-bromo-2-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl]benzene-sulfonamide (3i)mp 186-187°C. ESI MS (m/z): 503.8, 505.8, 507.8 [M]+.

4-Amino-N- [6, 8-dibromo-2-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl]benzene sulfonamide (3j)mp 183-184°C. ESI MS (m/z): 582.5, 584.5, 586.5, 588.5 [M]+.

General procedure for the diazotization of 4-amino-N-(2-methyl/aryl-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide derivatives(4a-4j)

The diazotized derivatives 4a-4j were prepared by following the reported method [23,25]. Schematic diagram to produce diazotized compounds 4a-4j are shown in Scheme 1. The reaction mass was cooled at 0-5°C for 1 hours and was directly used for the next step.

General procedure for the synthesis of hydrazono derivatives of compounds 4a-4j using acetyl acetone as an active methylene compound (5a-5j)

Hydrazonoquinazolinone compounds 5a-5j were prepared by following the reported method [23,26]. The synthetic route is shown in Scheme 1.

4-[N’-(1-Acetyl-2-oxo-propylidene)hydrazino]-N-(2-methyl-4-oxo-4H-quinazolin-3-yl)benzenesulfonamide (5a) m.p. 167–168°C, ESI MS (m/z): 442.2 [M+H]+.

4-[N’-(1-Acetyl-2-oxo-propylidene)hydrazino]-N-(6-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)benzenesulfonamide (5b) m.p. 145–1470C, ESI MS (m/z): 520.1, 522.3 [M]+.

4-[N’-(1-Acetyl-2-oxo-propylidene)hydrazino]-N-(6,8-dibromo-2-methyl-4-oxo-4H-quinazolin-3-yl)- benzenesulfonamide (5c) m.p. 172–174°C, ESI MS (m/z): 597.2, 599.1, 601.3 [M]+.

4-[N’-(1-Acetyl-2-oxopropylidene)hydrazino]-N-(2-methyl-6-nitro-4-oxo-4H-quinazolin-3-yl)benzenesulfonamide (5d) m.p. 189–190°C, ESI MS (m/z): 549.4 [M+H]+.

4-[N’-(1-Acetyl-2-oxo-propylidene)hydrazino]-N-(6-bromo-2-methyl-4-oxo-4H-quinazolin-[N’-(1-Acetyl-2-oxopropylidene)hydrazino]-N-(4-oxo-2-phenyl-4H-quinazolin-3-yl)benzenesulfonamide (5e) m.p. 164–166°C, ESI MS (m/z): 504.2 [M+H]+.

4-[N’-(1-Acetyl-2-oxopropylidene)hydrazino]-N-(6-bromo-4-oxo-2-phenyl-4H-quinazolin-3-yl)benzenesulfonamide (5f) m.p. 183–184°C, ESI MS (m/z): 582.3, 584.4 [M]+.

4-[N’-(1-Acetyl-2-oxo-propylidene)hydrazino]-N-(6,8-dibromo-4-oxo-2-phenyl-4H-quinazolin-3-yl)benzenesulfonamide (5g) m.p. 193–195°C, ESI MS (m/z): 660.0, 662.2, 663.9 [M]+.

4-[N’-(1-Acetyl-2-oxopropylidene)hydrazino]-N-[6-bromo-2-(4-chloro-phenyl)-4-oxo-4H-quinazolin-3-yl]benzenesulfonamide (5h) m.p. 178–180°C, ESI MS (m/z): 538.0, 539.8 [M]+.

4-[N’-(1-Acetyl-2-oxopropylidene)hydrazino]-N-[6-bromo-2-(4-chlorophenyl)-4-oxo-4H-quinazolin-3-yl]benzenesulfonamide (5i) m.p. 203–204°C, ESI MS (m/z): 616.2, 617.9, 620.0 [M]+.

4-[N’-(1-Acetyl-2-oxopropylidene)hydrazino]-N-[6,8-dibromo-2-(4-chlorophenyl)-4-oxo-4H-quinazolin-3-yl]benzenesulfonamide (5j) m.p. 214–215°C, ESI MS (m/z): 693.8, 695.7, 697.7, 699.9 [M]+.

Synthesis of pyrimidinone substituted quinazolinone derivatives 6a–6j

It was prepared using the appropriate hydazono compound 5a– 5j(0.01 mol) and urea (0.015) in 40 ml absolute ethanol using anhydrous sodium acetate as a catalyst (0.001 mol). The reaction mixture was heated under reflux for 5 hours. Completion of reaction was checked by TLC using 9:1 CHCl3:CH3OH solvent system. After cooling to room temperature the reaction mixture was poured into crushed ice and the mixtures was stirred for 1 hours. Separated product was collected by filtration, washed with water, dried and recrystallized from aqueous ethanol. The colors of the compounds were yellowish to dark orange and are soluble in polar organic solvents like methanol, ethanol and pyridine. The synthetic route is shown in Scheme 1. Yield was in the range of 55-68%.

General microwave assisted procedure for the synthesis of pyrimidinone substituted quinazolinone derivatives 6a–6j

Appropriate hydazono compound 5a–5j (0.01 mol), urea (0.015 mol), anhydrous sodium acetate (0.001 mol) and 2 ml ethanol were taken in a two-neck round bottomed flask fitted with a device condenser. The mixture was then heated under microwave irradiation at 350 W for 3-5 minutes. After cooling to room temperature the reaction mixture was poured into crushed ice and the mixtures was stirred for 30 minutes. Separated product was collected by filtration, washed with water, dried and recrystallized from aqueous ethanol. The colors of the compounds were yellowish to dark orange and are soluble in polar organic solvents like methanol, ethanol and pyridine. Yield was in the range of 71-83%.

4-[N’-(4,6-Dimethyl-2-oxo-2H-pyrimidin-5-ylidene) hydrazino] -N- (2-methyl -4-oxo-4H-quinazol in-3-yl) benzenesulfonamide (6a)

Off white solid (Yield 76%).Mp: 145-147°C. IR (KBr): 3108 (C-HAr), 1694 (C=O), 1600 (C=N), 1339, 1156 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H, SO2NH), 8.70 (s, 1H, -NH-), 7.79 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.71 (td, J = 13.16, 1.52 Hz, 1H, Ar- H), 7.49 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 7.37 (td, J = 7.17, 1.40 Hz, 1H, Ar-H), 7.25 (dd, J = 8.64, 2.63 Hz, 2H, Ar-H), 6.44 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.43 (s, 3H, CH3), 2.18 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 172.36, 158.76, 158.10, 157.37, 155.10, 146.51, 142.63, 134.45, 130.25, 130.10, 127.17, 126.81, 123.70, 121.03, 113.06, 24.8, 23.12.MS m/z: 466.40 (M+). Anal.Calcd for C21H19N7O4S: C-54.19, H-4.11, N-21.06, S-6.89. Found: C-54.35, H-4.22, N-20.98, S-5.70.

N-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonamide (6b)

Pale yellow (Yield 83%).Mp: 237-238 °C. IR (KBr): 3104 (C-HAr), 1697 (C=O), 1602 (C=N), 1336, 1154 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H, SO2NH), 8.77 (s, 1H, -NH-), 7.79 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.71 (td, J = 13.16, 1.52 Hz, 1H, Ar-H), 7.49 (dd, J = 7.88, 1.41 Hz, 2H, Ar-H), 7.64 (td, J = 7.17, 1.40 Hz, 1H, Ar- H), 6.67 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.20 (s, 3H, CH3), 2.54 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 171.46, 159.15, 158.62, 158.11, 152.56, 148.82, 142.34, 137.18, 131.34, 127.56, 126.21, 125.78, 123.83, 122.29, 115.11, 24.7, 23.08. MS m/z: 545.1 (M+). Anal.Calcd for C21H18BrN7O4S: C-46.33, H-3.33, N-18.01, S-5.89. Found: C-46.10, H-3.47, N-17.88, S-5.62.

N-(6,8-Dibromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-4-[N’-(4,6-dimethyl-2-oxo-2H-pyrimidin-5-ylidene)hydrazino] benzenesulfonamide (6c)

Dark yellow (Yield 79%).Mp: 180-182°C. IR (KBr): 3102 (C-HAr), 1691 (C=O), 1598 (C=N), 1340, 1156 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H, SO2NH), 8.83 (s, 1H, -NH-), 8.32 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 8.01 (td, J = 13.16, 1.52 Hz, 1H, Ar-H), 7.29 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 7.37 (td, J = 7.17, 1.40 Hz, 1H, Ar- H), 6.78 (dd, J = 8.64, 2.63 Hz, 2H, Ar-H), 2.48 (s, 3H, CH3), 2.19 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 172.55, 162.17, 159.45, 157.76, 152.57, 151.62, 143.67, 138.32, 133.67, 131.29, 127.42, 125.10, 119.21, 113.87, 112.13, 24.04, 22.88. MS m/z: 623 (M+). Anal.Calcd for C21H17Br2N7O4S: C-40.47, H-2.75, N-15.73, S-5.14. Found: C-40.29, H-2.54, N-15.88, S-5.25.

4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl)-N-(2-methyl-6-nitro-4-oxoquinazolin-3(4H)-yl) benzenesulfonamide (6d)

Bright yellow (Yield 75%).Mp: 194-195°C. IR (KBr): 3110 (C-HAr), 1690 (C=O), 1594 (C=N), 1335, 1154 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H, SO2NH), 8.78 (s, 1H, -NH-), 8.67 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.83 (td, J = 13.16, 1.52 Hz, 1H, Ar-H), 7.49 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 7.37 (td, J = 7.17, 1.40 Hz, 1H, Ar- H), 7.42 (dd, J = 8.64, 2.63 Hz, 1H, Ar-H), 6.87 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.48 (s, 3H, CH3), 2.23 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 171.32, 159.11, 159.11, 158.93, 156.43, 154.88, 152.21, 144.67, 141.21, 132.65, 130.21, 127.43, 125.76, 123.47, 121.51, 113.11, 24.10, 22.83. MS m/z: 511 (M+). Anal.Calcd for C21H18N8O6S: C-49.41, H-3.55, N-21.95, S-6.28. Found: C-49.22, H-3.31, N-22.09, S-6.47.

4-[N’-(4,6-Dimethyl-2-oxo-2H-pyrimidin-5-ylidene)hydrazino]-N-(4-oxo-2-phenyl-4H-quinazolin-3-yl) benzenesulfonamide (6e)

Cream solid (Yield 72%).Mp: 177-179°C. IR (KBr): 3103 (C-HAr), 1689 (C=O), 1601 (C=N), 1337, 1153 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H, SO2NH), 8.34 (s, 1H, -NH-), 7.75 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.45 (m, 4H, Ar-H), 7.38 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 7.37 (m, 5H, Ar-H), 7.17 (dd, J = 8.64, 2.63 Hz, 1H, Ar- H), 6.31 (dd, J = 10.68, 2.14 Hz, 1H, Ar-H), 2.09 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 169.12, 161.57, 157.87, 153.38, 152.39, 149.24, 139.22, 137.22, 132.45, 131.45, 130.27, 129.71, 127.21, 126.77, 126.02, 125.66, 123.42, 122.21, 115.18, 23.12. MS m/z: 528 (M+). Anal.Calcd for C26H21N7O4S: C-59.19, H-4.01, N-18.59, S-6.08. Found: C-58.87, H-4.26, N-18.43, S-6.17.

N-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-yl)-4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonamide (6f)

Light yellow (Yield 80%). Mp: 192-193°C. IR (KBr): 3112 (C-HAr), 1698 (C=O), 1605 (C=N), 1332, 1152 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H, SO2NH), 8.37 (s, 1H, -NH-), 7.71 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.39 (m, 4H, Ar-H), 7.31 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 7.15 (m, 4H, Ar-H), 6.69 (dd, J = 8.64, 2.63 Hz, 1H, Ar- H), 6.44 (dd, J = 10.68, 2.14 Hz, 1H, Ar-H), 2.11 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 171.45, 163.54, 157.76, 155.53, 153.83, 148.33, 143.71, 139.46, 135.17, 132.56, 131.65, 130.45, 129.67, 129.14, 125.76, 124.32, 123.88, 117.78, 113.95, 23.07. MS m/z: 607 (M+). Anal.Calcd for C26H20BrN7O4S: C-51.49, H-3.32, N-16.17, S-5.29. Found: C-51.31, H-3.07, N-16.41, S-5.35.

N-(6,8-dibromo-4-oxo-2-phenylquinazolin-3(4H)-yl)-4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonamide (6g)

Brownish yellow (Yield 77%).Mp: 209-211°C. IR (KBr): 3105 (C-HAr), 1694 (C=O), 1595 (C=N), 1334, 1151 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H, SO2NH), 8.30 (s, 1H, -NH-), 7.63 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.57 (m, 3H, Ar-H), 7.34 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 6.99 (m, 3H, Ar-H), 6.54 (dd, J = 8.64, 2.63 Hz, 1H, Ar-H), 6.36 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.21 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 173.42, 162.74, 160.47, 158.87, 153.78, 152.32, 143.12, 137.32, 134.01, 132.65, 131.48, 130.37, 127.47, 129.54, 125.51, 124.91, 118.56, 115.11, 110.23, 23.05. MS m/z: 686 (M+). Anal. Calcd for C26H19Br2N7O4S: C-45.57, H-2.79, N-14.31, S-4.68. Found: C-45.35, H-2.96, N-14.18, S-4.77.

N-(2-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonamide (6h)

Creamy white solid (Yield 71%).Mp: 215-217°C. IR (KBr): 3113 (C-HAr), 1688 (C=O), 1603 (C=N), 1329, 1158 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H, SO2NH), 8.25 (s, 1H, -NH-), 7.81 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.45 (m, 3H, Ar-H), 7.37 (dd, J = 7.88, 1.41 Hz, 1H, Ar-H), 7.22 (d, J = 7.88 Hz, 2H, Ar-H), 6.82 (d, J = 7.88 Hz, 2H, Ar-H), 6.70 (dd, J = 8.64, 2.63 Hz, 1H, Ar-H), 6.38 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.17 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 173.32, 164.58, 155.11, 153.65, 152.85, 149.75, 144.65, 137.83, 136.27, 132.17, 130.55, 129.41, 126.81, 126.61, 126.17, 126.02, 125.24, 122.66, 113.76, 23.19. MS m/z: 563 (M+). Anal.Calcd for C26H20ClN7O4S: C-55.57, H-3.59, N-17.45, S-5.71. Found C-55.29, H-3.68, N-17.27, S-5.53.

N-(6-bromo-2-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonamide (6i)

Pale yellow (Yield 79%).Mp: 188-190°C. IR (KBr): 3104 (C-HAr), 1698 (C=O), 1606 (C=N), 1337, 1155 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H, SO2NH), 8.31 (s, 1H, -NH-), 7.83 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.49 (m, 3H, Ar-H), 7.38 (d, J = 7.88 Hz, 1H, Ar-H), 7.26 (d, J = 7.88 Hz, 2H, Ar-H), 6.85 (d, J = 7.88 Hz, 1H, Ar-H), 6.72 (dd, J = 8.64, 2.63 Hz, 1H, Ar-H), 6.41 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.18 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 172.67, 161.32, 159.11, 155.41, 152.35, 147.63, 142.14, 137.51, 136.71, 135.57, 134.17, 132.43, 130.64, 129.56, 126.33, 125.81, 123.09, 114.12, 113.59, 23.22. MS m/z: 641 (M+). Anal.Calcd for C26H19BrClN7O4S: C-48.73, H-2.99, N-15.30, S-5.00. Found: C-48.56, H-2.73, N-15.42, S-5.17.

N-(6,8-dibromo-2-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-4-(2-(4,6-dimethyl-2-oxopyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonamide (6j)

Yellowish orange (Yield 81%).Mp: 224-225°C. IR (KBr): 3110 (C-HAr), 1699 (C=O), 1603 (C=N), 1338, 1154 (S=O) cm-1. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H, SO2NH), 8.27 (s, 1H, -NH-), 7.82 (dd, J = 7.71, 1.56 Hz, 1H, Ar-H), 7.52 (m, 3H, Ar-H), 7.39 (d, J = 7.88 Hz, 1H, Ar-H), 7.24 (d, J = 7.88 Hz, 2H, Ar-H), 6.86 (d, J = 7.88 Hz, 1H, Ar-H), 6.36 (dd, J = 10.68, 2.14 Hz, 2H, Ar-H), 2.21 (s, 6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 171.78, 162.84, 160.78, 157.72, 154.35, 152.51, 143.56, 137.78, 136.32, 132.21, 133.17, 132.45, 131.42, 130.77, 128.21, 124.43, 117.69, 116.21, 110.18, 23.12. MS m/z: 720 (M+). Anal. Calcd for C26H18Br2ClN7O4S: C-43.38, H-2.52, N-13.62, S-4.45. Found: C-43.22, H-2.71, N-13.48, S-4.60.

In vitro antimicrobial studies

All the synthesized compounds were screened for their in vitro antimicrobial activities against selected pathogenic bacterial strains to determine minimum inhibitory concentrations (MIC) by broth micro dilution method [27] using Sulfanilamide as reference drugs of parent moieties, while Streptomycin was employed as a standard antibacterial drug.

The in vitro antimicrobial activities of all the synthesized compounds were screened for their antibacterial against Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium (Gram Positive) and Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa (Gram Negative), using the broth dilution method [27]. All the ATCC culture was collected from institute of microbial technology, Bangalore. 2% Luria broth solution was prepared in distilled water while, pH of the solution was adjusted to 7.4 ± 0.2 at room temperature and sterilized by autoclaving at 15 lb pressure for 25 min. The tested bacterial and fungal strains were prepared in the luria broth and incubated at 37°C and 200 rpm in an orbital incubator for overnight. Sample solutions were prepared in DMSO for various concentration. The standard drug solution of Streptomycin (antibacterial drug) was prepared in DMSO. Serial broth micro dilution was adopted as a reference method. 10 μL solution of test compound was inoculated in 5 mL luria broth for each concentration respectively and additionally one test tubes was kept as control. Each of the test tubes was inoculated with a suspension of standard microorganism to be tested and incubated at 35°C for 24 h. At the end of the incubation period, the tubes were examined for the turbidity. Turbidity in the test tubes indicated that microorganism growth has not inhibited by the antibiotic contained in the medium at the test concentration. The antimicrobial activity tests were performed in triplicate and the deviation for any triplicate results was not more than ± 1% to 5% while average MIC values of the compounds are represented in Table 1.

Compound Minimum Inhibition Concentration in µg/mL
Gram positive bacteria Gram negative bacteria
B. megaterium S. aureus B. subtilis E. coli P. vulgaris P. aeruginosa
6a 300 200 300 225 200 250
6b 375 350 350 300 225 350
6c 400 395 400 250 300 420
6d 375 400 350 300 275 350
6e 225 200 225 175 200 225
6f 300 300 275 225 225 225
6g 250 200 225 225 250 200
6h 175 125 150 50 50 75
6i 200 175 200 75 50 150
6j 200 150 100 100 75 100
Sf* 425 375 400 375 400 425
Sm* 20 20 20 20 20 20

*Sf= Sulfanilamide, Sm = Streptomycin

Table 1: Antimicrobial activities of the synthesized compounds 6a-6j.

Results and Discussion

The intention of the present study was to synthesize and investigate the antimicrobial activities of pyrimidinone ring substituted at 3rd position of quinazolinone derivatives (6a-6j) through hydrazono benzenesulfonamide linkage in a single molecular frame work. Synthetic rout of the target molecules is outlined in the Scheme 1 under both conventional and microwave heating condition. When cyclization for the formation of pyrimidinone derivatives was performed under microwave irradiation, the reaction was taken place in 3 minutes in an improved yield.

All the synthesized compounds were characterized by their physical, analytical and spectral properties. The IR, ESI-MS and NMR (1H and 13C) spectral data of all the synthesized compounds were in good agreement with the structure assigned. Further, in the MS-ESI with positive mode spectra exhibited molecular ion peak ([M+H]+), appeared at different intensities, confirmed the exact mass or molecular weights of the examined compounds 6a-6j, while appearance of a characteristic two isotope peak ([(M+H)+2]+) along with molecular ion peak ([M+H]+) in an intense ratio almost 3:1 or 1:1 to the molecular ion peak confirmed the presence of halogen (Cl or Br) atoms of high abundance nature. The IR spectrum of 6a-6j showed the presence of C-O group at ~1690 cm-1 due to -CONH and -COCH3 groups. Two sharp bands at ~1340 and ~1160 cm-1 were due to asymmetric and symmetric stretching vibrations of SO2 group respectively. The 1H NMR of entitled compounds 6a-6j showed singlet around δ ~10.50 ppm due to highly deshielded proton of -NHSO2 group. One singlet was observed about δ ~8.77 ppm due to secondary amine group. The two more singlet appeared in the aliphatic region at δ 2.43 and 2.18 ppm due to -CH3(second position of the quinazolinone ring) and -CH3 (two methyl group of pyrimidinone ring) protons. All the eight aromatic protons resonated in the region of δ7.79 to 6.44 ppm. The 13C NMR of final compounds 6a-6j showed two signals of carbonyls carbon around δ ~170 (CO of pyrimidinone ring), ~160 (CO of quinazolinone ring). The aromatic carbons appeared between δ 113-158 ppm. The signals due to aliphatic carbons appeared about ~24 and ~22.5 due to presence of two different methyl groups in quinazolinone ring and pyrimidinone ring.

In vitro antimicrobial activities

Inspection of the data of Table 1, on the preliminary in vitro antimicrobial evaluations of the entitled compounds 6a-6j revealed that all the screened compounds have a varied degree of antibacterial activity, evident from their MIC values in μg/mL. Among the screened compounds, most of the compounds have shown more or equal antimicrobial activities compare to the reference drug Sulfanilamide (Sf), while a very few of the screened compounds found to be equipotent to the standard drugs, Streptomycin (Sm). From the results of in vitro antibacterial activity data, it was observed that compounds 6e, 6h, 6i and 6j demonstrated excellent activity against E. coli and P. vulgaris bacterial species. In general, compounds showed more selectivity against Gram negative over Gram positive species amongst all the bacterial strains. All the compounds were screened for their in vitro antimicrobial activities and results revealed that the group 4-chlorophenyl substitution at the 2nd position in quinazolin-4(3H)- one nucleus led to increase their biological activities.

Conclusion

In summary, a series of new pyrimidinone substituted Quinazolin- 4(3H)-one derivatives have been synthesized by adapting a simple and facile manner using both conventional and microwave heating condition in a good amount of yields. All the compounds were screened for their in vitro antimicrobial activity and results revealed that compounds 6e, 6h, 6i and 6j demonstrated excellent activity against E. coli and P. vulgarisbacterial species.

Acknowledgements

We are thankful to the Principal, V. P. & R. P. T. P. Science College, VallabhVidyanagar for providing necessary research facilities. We are also grateful to SICART, VallabhVidyanagar for FT-IR and Mass analysis; CDRI, Lucknow for NMR analyses.

References

  1. Li LH, Wallace TL, Wierenga W, Skulnick HI, DeKoning TF (1987) Antitumor activity of pyrimidinones, a class of small-molecule biological response modifiers. J Biol Response Mod 6: 44-55.
  2. Li LH, Wallace TL, Hamilton RD, DeKoning TF (1987) Pharmacological evaluation of combination therapy of P388 leukemia with cyclophosphamide and pyrimidinones. Int J Immunopharmacol 9: 31-39.
  3. Eggermont AM, Marquet RL, De Bruin RW, Weimar W, Jeekel J (1986) Site-specific antitumour effects of 2-pyrimidinone compounds in rats. Br J Cancer 54: 337-339.
  4. Li LH, Johnson MA, Moeller RB, Wallace TL (1984) Chemoimmunotherapy of B 16 melanoma and P388 leukemia with cyclophosphamide and pyrimidinones. Cancer Res 44: 2841-2847.
  5. Li LH, Wallace TL, Richard KA, Tracey DE (1985) Mechanism of antitumor action of pyrimidinones in the treatment of B16 melanoma and P388 leukemia. Cancer Res 45: 532-538.
  6. Driscoll JS, Marquez VE, Plowman J, Liu PS, Kelley JA, et al. (1991) Antitumor properties of 2(1H)-pyrimidinoneriboside (zebularine) and its fluorinated analogues. J Med Chem 34: 3280-3284.
  7. Li LH, DeKoning TF, Nicholas JA, Kramer GD, Wilson D, et al. (1987) Effect of mouse hepatitis virus infection on combination therapy of P388 leukemia with cyclophosphamide and pyrimidinones. Lab Anim Sci 37: 41-44.
  8. Rashad AE, Shamroukh AH, Yousif NM, Salama MA, Ali HS, et al. (2012) New pyrimidinone and fused pyrimidinone derivatives as potential anticancer chemotherapeutics. Archiv der Pharmazie 345: 729-738.
  9. Holla BS, Rao BS, Sarojini BK, Akberali PM (2004) One pot synthesis of thiazolodihydropyrimidinones and evaluation of their anticancer activity. Eur J Med Chem 9: 777-783.
  10. Zhang X, Glunz PW, Jiang W, Schmitt A, Newman M, et al. (2013) Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors. Bioorg Med Chem Lett 23: 1604-1607.
  11. Paul JH, Alan JW, Geoffrey SB, Sharon MK, Jonathan PW, et al. (1999) Mechanism-based inhibition of C5-cytosine DNA methyltransferases by 2-H pyrimidinone. J Mol Bio 286: 389-401.
  12. Aly MM, Mohamed YA, El-Bayouki KA, Basyouni WM, Abbas SY (2010) Synthesis of some new 4(3H)- quinazolinone-2-carboxaldehyde thiosemicarbazones and their metal complexes and a study on their anticonvulsant, analgesic, cytotoxic and antimicrobial activities - part-1. Eur J Med Chem 45: 3365-3373.
  13. Kidwai M, Saxena S, Khan MKR, Thukral SS (2005) Synthesis of 4-aryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2-one/thione-5-one derivatives and evaluation as antibacterials. Eur J Med Chem 40: 816-819.
  14. Dahiya R, Kumar A (2008) Synthesis and biological activity of peptide derivatives of iodoquinazolinones/nitroimidazoles. Molecules 13: 958-976.
  15. El-Azab AS, Al-Omar MA, Sayed-Ahmed MM, Abdel-Hamide SG (2010) Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: molecular docking study. Eur J Med Chem 45: 4188-4198.
  16. Giri RS, Thaker HM, Giordano T, Chen B, Vasu KK (2010) Synthesis and evaluation of quinazolinone derivatives as inhibitors of NF-kappaB, AP-1 mediated transcription and eIF-4E mediated translational activation: inhibitors of multi-pathways involve in cancer. Eur J Med Chem 45: 3558-3563.
  17. Kumar A, Rajput CS (2009) Synthesis and anti-inflammatory activity of newer quinazolin-4-one derivatives. Eur J Med Chem 44: 83-90.
  18. Kashaw SK, Kashaw V, Mishra P, Jain NK, Stables JP (2009) Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea. Eur J Med Chem 44: 4335-4343.
  19. Ghorab MM, Gawad SMA, El-Gaby MS (2000) Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents. Farmaco 55: 249-255.
  20. Mei H, Chun C (2009) Three-component one-pot synthesis of pyrimidinone derivatives in fluorous media: Ytterbium bis(perfluorooctanesulfonyl)imide complex catalyzed Biginelli-type reaction. J Het Chem 46: 1430-1432.
  21. Hossan ASM, Abu-Melha HMA, Al-Omar MA, Amr AEGE (2012) Synthesis and antimicrobial activity of some new pyrimidinone and oxazinone derivatives fused with thiophene rings using 2-chloro-6-ethoxy-4-acetylpyridine as starting material. Molecules 17: 13642-13655.
  22. Jagani CL, Sojitra NA, Vanparia SF, Patel TS, Dixit RB, et al. (2011) A comparative study of solution phase as well as solvent free microwave assisted syntheses of 3-benzothiazole/isoxazole substituted 2-styryl-4(3H)-quinazolinones.ARKIVOC ix: 281-294.
  23. Sojitra NA, Dixit RB, Patel RK, Patel JP, Dixit BC (2012) Classical and microwave assisted synthesis of new-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylazo)-N-(2-substituted-4-oxo-4H-quinazolin-3-yl)benzenesulfonamide derivatives and their antimicrobial activities. J Saudi Chem Soc.
  24. Vogel AI (2004) A Textbook of Practical Organic Chemistry.(5thedn) Singapore.
  25. Dixit BC, Patel HM, Dixit RB, Desai DJ (2010) Synthesis, characterization and dyeing assessment of novel acid azo dyes and mordent acid azo dyes based on 2- hydroxy-4- methoxybenzophenone on wool and silk fabrics. J Serb ChemSoc 75: 605-614.
  26. Singh SP, Parmar SS, Raman K, Stenberg VI (1981) Chemistry and biological activity of thiazolidinones. Chem Rev 81: 175-203.
  27. Jani DH, Patel HS, Keharia H, Modi CH (2010) Novel drug-based Fe(III) heterochelates: synthetic, spectroscopic, thermal and in-vitro antibacterial significance Applorganometalchem 24: 99-111.
Citation: Sojitra NA, Patel RK, Dixit RB, Dixit BC (2013) Synthesis and Antimicrobial Study of Pyrimidinone Substituted 4(3H)-Quinazolinone Derivatives. Organic Chem Curr Res 2: 118.

Copyright: ©2013 Sojitra NA, 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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