synthesis, molecular modelling and biological evaluation of 4-amino-2(1h)-quinazolinone and...

Full Paper

Synthesis, Molecular Modelling and Biological Evaluation of4-Amino-2(1H)-quinazolinone and 2,4(1H,3H)-QuinazolidoneDerivatives as Antitumor Agents

Stephanie Richter and Barbara Gioffreda

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Heinrich Heine University, Dusseldorf,Germany

A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)-quinazolinones and -2,4(1H,3H)-

quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the

NCI-60 cancer cell lines.

Keywords: 4-Amino-2(1H)-quinazolinone / Antitumor activity / 2,4(1H,3H)-Quinazolidone

Received: October 18, 2010; Revised: December 1, 2010; Accepted: December 14, 2010

DOI 10.1002/ardp.201000312

Introduction

Cancer poses a serious human health problem despite much

progress in understanding its biology and pharmacology.

Consequently, the design of new lead structures of antitumor

agents is one of the most urgent research areas in contem-

porary medicinal chemistry. Among the wide range of

pharmacologically active heterocycles some have attracted

great attention as potential chemotherapeutic agents [1–3].

In the last years anticancer drug strategies involve molecular

targets which are crucial for tumorigenesis. Targets like EGF

receptor tyrosine kinase (EGFR), the protein kinases like CK2

or the chaperone HSP90 have moved into the circle of inter-

est. All these targets are involved in maturation and activity

of a diverse group of proteins involved in signal transduction,

cell cycle regulation and apoptosis. All of them show over-

expression in a variety of cancer cell lines. These protein

targets have all a weak ATPase activity and it could be shown,

that blocking of the ATPase activity leads to apoptosis and cell

death [4–6]. Known cytotoxic compounds (see Scheme 1) like

radicicol 6 (HSP90) [4], quercetine 5 (EGRF) [5] or emodine 1

(CK2) [6] bind to ATP/ADP domains of the protein, so the

synthesis of novel heterocyclic compounds, which underlie

ATP mimicry, seem to be a successful way to find antitumoric

lead compounds.

Looking on structures which were synthesized to bind in

the ATP/ADP-binding site, a broad amount of heterocyclic

compounds was found. Starting from anthraquinones like

emodine 1, indoles like IQA 2 or halogenated benzoimida-

zoles like DMAT 3 as inhibitors of CK2 [6, 7], over flavones like

quercetin 4 and its derivatives as inhibitors of EGRF [5] to

purines 7 [8], pyrazoles and phenolic [8, 9] structures (6 and 8)

as inhibitors of HSP90 were found. They all show ATPase

inhibiting activity at micromolar range and cell growth

arrest with IC50 values up to micromolar range [4–9].

Motivated by the above mentioned findings, the aim of our

study was to find novel lead structures with cytostatic activi-

ties, which may underlie ATP/ADP mimicry. In a thought

experiment we substituted the adenine ring system of ATP

by the pyrimidine base cytosine and enlarged it to the 4-

amino-2(1H)-quinazolinone ring system. Comparison of the

known structures which underlie ADP/ATP mimicry show

that most of them combine the heterocyclic ring system over

a linking structure with an aromatic system. So we combined

the quinazoline system over different linkers with an aromatic

ring system to get the described quinazoline derivatives (see

Scheme 2). As variation of the heterocyclic ring system some

analogous quinazolinedione derivatives were synthesized

too. The in-vitro antitumor activity of the newly synthesized

compounds was evaluated on the NCI-60 cell line.

Results and discussion

Chemistry

Synthesis of intermediate and target compounds was per-

formed according to the reactions outlined in Schemes 3

Correspondence: Dr. Barbara Gioffreda, Department of PharmaceuticalChemistry, Faculty of Pharmacy, Heinrich Heine University, Dusseldorf,Germany.E-mail: [email protected]: þ49-211-8113847

810 Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820

� 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

O

O

CH3

OH OH

OH

NNH

ONH

N

BrBr

BrBr

R

OH

OH

O

OHOH

O

OOH

OHOH

NN

NN

NH2

F

OMe

MeOCH

ClOH

OH N NH

N O

N

N

OH OHN

NH2

OPO

OPO

OPO

OOOO

OH

ClOH

OO

O

O H

CH3

Emodine 1 IQA 2 DMAT 3

CK2-inhibitors

EGFR-inhibitors

Butein 4 Quercetine 5

Hsp90-inhibitors

ATP

PU derivative 7 Dihydroxyphenylpyrazole 8Radicicol 6

Scheme 1. Known anticancer compounds with ATPase inhibiting activity.

NH

N

NH2

O NH

N

NH2

O NH

N

NH2

O

X

RScheme 2. Development of the novel scaffold4-amino-2(1H)-quinazolinone.

Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820 Aminoquinazolinones and Quinazolidones as Antitumor Agents 811

� 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com

and 4. The 6-benzoyl-derivates were synthesized by Friedel-

Crafts-acylation starting from commercially available 4-nitro-

benzoylchloride 10 to obtain the (4-nitrophenyl)arylmetha-

nones 11a–e [11, 12]. After reduction of the nitro group with

the help of iron(II) and elemental zinc [14], iodine was

inserted by treating the resulting amine 12a–e with iodine

monochloride in acetic acid for 30 min to obtain (4-amino-3-

iodophenyl)arylmethanone 13a–e [18]. The iodine was

replaced by a nitril group by heating 13a–e in the presence

of copper(I)cyanide in DMF for 3 h [19]. Cyclocondensation of

the resulting 2-amino-5-benzoylbenzonitrile derivatives 14a–

e with chlorosulfonyl isocyanate and subsequent hydrolysa-

tion in alkaline solution leads to the desired 6-benzoyl-4-

amino-2(1H)-quinazolinone derivatives 17a–e [20].

The classes 20–22 were synthesized from 2-amino-5-iodo-

benzonitrile 18 by cyclisation with chlorosulfonyl isocyanate

to get 19. On the basis of [20a,b] the iodine compound 18 was

coupled to different thiols to achieve the desired thioethers

20. They were hydrolyzed to quinazolinediones 21a–d by

refluxing the compounds in concentrated potassium hydrox-

ide for 4 h and oxidized to sulfones 22a–g using potassium

permanganate in acetic acid [20c]. For coupling the thiols

with 19 copper(I)iodide is used as a catalyst, which complexes

the desired quinazolinones. Although the copper is removed

with ethylene diamine as a ligand, the elemental analysis

differs by more than 0.4% from the calculated data. A

HPLC method was developed to confirm the purity of the

compounds by values more than 95% AUC.

O

NH

N

NH

SO2Cl

O

R1

R2

R1

R2

O

NO2

R1

R2

O

NH2

R1

R2

O

NH2

IR1

R2

O

NH2

CNR1

R2

O

NH

NH

NH

O

R1

R2

O

NH

NH2

R1

R2

AlCl3, ClCH2CH2Cl,RT, over night

+

ICl, AcOH,30°C, 30 min

CuCN, DMF,rf, 3 h

OCNSO2Cl,CH2Cl2,

RT, 3 h

H2O, EtOH, RT, 60 min

FeSO4, NH4Cl,Zn, EtOH, H2O,

50°C, 2 h

9 a-e 10 11 a-e

12 a-e 13 a-e

14 a-e 15 a-e

16 a-e 17 a-e

O

NO2

Cl

O

Scheme 3. Synthesis of compounds 17a–e (a: R1 ¼ R2 ¼ H; b: R1 ¼ H, R2 ¼ OCH3; c: R1 ¼ R2 ¼ OCH3; d: R1 ¼ R2 ¼ CH3;e: R1 ¼ H, R2 ¼ Cl).

812 S. Richter and B. Gioffreda Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820


In structures of type 16 two isomeric forms 16 and 17 are

thinkable. The infrared spectrum (KBr) of 16a shows a band

at about 1621 cm�1, which indicates a C––N–bonding. At

1680 cm�1 a shoulder indicates the CO stretching of

the cyclic urea derivative. The CO stretching mode at

1650 cm�1 is typical for a diaryl ketone. The region between

3100 and 3400 cm�1 shows no clear signals, so no statement

about the existence of the imino nor of the amino group can

be made. Further, the 1H-NMR spectrum (DMSO-d6) of the

compound shows three separated signals for NH, two of them

coalescing. This might be affected by H-bonds between two

molecules, so that the two protons of the amino group are no

longer equivalent. The authors assume that the compounds

exist in the tautomeric form 17 in the solid state and as well

in solution in polar liquids like DMSO. In compounds 21a–d

and 22f and g the band at 1620 cm�1 has disappeared and a

new band around 1730 cm�1 from the imide can be detected.

All the other analytical data indicate the given compounds

(see Table 1).

Bioactivity

Out of the compounds derivatives 17a–c, 17e, 20b–3, 21b–d,

22a–c and 22g were selected by the National Cancer Institute

(NCI) in-vitro disease-oriented human cells screening panel

assay to be evaluated for their in-vitro antitumor activity.

The effective one-dose assay has been added to the NCI 60

No. Ar

20a C6H5

b 4-(CH3)C6H4

c 4-(OCH3)C6H4

d 4-ClC6H4 No. Ar X

e 4-FC6H4 22a 4-(CH3)C6H4 NH

f 4-(CH(CH3)2)C6H4 b 4-(OCH3)C6H4 NH

g 2-C10H7 c 4-ClC6H4 NH

21a C6H5 d 2-C10H7 NH

b 4-(CH3)C6H4 e 4-(CH(CH3)2)C6H4 NH

c 4-ClC6H4 f 4-ClC6H4 O

d 4-FC6H4 g 4-(CH3)C6H4 O

1): OCNSO2Cl, CH2Cl2, rt. 3 h; 2): K2CO3, CuI, DMF, H2NC2H4NH2, argon, 120°C, 16 h; 3): KOH, rt, 6 h; 4):

KMnO4, HOAc, rt, 1 h

CN

NH2

I

NH

N

NH2

O

I

NH

N

NH2

O

SAr

NH

NH

O

O

SAr

NH

NH

X

O

SAr

O O

X = NH, O

i ii

iii iv

iv

18 0291

21 22

Scheme 4. Synthesis of the classes 20–22.



cell screen in order to increase the compound throughput

and reduce data turnaround time to suppliers while main-

taining efficient identification of active compounds [21–23].

In this protocol, all compounds submitted to the NCI 60 cell

screen are tested initially at a single high dose (10 mM) in the

full NCI 60 cell panel including leukemia, non-small lung,

colon, CNS, melanoma, ovarian, renal, prostate and breast

cancer cell lines. Only compounds which satisfy pre-determi-

nate would progress to five-dose screen. The threshold inhi-

bition criteria for progression to the five dose screen were

designed to efficiently capture compounds with antiprolifer-

ative activity and are based on careful analysis of historical

Development Therapeutic Program (DTP) screening data. The

data are reported as a mean graph of the percent growth of

the treated cells, and presented as percentage growth inhi-

bition (GI%) caused by the test compounds (see Table 2).

The obtained data revealed that some of the tested subpanel

tumor cell lines exhibited variable sensitivity profiles against

most of the tested compounds. Among these, the leukemia SR

cell line shows moderate sensitivity against compounds 17c,

17e, 20b, 20d, 22c and 22g with GI range between 14.1 to

22.7%. Furthermore, the growth of the non-small cell lung

cancer NCI-H55 cell line was moderately affected by com-

pounds 17e, 20b, 20e, 21b–d, 22a and 22g, whereas com-

pounds 20c and 22g were most active on the A549/ATCC

cell line of the same panel (GI value of 19.7 and 19.3% respect-

ively). The CNS cancer SNB-75 cell line showed moderate

sensitivity against compounds 17b, 20b, 20e, 21c, 22b and 22g.

Table 1. Analytical data of compound classes 17, 20–22.

No. Ar X Yield (%) mp (8C) IR shift

XAr

NH

N

NH2

O

17a C6H5 CO 23 >350 1698, 1650, 1621b 4-(OCH3)C6H4 CO 31 303–306 1684, 1652, 1620c 3,4-(OCH3)2C6H3 CO 25 310–313 1623d 3,4-(CH3)2C6H3 CO 44 337–340 1677, 1639, 1623e 4-ClC6H4 CO 33 >350 1698, 1646, 162220a C6H5 S 17 >350 1671, 1631b 4-(CH3)C6H4 S 21 352 1680,1627c 4-(OCH3)C6H4 S 9 334–337 1668, 1628d 4-ClC6H4 S 13 >350 1673, 1627e 4-FC6H4 S 22 >350 1671,1630f 4-(CH(CH3)2)C6H4 S 18 >350 1671, 1630g 2-C10H7 S 23 >350 1667, 163022a 4-(CH3)C6H4 SO2 21 >350 1669, 1621b 4-(OCH3)C6H4 SO2 29 350–352 1687, 1656, 1625c 4-ClC6H4 SO2 14 >350 1683, 1658, 1622d 2-C10H7 SO2 18 >350 1684, 1653, 1619e 4-(CH(CH3)2)C6H4 SO2 15 >350 1673, 1650, 1624

XAr

NH

NH

O

O

21a C6H5 S 45 >350 1727, 1698b 4-(CH3)C6H4 S 51 >350 1728, 1699c 4-ClC6H4 S 63 325 1735, 1688d 4-FC6H4 S 38 307–310 1731, 169822f 4-ClC6H4 SO2 11 >350 1727, 168022g 4-(CH3)C6H4 SO2 20 >350 1720, 1675



Due to the small number of tested compounds and the

small variety of derivatives a structure–activity relationship

is hard to find, but the moderate growth inhibitory potential

on leukemia SR cell lines, non-small cell lung cancer NCI-

H522 and A549/ATCC cell lines and CNS cancer SNB-75 cell

lines shows that the 4-amino-2(1H)-quinazolinone and

2,4(1H,3H)-quinazolinediones heterocyclic structures could

be considered as useful templates for future development

and derivatization to obtain more potent and selective anti-

cancer agents. To understand the mode of action and evalu-

ate whether the antitumor activity of these compounds is

caused by inhibition of the ATPase activity of antitumor

targets further investigations have to be carried out. So as

the next step molecular modeling studies on ATP/ADP bind-

ing targets and investigation on the inhibition of the ATPase

activity of the pure enzymes by the novel compounds should

be carried out.

Experimental

SynthesisAll reagents were purchased from commercial sources and wereused without further treatment, unless otherwise indicated.Melting points were determined with a Gallenkamp meltingpoint apparatus MPD350 and have not been corrected. The1H-NMR spectra were recorded on a Bruker AC200, using TMSas the internal standard. IR spectra were taken as KBr pellets on aPerkin Elmer 1600 FT-IR. Mass spectra were recorded using aFinnigan 4000.

The HPLC data were recorded on a VWR Hitachi LaChrom Elitewith a LiChroCART1 125-4 LiChrospher1 60 column. The com-pounds were dissolved in methanol, the mobile phase is amixture of methanol and phosphate buffer (5 mM, pH 7.2). Agradient was run from methanol/buffer (65:35) to methanol100% at minute 14, the run stopped after 22 min.

Synthesis of 4-nitrobenzophenones 11a–dTo a solution of 11.7 g (63 mmol) 4-nitrobenzoyl chloride 10 in1,2-dichlorethane 9.6 g (72 mmol) anhydrous aluminumchloride were added. To this mixture the corresponding aro-matic compound was added from a dropping-funnel under cool-ing in an ice-bath, so that the temperature did not rise over 208C.Then the ice-bath was removed and the mixture was stirredovernight at room temperature. It was poured on ice andextracted with dichloromethane two times. The combinedextracts where washed with water, 5% sodiumhydroxidesolution and again water. The organic layer was dried (MgSO4)and the solvent was evaporated under reduced pressure.

(4-Nitrophenyl)(phenyl)methanone (11a)Yield: 87%, yellowish crystals, mp 1398C ([10]: 138–1398C).

(4-Methoxyphenyl)(4-nitrophenyl)methanone (11b)Yield: 66%, yellowish crystals, mp 123–1258C ([11]: 126–1278C).

(3,4-Dimethoxyphenyl)(4-nitrophenyl)methanone (11c)Yield: 71%, yellow crystals, mp 1668C ([12]: 174–1758C).

(3,4-Dimethylphenyl)(4-nitrophenyl)methanone (11d)Yield: 74%, yellowish crystals, mp 125–1288C ([4]: 1118C). 1H-NMR(CDCl3): 2.34 (s, 3H), 2.37 (s, 3H), 7.27 (d, 1H, 3J ¼ 7.8 Hz), 7.52(d, 1H, 3J ¼ 7.8 Hz), 7.60 (s, 1H), 7.91 (d, 2H, 3J ¼ 8.9 Hz), 8.34(d, 2H, 3J ¼ 8.9 Hz); IR: 1645 (C––O). MS: 255, 133, 105; Anal. calcd.(%) for C15H13NO3: C 70.50; H 5.13; N 5.49. Found: C 70.31; H 5.17;N 5.48.

Synthesis of (4-chlorophenyl)(4-nitrophenyl)methanone (11e)11.7 g (63 mmol) nitrobenzoyl chloride 10 was dissolved inchlorobenzene, then 9.6 g (72 mmol) anhydrous aluminumchloride were added carefully. The reaction mixture was heatedto 508C for 4 h and stirred at room temperature overnight. Thenext steps were carried out as described above for compounds11a–d.

Table 2. Growth inhibition rate of four cell lines after treating with compound classes 17, 20–22.

Growth inhibitory activity [%]No. NSC No. SR NCI-H522 SNB-75 Most active (GI [%]), panel

17a 751601 – – 9.6 CCRF-CEM (16.6), leukemia17b 751602 2 2.7 14.2 SNB-75 (14.2), CNS cancer17c 751603 14.1 13.2 11.3 SR (14.1), leukemia17e 751604 20.6 17.8 13.8 SR (20.6), leukemia20b 752549 22.7 15.7 22.4 SR (22.7), leukemia20c 752551 12.9 – 8.7 A549/ATCC (19.7), non small cell lung cancer20d 752550 15.5 12.8 12.5 SR (15.5), leukemia20e 752552 8.5 26.2 22.5 NCI-H522 (26.2), non small cell lung cancer21b 752556 9.8 22.8 20 NCI-H522 (22.8), non small cell lung cancer21c 752557 12 18.9 27.3 SNB-75 (27.3), CNS cancer21d 752558 15 27 3.8 NCI-H522 (27.0), non small cell lung cancer22a 752553 8.3 17.9 10.4 NCI-H522 (17.9), non small cell lung cancer22b 752555 9.2 10.4 21.8 SNB-75 (21.8), CNS cancer22c 752554 20.9 13.5 11.5 SR (20.9), leukemia22g 752559 17.7 15 17.5 A549/ATCC (19.3), non small cell lung cancer

– ¼ no growth inhibition detected



(4-Chlorophenyl)(4-nitrophenyl)methanone (11e)Yield: 69%, yellowish crystals, mp 988C ([11]: 102–1038C).

Synthesis of 4-aminobenzophenones 12a–eAccording to [13] 10 mmol of the nitrobenzophenone 11a–e weresuspended in 50 mL ethanol in a 250 mL-round-bottomed flask.8.3 g (30 mmol) iron(II)sulfate heptahydrate, 9 mL water, 4.3 g(80 mmol) ammonium chloride and 2.0 g (30 mmol) powderedzinc were added subsequently with efficient stirring. The reac-tion was slightly exothermic and the mixture was stirred at 508C(bath temperature) for 2 h. After cooling it has been filtered andthe residue has been washed with warm ethanol. The combinedfiltrates were concentrated under reduced pressure, ethylacetatewas added and the organic phase was washed with 25%ammonium chloride solution and water. The organic layerwas dried (MgSO4) and the solvent was evaporated under reducedpressure.

(4-Aminophenyl()phenyl)methanone (12a)Yield: 63%, yellow crystals, mp: 1238C ([14]: 1248C).

(4-Aminophenyl)(4-methoxyphenyl)methanone (12b)Yield: 68%, yellow crystals, mp: 139–1408C ([15]: 1408C).

(4-Aminophenyl)(3,4-dimethoxyphenyl)methanone (12c)Yield: 75%, yellowish crystals, mp 1918C ([16]: 191–1928C).

(4-Aminophenyl)(3,4-dimethylphenyl)methanone (12d)Yield: 93%, brownish crystals, mp 122–1258C. 1H-NMR (CDCl3):2.31 (s, 3H), 2.33 (s, 3H), 4.10 (s, 2H, NH2) 6.69 (d, 2H, 3J ¼ 8.6 Hz),7.20 (d, 1H, 3J ¼ 7.7 Hz), 7.46 (d, 1H, 3J ¼ 7.7 Hz), 7.53 (s, 1H), 7.71(d, 2H, 3J ¼ 8.6 Hz); IR: 3453, 3351, 3221 (NH2), 1636 (C––O), MS:225, 210, 133, 120, 105, 92; Anal. calcd. (%) C15H15NO: C 79.97; H6.71; N 6.22. Found: C 79.97; H 6.42; N 6.19.

(4-Aminophenyl)(4-chlorophenyl)methanone (12e)Yield: 82%, yellowish crystals, mp 179–1808C ([17]: 1858C).

Synthesis of 4-amino-3-iodobenzophenones 13a–eThe corresponding aminobenzophenone (10 mmol) 12a–e wasdissolved in a small amount of acetic acid. A solution of iodinemonochloride (1.62 g, 10 mmol) in 5 mL acetic acid was addedslowly so that the temperature of the reaction mixture did notrise over 308C. After 15 to 30 min a solid product appeared.500 mL water were added and excessive iodine monochloridewas reduced by aqueous sodium hydrogen sulfite. The residuewas filtered off, washed with water and dissolved in dichloro-methane. The organic phase has been washed with sodiumhydrogen carbonate solution and water, dried over MgSO4 andevaporated under reduced pressure.

(4-Amino-3-iodophenyl)(phenyl)methanone (13a)Yield: 49%, yellow solid, mp 1738C ([18]: 1778C).

(4-Amino-3-iodophenyl)(4-methoxyphenyl)methanone

(13b)Yield: 53%, yellowish crystals, mp 1408C. 1H-NMR (CDCl3): 3.96 (s,3H), 4.64 (s, 2H, NH2), 6.82 (d, 1H, 3J ¼ 8.57 Hz), 7.04 (d, 2H,

3J ¼ 8.57 Hz), 7.72 (d, 1H, 3J ¼ 8.57), 7.82 (d, 2H, 3J ¼ 8.57 Hz),8.23 (s, 1H); 13C-NMR (DMSO-d6): 55.42 (–OCH3), 82.20, 112.89,113.43 (s, 2C), 128.52, 130.62, 131.79 (s, 2C), 131.99, 141.60,151.22, 162.57, 192.57 (C––O); IR: 3460, 3358, 2837, 1620.MS: 353, 246, 135, 119. Anal. calcd. (%) for C14H12INO2: C47.61; H 3.43; N 3.97. Found: C 47.33; H 3.61; N 4.11.

(4-Amino-3-iodophenyl)(3,4-dimethoxyphenyl)methanone

(13c)Yield: 45%, orange solid, mp 1738C. 1H-NMR (CDCl3): 3.94 (s, 3H),3.96 (s, 3H), 6.76 (d, 1H, 3J ¼ 8.3 Hz), 6.91 (d, 1H, 3J ¼ 8.3 Hz),7.34 (d, 1H, 3J ¼ 8.2 Hz), 7.38 (s, 1H), 7.66 (d, 1H, 3J ¼ 8.3 Hz),8.17 (s, 1H); 13C-NMR (DMSO-d6): 55.84 (–OCH3), 56.04 (–OCH3),81.77, 110.96, 112.34, 113.07, 123.92, 127.09, 130.68, 132.07,141.76, 148.81, 152.33, 153.01, 191.67 (C––O); IR: 3446, 3341,2836, 1616. MS: 383, 246, 165, 119, 91. Anal. calcd. (%)for C15H14INO3: C 47.02; H 3.68; N 3.66. Found: C 47.27;H 3.73; N 3.45.

(4-Amino-3-iodophenyl)(3,4-dimethylphenyl)methanone

(13d)Yield: 55%; orange solid, mp 1528C. 1H-NMR (CDCl3): 2.32 (s, 3H),2.34 (s, 3H), 4.58 (s, 2H, NH2), 6.75 (d, 1H, 3J ¼ 8.4 Hz), 7.22 (d, 1H,3J ¼ 7.7 Hz), 7.45 (d, 1H, 3J ¼ 7.7 Hz), 7.53 (s, 1H), 7.66 (d, 1H,3J ¼ 8.4 Hz), 8.19 (s, 1H); 13C-NMR (DMSO-d6): 19.73 (CH3), 19.97(CH3), 82.44, 112.96, 127.46, 129.33, 129.37, 130.74, 132.29,135.81, 141.24, 141.95, 150.43, 193.96 (C––O); IR: 3462, 3340,2935, 1608. MS: 351, 336, 246, 225, 133, 120; Anal. calcd. (%)for C15H14INO: C 51.30; H 4.02; N 3.99. Found: C 51.39; H 3.80;N 3.83.

(4-Amino-3-iodophenyl)(4-chlorophenyl)methanone (13e)Yield: 41%, yellowish solid, mp 1458C. 1H-NMR (CDCl3): 4.58(s, 2H, NH2), 6.74 (d, 1H, 3J ¼ 8.4 Hz), 7.45 (d, 2H, 3J ¼ 8.5 Hz),7.64 (d, 1H, 3J ¼ 8,4 Hz), 7.67 (d, 2H, 3J ¼ 8.5 Hz), 8.16 (s, 1H);13C-NMR (DMSO-d6): 81.75, 112.69, 126.42, 128.28 (s, 2C), 131.92(s, 2C), 141.58, 152.57, 191.56 (C––O); IR: 3462, 3340, 1618. MS:357, 246, 230, 195, 167, 139, 111, 91; Anal. calcd. (%)for C13H9ClINO: C 43.67; H 2.54; N 3.92. Found: C 43.88; H2.46; N 3.83.

Synthesis of 3-cyano-4-amino-benzophenones 14a–eAccording to [19] 0.51 g (5 mmol) copper(I) cyanide were addedto 5 mmol of the iodinated compound 13a–e in 15 mL DMF. Themixture was heated under reflux for 3 h. After cooling it wasstirred with 10% aqueous ethylenediamine and extracted twotimes with dichloromethane. The solid appearing between thelayers containing copper was filtered off. The combined organiclayers were washed with water, 10% sodium cyanide solutionand water again, dried over MgSO4 and evaporated underreduced pressure.

2-Amino-5-benzoyl-benzonitrile (14a)Yield: 43%, brown solid, mp 157–1598C. 1H-NMR (DMSO-d6): 6.88(d, 1H, 3J ¼ 8.4 Hz), 7.04 (s, 2H, NH2), 7.61 (m, 5H), 7.76 (d, 1H,3J ¼ 8.5 Hz), 7.77 (s, 1H); IR: 3464, 3328, 3222 (-NH2), 2214 (–CN),1651 (C––O). MS: 222, 145, 117, 105, 77. Anal. calcd. (%)for C14H10N2O: C 75.66; H 4.54; N 12.60. Found: C 75.37; H4.48; N 12.60.



2-Amino-5-(4-methoxybenzoyl)-benzonitrile (14b)Yield: 39%, brown solid, mp 2008C. 1H-NMR (DMSO-d6): 3.85(s, 1H), 6.87 (d, 1H, 3J ¼ 9.4 Hz), 6.96 (s, 2H, –NH2), 7.07 (d, 2H,3J ¼ 8.8 Hz), 7.70 (m, 4H); 13C-NMR (DMSO-d6): 55.84 (–OCH3),92.89, 114.15 (s, 2C), 115.16 (–CN), 117.65, 125.20, 130.28,131.94 (s,2C), 135.71, 136.50, 154.87, 162.73, 191.60 (C––O);IR: 3400, 3367, 3225, 2222, 1657. MS: 252, 145, 135, 117, 107;Anal. calcd. (%) for C15H12N2O2: C 71.41; H 4.79; N 11.11. Found: C71.24; H 4.70; 10.91.

2-Amino-5-(3,4-dimethoxybenzoyl)-benzonitrile (14c)Yield: 34%, brown solid, mp 2088C. 1H-NMR (DMSO-d6): 3.94(s, 3H), 3.97 (s, 3H), 4.90 (s, 2H, NH2), 6.81 (d, 1H, 3J ¼ 7.9 Hz),6.91 (d, 1H, 3J ¼ 8.4 Hz), 7.30 (d, 1H, 3J ¼ 8.3 Hz), 7.39 (s, 1H), 7.87(d, 1H, 3J ¼ 8.0 Hz), 7.90 (s, 1H); 13C-NMR (DMSO-d6): 55.84, 92.89,114.15 (s, 2C), 115.16, 117.65, 125.20, 130.28, 131.94 (s, 2C),135.71, 136.50, 154.87, 162.73, 191.60 (C––O); IR: 3456, 3362,3232, 2218, 1639. MS: 282, 251, 165, 145; Anal. calcd. (%)for C16H14N2O3: C 68.07; H 5.00; N 9.92. Found: C 68.02; H4.73; N 9.84.

2-Amino-5-(3,4-dimethylbenzoyl)-benzonitrile (14d)Yield: 45%, brown solid, mp 1718C. 1H-NMR (DMSO-d6): 2.29(s, 3H), 2.31 (s, 3H), 6.85 (d, 1H, 3J ¼ 6.8 Hz), 6.99 (s, 2H, NH2),7.29 (d, 1H, 3J ¼ 7.8 Hz), 7.39 (d, 1H, 3J ¼ 7.8 Hz), 7.45 (s, 1H), 7.72(d, 1H, 3J ¼ 6.9 Hz), 7.75 (s, 1H); 13C-NMR (DMSO-d6): 19.71 (CH3),19.88 (CH3), 92.93, 115.16, 117.61, 124.99, 127.25, 129.77, 130.39,135.70, 141.34, 155.01, 192.68 (C––O); IR: 3400, 3338, 3227,2224, 1658. MS: 250, 235, 145, 133, 117, 105. Anal. calcd. (%)for C16H14N2O: C 76.78; H 5.64; N 11.19. Found: C 77.01; H 5.51;N 10.91.

2-Amino-5-(4-chlorobenzoyl)-benzonitrile (14e)Yield: 41%, brown solid, mp: 223–2258C. 1H-NMR (DMSO-d6): 6.87(d, 1H, 3J ¼ 8.4 Hz), 7.07 (s, 2H, NH2), 7.60 (d, 2H, 3J ¼ 8.7 Hz),7.69 (d,2H, 3J ¼ 8.7 Hz), 7.73–7.78 (m, 2H); 13C-NMR (DMSO-d6):55.87 (–OCH3), 56.06 (–OCH3), 92.91, 111.02, 112.23, 115.12,117.65, 124.18, 125.26, 130.23, 135.77, 136.50, 148.93, 152.60,154.84, 191.67 (C––O); IR: 4000, 3338, 3227, 2224, 1658. MS: 256,221, 145, 139, 117, 111. Anal. calcd. (%) for C14H9ClN2O: C 65.51;H 3.53; N 10.92. Found: C 65.29; H 3.67; N 11.05.

Synthesis of 4-aminoquinazolinones 17a–e, 19According to [20] 2.5 mmol starting material 14a–e, 18 weresuspended in 10 mL dry dichloromethane. 0.24 mL of chlorosul-fonyl isocyanate (2.8 mmol) in 5 mL dry dichloromethane wereadded slowly. After stirring for 3 h at room temperature thesolvent is removed under reduced pressure and 20 mL ethanol/water (1:1) were added. After 60 min the residue is filtered off,washed with water and stirred in sodium hydrogencarbonatesolution (10%) for 30 min to achieve the free base. The solid isfiltered off and dried to give the crude product.

4-Amino- 6-benzoyl-2(1H)-quinazolinone (17a)Yield: 23%, white solid, mp >3508C. 1H-NMR (DMSO-d6): 7.26(d, 1H, 3J ¼ 8.6 Hz), 7.57 (t, 2H, 3J ¼ 7.6 Hz), 7.68 (t, 1H,3J ¼ 7.4 Hz), 7.74 (d, 2H, 3J ¼ 7.8 Hz), 7.92 (d, 1H, 3J ¼ 8.5 Hz),7.96 (s, 1H, NH), 8.29 (s, 1H, NH), 8.52 (s, 1H), 11.11 (s, 1H, NH);13C-NMR (DMSO-d6): 108.21, 115.44, 127.78, 128.98 (s, 2C), 130.04(s, 2C), 130.39, 132.94, 135.37, 137.54, 145.99, 155.81 (C––O cycl.),

162.69 (C––NH), 194.69 (biaryl-C––O); IR: 3424, 1698, 1651,1621, 1596. MS: 265, 222, 189, 145, 105. Anal. calcd. (%) forC15H11N3O2 � 0.5 H2O: C 68.07; H 5.00; N 9.92. Found: C68.02; H 4.73; N 9.84. HPLC: 5.4 min, 99.2%.

4-Amino-6-(4-methoxybenzoyl)-2(1H)-quinazolinone

(17b)Yield: 31%, white solid, mp 303–3068C. 1H-NMR (DMSO-d6): 3.87(s, 3H), 7.10 (d, 2H, 3J ¼ 8.7 Hz), 7.23 (d, 1H, 3J ¼ 8.5 Hz), 7.75(d, 2H, 3J ¼ 8.7 Hz), 7.85 (s, 1H, NH), 7.88 (d, 1H, 3J ¼ 8.6 Hz), 8.14(s 1H, NH), 8.45 (s, 1H), 11.00 (s, 1H, NH); 13C-NMR (DMSO-d6):55.92 (–OCH3), 108.12, 114. 25 (s, 2C), 115.20, 127.28, 129.99,132.56, 134.91 (s, 2C), 145.71, 156.34 (C––NH), 163.21(C––O cycl.),164.13, 193.40 (biaryl-C––O); IR: 3400, 3083, 2859, 1684, 1652,1620, 1597. MS: 295, 252, 221, 145, 135. Anal. calcd. (%) forC16H13N3O3: C 65.08; H 4.44; N 14.23. Found: C 64.82; H 4.73;N 14.35. HPLC: 5.7 min, 95.3%.

4-Amino-6-(3,4-dimethoxybenzoyl)-2(1H)-quinazolinone

(17c)Yield: 25%, white solid, mp 310–3138C. 1H-NMR (DMSO-d6):3.82 (s, 3H), 3.88 (s, 3H), 7.12 (d, 1H, 3J ¼ 8.3 Hz), 7.30(d, 1H, 3J ¼ 8.5 Hz), 7.32 (d, 1H, 3J ¼ 8.2 Hz), 7.36 (s, 1H),8.04 (d, 1H, 3J ¼ 8.5 Hz), 8.19 (s, 1H); 13C-NMR (DMSO-d6):55.92 (–OCH3), 56.15 (–OCH3), 11.09, 112.25, 114.19, 116.08,124.87, 129.61, 129.69, 13.73, 136.11, 144.13, 149.07, 150.58,153.17 (C––O cycl.), 162.80 (C ¼ NH), 192.99 (diaryl-C––O);IR: 3200, 1736, 1688, 1653, 1617. MS: 325, 282, 165. Anal. calcd.(%) for C17H15N3O4: C 62.76; H 4.65; N 12.92. Found: C 63.00;H 8.84; N 12.65. HPLC: 5.1 min, 95.2%.

4-Amino-6-(3,4-dimethylbenzoyl)-2(1H)-quinazolinone

(17d)Yield: 44%, white solid, mp 3158C. 1H-NMR (DMSO-d6): 2.30 (s, 3H),2.33 (s, 1H), 7.24 (d, 1H, 3J ¼ 8.6 Hz), 7.33 (s, 1H, 3J ¼ 7.8 Hz), 7.46(d, 1H, 3J ¼ 7.9 Hz), 7.54 (s, 1H), 7.90 (d, 1H, 3J ¼ 8.6 Hz), 7.96(s, 1H, NH), 8.34 (s, 1H, NH), 8.50 (s, 1H), 11.13 (s, 1H, NH); 13C-NMR(DMSO-d6): 19.25 (CH3), 19.47 (CH3), 107.67, 114.84, 127.10,127.49, 129.47, 130.38, 130.50, 134.78, 134.83, 136.61, 141.69,145.28, 155.28, 163.34, 194.06; IR: 3383, 3183, 2975, 1677, 1639,1623, 1589. MS: 293, 279, 250, 209, 189, 133. Anal. calcd. (%) forC17H15N3O2: C 69.61; H 5.15; N 14.33. Found: C 69.33; H 5.43;N 14.01. HPLC: 7.4 min, 99.1%.

4-Amino-6-(4-chlorobenzoyl)-2(1H)-quinazolinone (17e)Yield: 33%, white solid; mp 3258C. 1H-NMR (DMSO-d6): 7.27 (d, 1H,3J ¼ 8.6 Hz), 7.64 (d, 2H, 3J ¼ 8.5 Hz), 7.75 (d, 2H, 3J ¼ 8.4 Hz),7.98 (d, 1H, 3J ¼ 8.7 Hz), 8.10 (s, 1H, NH), 8.50 (s, 1H, NH), 8.51(s, 1H), 11.25 (s, 1H, NH); 13C-NMR (DMSO-d6): 107.57, 115.25,127.63, 128.62 (s, 2C), 129.66, 131.43 (s, 2C), 134.99, 135.80,137.30, 144.81, 145.58, 154.66 (C––O cycl.), 162.98 (C––NH),193.09 (biaryl-C––O); IR: 3348, 1706, 1648, 1623, 1588. MS:299/301, 256/258, 145, 139/141. Anal. calcd. (%) for C15H10ClN3O2:C 60.11; H 3.36; N 14.02. Found: C 59.86; H 3.56; N 13.73. HPLC:6.6 min, 99.5%.

4-Amino-6-iodo-2(1H)-quinazolinone (19)Yield: 15%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 6.95(d, 1H, 3J ¼ 8.7 Hz), 7.83 (d, 1H, 3J ¼ 8.7 Hz), 7.90–7.92 (d, 2H,NH), 8.39 (s, 1H), 10.77 (s, 1H, NH); 13C-NMR (DMSO-d6): 83.89,



110.77, 117.51, 132.90, 142.08, 142.49, 156.12, 162.93; IR: 3352,3118, 1669, 1628, 1592. MS: 287, 244, 160. Anal. calcd. (%) forC8H6IN3O: C 33.47; H 2.11; N 14.64. Found: C 33.39; H 1.90;N 14.24. HPLC: 5.5 min, 98.4%.

Synthesis of 6-phenylthio-2(1H)-quinazolinones 20a–gIn a 25-mL 2-neck pear-shaped flask dry argon was bubbledthrough 5 mL dimethyl formamide. Consecutively 2.5 mmolof 19 and 5 mmol (0.72 g) potassium carbonate were addedand the mixture was stirred for 5 min. After adding 0.25 mmol(50 mg) copper(I)iodide and 0.3 mL ethylene diamine the argonflow was stopped, the flask was sealed and the mixture wasstirred for 16 h on an oil bath at 1208C.

After cooling water was added and the precipitate was filteredoff. It was treated with ethanol and diethyl ether, then it wasstirred with 10 mL ethylene diamine solution (20%) and 10 mLmethanol for 30 min. The solution turned deep purple, the solidwas filtered off and washed with water, methanol and diethylether.

4-Amino-6-phenylthio-2(1H)-quinazolinone (20a)Yield: 17%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.15–7.22(m, 4H), 7.31 (t, 2H, 3J ¼ 7.7 Hz), 7.61 (d, 1H, 3J ¼ 8.6 Hz), 7.82(s, 1H, NH), 7.95 (s, 1H, NH), 8.30 (s, 1H), 10.84 (s, 1H, NH);13C-NMR(DMSO-d6): 109.51, 116.90, 123.96, 126.53, 128.02 (s, 2C),129.73 (s, 2C), 130.95, 137.86, 139.68, 143.40, 156.29 (C––O),163.52 (C––NH); IR: 3410, 3070, 1671, 1631, 1590. MS: 269, 226,149. Anal. calcd. (%) for C15H13N3OS: C 62.43; H 4.12; N 15.60.Found: C 61.32; H 4.21; N 15.34. HPLC: 7.5 min, 97.0%.

4-Amino-6-(4-tolylthio)-2(1H)-quinazolinone (20b)Yield: 21%, white solid. 1H-NMR (DMSO-d6): 2.26 (s, 3H), 7.11–7.15(m, 5H), 7.54 (d, 1H, 3J ¼ 8.6 Hz), 7.84 (s, 1H, NH), 7.94 (s, 1H, NH),8.26 (s, 1H), 10.84 (s, 1H, NH); 13C-NMR (DMSO-d6): 104.99, 116.30,124.87, 128.73 (s, 2C), 129.48, 129.91 (s, 2C), 133.22, 135.99,1384.1, 142.56, 155.79, 163.04; IR: 3284, 3018, 1671, 1630,1581. MS: 283, 240, 224, 196, 160, 149, 105. Anal. calcd. (%)for C15H13N3OS: C 63.58; 4.62; N 14.83. Found: C 62.28; H 4.68;N 14.73; HPLC: 9.5 min, 97.3%.

4-Amino-6-(4-methoxyphenylthio)-2(1H)-quinazolinone

(20c)Yield: 9%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 3.74 (s, 3H,–OCH3), 6.94 (d, 2H, 3J ¼ 8.7 Hz), 7.10 (d, 1H, 3J ¼ 8.6 Hz), 7.28 ((d,2H, 3J ¼ 8.7 Hz), 7.46 (d, 1H, 8.7), 7.79 (s, 1H, NH), 7.94 (s, 1H, NH),8.20 (s, 1H), 10.79 (s, 1H, NH); 13C-NMR (DMSO-d6): 55.62 (–O–CH3),109.34, 115.50 (s, 2C), 116.64, 126.54, 127.33, 128.36, 132.71(s, 2C), 137.56, 142.62, 156.28, 159.20 (C––O), 163.55 (C––NH);IR: 3350, 3105, 1668, 1628, 1590. MS: 299, 256, 224, 196, 149.Anal. calcd. (%) for C15H13N3O2S: C 60.18; H 4.38; N 14.04. Found:C 59.35; H 4.33; N 13.70. HPLC: 8.0 min, 97.8%.

4-Amino-6-(4-chlorophenylthio)-2(1H)-quinazolinone (20d)Yield: 13%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.15(d, 2H, 3J ¼ 8.6 Hz), 7.18 (d, 1H, 3J ¼ 8.6 Hz), 7.37 (d, 2H,3J ¼ 8.6 Hz), 7.63 (d, 1H, 3J ¼ 8.6 Hz), 7.83 (s, 1H, NH), 7.95(s, 1H, NH), 8.30 (s, 1H), 10.86 (s, 1H, NH); 13C-NMR (DMSO-d6):107.04, 116.57, 124.51, 129.09 (s, 2C), 129.12 (s, 2C), 130.69,130.80, 136.61, 139.15, 145.00, 156.24 (C––O), 161.78 (C––NH);

IR: 3280, 3018, 1673, 1627, 1584. MS: 303/305, 260/262, 224,196, 160, 149,105; Anal. calcd. (%) for C14H10ClN3OS: C 55.35;H 3.32; N 13.84. Found: C 53.87; H 3.14; N 13.79; HPLC: 9.3 min,97.0%.

4-Amino-6-(4-fluorophenylthio)-2(1H)-quinazolinone (20e)Yield: 22%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.11–7.22(m, 4H), 7.25–7.28 (m, 2H), 7.58 (d, 1H, 3J ¼ 8.6 Hz), 7.82 (s, 1H,NH), 7.95 (s, 1H, NH), 8.27 (s, 1H); 13C-NMR (DMSO-d6): 109.11,116.74–116.91 (d, 2C, 2JCF ¼ 22 Hz), 116.89, 127.00, 130.20,131.13–131.19 (d, 2C, 2JCF ¼ 9 Hz), 132.86 (d, 1C, 4JCF ¼ 3 Hz),138.99, 143.25, 156.26, 160.51–162.48 (d, 1C, 1JCF ¼ 248 Hz),163.50; IR: 3291, 3034 (NH), 1630 (C––N), 1585 (NH). MS:287, 244, 212, 149. Anal. calcd. (%) for C14H10FN3OS: C 58.53;H 3.51 N 14.63. Found: C 58.78; H 3.41; N 14.36. HPLC: 7.9 min,95.2%.

4-Amino-6-[(4-isopropylphenyl)thio]-2(1H)-quinazolinone

(20f)Yield: 18%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 1.15(s, 3H, CH3), 1.17 (s, 3H, CH3), 7.12 (d, 2H, 3J ¼ 8.1 Hz), 7.15(d, 1H, 3J ¼ 8.7 Hz), 7,20 (d, 2H, 3J ¼ 8.2 Hz), 7.58 (d, 1H,3J ¼ 8.5 Hz), 7.84 (s, 1H, NH), 7.94 (s, 1H, NH), 8.28 (s, 1H),10.83 (s, 1H, NH); 13C-NMR (DMSO-d6): 24.08 (s, 2C, (CH3)2CH),33.35 ((CH3)2CH), 108.79, 117.79, 127.94 (s, 2C), 128.03, 129.97(s, 2C), 130.16, 132.96, 140.72, 142.06, 147.96, 150.20 (C––O),160.73 (C––NH); IR: 3419, 3048, 2962, 2865, 1671, 1631, 1587.MS: 311, 296, 268. Anal. calcd. (%) for C17H17N3OS: C 65.57;H 5.50; N 13.49. Found: C 61.92; H 5.13; N 12.59. HPLC:17.3 min, 95.2%.

4-Amino-6-(2-naphthylthio)-2(1H)-quinazolinone (20g)Yield: 23%, white solid; mp >3508C (lit.: 380–3828C). 1H-NMR(DMSO-d6): 7.20 (d, 1H, 3J ¼ 8.5 Hz), 7.30 (d, 1H, 3J ¼ 8.6 Hz), 7.48(m, 2H), 7.65 (d, 1H, 3J ¼ 8.5 Hz), 7.70 (s, 1H), 7.80 (s, 1H, NH), 7.82(d, 1H, 3J ¼ 7.5 Hz), 7.87 (d, 2H, 3J ¼ 8.7 Hz), 7.96 (s, 1H, NH), 8.34(s, 1H), 10.86 (s, 1H, NH). IR: 3411, 3052, 1667, 1630, 1591. MS:319, 276, 149, 127. Anal. calcd. (%) for C18H13N3OS: C 67.69; H4.10; N 13.16. Found: C 68.31; H 4.65; N 12.69. HPLC: 16.3 min,98.4%.

Synthesis of 6-(4-phenylthio)-2,4(1H,3H)-

quinazolinediones 21a–d100 mg aminoquinazolinone were suspended in 20 mL concen-trated potassium hydroxide solution and refluxed for 6 h. Thedeposit was filtered of and washed with methanol. Then it wasstirred with 5 mL acetic acid/sodium acetate buffer (pH 5.5) for1 h and filtered off again. It was washed with water.

6-(4-Phenylthio)-2,4(1H,3H)-quinazolinedione (21a)Yield: 45%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.14(d, 1H, 3J ¼ 8.5 Hz), 7.25 (m, 3H), 7.35 (d, 2H, 3J ¼ 7.5 Hz), 7.59(d, 1H, 3J ¼ 8.5 Hz), 7.79 (s, 1H); 13C-NMR (DMSO-d6): 115.33,116.88, 126.88, 127.15, 129.33, 129.49, 130.38, 130.99, 138.49,139.67, 150.75 (C ¼ O), 162.09 (C ¼ NH); IR: 3461, 3053,1727, 1698, 1617, 1613. MS: 270, 227, 199, 172. Anal.calcd. (%) for C14H10N2O2S: C 62.21; H 3.73; N 10.36. Found: C58.33; H 3.39; N 9.55. HPLC: 13.9 min, 99.13%. HPLC: 8.8 min,97.7%.



6-(4-Tolylthio)-2,4(1H,3H)-quinazolinedione (21b)Yield: 51%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 2.30(s, 3H, CH3), 7.17 (d, 1H, 3J ¼ 8.5 Hz), 7.21 (d, 2H, 3J ¼ 8.0 Hz),7.25 (d, 2H, 3J ¼ 8.0 Hz), 7.61 (d, 1H, 3J ¼ 8.4 Hz), 7.71 (s, 1H),11.25 (s, 1H, NH), 11.38 (s, 1H, NH); 13C-NMR (DMSO-d6): 21.00(CH3), 115.62, 117.15, 129.08, 129.11, 130.66 (s, 2C), 131.41 (s, 2C),131.51, 137.71, 137.77, 1450.52, 150.44, 162.54; IR: 3247, 3057,1717, 1701, 1687, 1674, 1614. MS: 284, 241, 213, 186. Anal. calcd.(%) for C15H12N2O2S: C 63.36; H 4.25; N 9.85. Found: C 63.55; H4.32; N 9.67. HPLC: 10.2 min, 98.0%.

6-(4-Chlorophenylthio)-2,4(1H,3H)-quinazolinedione (21c)Yield: 63%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.21(d, 1H, 3J ¼ 8.5 Hz), 7.27 (d, 2H, 3J ¼ 8.4 Hz), 7.42 (d, 2H,3J ¼ 8.4 Hz), 7.69 (d, 1H, 3J ¼ 8.5 Hz), 7.84 (s, 1H), 11.38 (s, 2H,NH); 13C-NMR (DMSO-d6): 115.81, 117.50, 126.70, 129.86, 131.13,132.10, 135.43, 139.36, 141.29, 150.46 (C––O), 162.48 (C––O); IR:3424, 3048, 1735, 1688, 1616. MS: 304/306, 261/263, 206/208,150. Anal. calcd. (%) for C14H9ClN2O2S: C 55.18; H 2,98; N 9,19.Found: C 55.00; H 3.10; N 9.08. HPLC: 10.2 min, 96.9%.

6-(4-Fluorophenylthio)-2,4(1H,3H)-quinazolinedione (21d)Yield: 38%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.18(d, 1H, 3J ¼ 8.5 Hz), 7.24 (m, 2H), 7.39 (m, 2H), 7.64 (d, 1H,3J ¼ 8.5 Hz), 7.75 (s, 1H), 11.35 (s, 2H, NH); 13C-NMR (DMSO-d6):115.70, 117.02–117.20 (d, 2C, 2JCF ¼ 22 Hz), 117.34, 128.41,129.65, 130.93 (d, 1C, 4JCF ¼ 3 Hz), 133.39–133.46 (d, 2C,2JCF ¼ 8 Hz), 138.18, 140.86, 150.47, 161.05–163.01 (d, 1C,1JCF ¼ 245 Hz), 162.52; IR: 3189, 3055, 1731, 1698, 1673, 1613.MS: 288, 245, 217, 189. Anal. calcd. (%) for C14H9FN2O2S: C 58.32;H 3.15; N 9.72. Found: C 54.47; H 3.01; N 8.75. HPLC: 8.7 min,90.1%.

Synthesis of 6-(4-phenylsulfonyl)quinazolinones 22 a–g100 mg thioaminoquinazolinone was suspended in 5 mL aceticacid. 0.1 g potassium permanganate in 5 mL acetic acid wasadded over 30 min. After another hour the brown solutionwas basified with concentrated ammonia. The precipitate wasfiltered off, washed with water and methanol and was thentreated with 1 mL of hot dimethyl formamide in the filter.The solution was diluted with water until a deposit appears,which was filtered off and washed with water.

4-Amino-6-(4-tolylsulfonyl)-2(1H)-quinazolinone (22a)Yield: 21%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 2.36(s, 3H, CH3), 7.24 (d, 1H, 3J ¼ 8.8 Hz), 7.43 (d, 2H, 3J ¼ 8.1 Hz),7.85 (d, 2H, 3J ¼ 8.2 Hz), 8.00 (s, 1H, NH), 8.02 (d, 1H, 3J ¼ 8.8 Hz),8.32 (s, 1H, NH), 8.72 (s, 1H), 11.09 (s, 1H, NH); 13C-NMR: 21.36(CH3), 108.66, 116.47, 125.70, 127.50 (s, 2C), 130.52 (s, 2C), 132.26,133.69, 139.10, 144.51, 146.35, 156.03 (C––O), 163.51 (C––NH); IR:3399, 3035, 1668, 1621, 1593. MS: 315, 287, 208, 176, 165, 133.Anal. calcd. (%) for C15H13N3O3S: C 57.13; H 4.16; N 13.33. Found:C 55.39; H 3.90; N 13.14. HPLC: 5.3 min, 98.5%.

4-Amino-6-(4-methoxyphenylsulfonyl) -2(1H)-

quinazolinone (22b)Yield: 29%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 3.82(s, 3H, CH3), 7.14 (d, 2H, 3J ¼ 9.0 Hz), 7.23 (d, 1H, 3J ¼ 8.8 Hz),7.89 (d, 2H, 3J ¼ 9.0 Hz), 7.98 (s, 1H, NH), 8.02 (d, 1H, 3J ¼ 8.7 Hz),8.30 (s, 1H, NH), 8.71 (s, 1H), 11.07 (s, 1H, NH); 13C-NMR (DMSO-d6):

56.17 (–OCH3), 108.62, 115.30 (s, 2C), 116.42, 125.43, 129.78(s, 2C), 132.11, 133.44, 134.22, 146.20, 156.02 (C––O), 163.37(C––NH), 163.51; IR: 3437, 3053, 1687, 1656, 1625, 1595. MS:331, 288, 208, 176, 165, 133. Anal. calcd. (%) for C15H13N3O4S:C 54.37; H 3.95; N 12.68. Found: C 54.28; H 3.71; N 12.39. HPLC:5.0 min, 95.2%.

4-Amino-6-(4-chlorophenylsulfonyl)-2(1H)-quinazolinone

(22c)Yield: 14%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.26(d, 1H, 3J ¼ 8.8 Hz), 7.72 (d, 2H, 3J ¼ 8.6 Hz), 7.97 (d, 2H,3J ¼ 8.7 Hz), 8.01 (s, 1H, NH), 8.06 (d, 1H, 3J ¼ 8.7 Hz), 8.31(s, 1H, NH), 8.74 (s, 1H), 11.11 (s, 1H, NH); 13C-NMR (DMSO-d6):108.77, 116.61, 126.08, 129.42 (s, 2C), 130.28 (s, 2C), 132.39,132.72, 138.99, 140.77, 146.63, 156.00 (C––O), 163.49 (C––NH);IR: 3481, 3052, 1683, 1658, 1621, 1593. MS: 303/305, 260/262,224, 196, 160, 149, 105. Anal. calcd. (%) for C14H10ClN3O3S: C50.08; H 3.00; N 12.51. Found: C 50.37; H 3.18; N 12.30. HPLC:5.8 min, 95.4%.

4-Amino-6-(4-naphthylsulfonyl)-2(1H)-quinazolinone

(22d)Yield: 18%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.26(d, 1H, 3J ¼ 8.8 Hz), 7.72 (m, 2H), 7.93 (d, 1H, 3J ¼ 8.7 HZ), 8.05(d, 1H, 3J ¼ 7.9 Hz), 8.06 (s, 1H, NH), 8.11 (d, 1H, 3J ¼ 8.7 Hz), 8.15(d, 1H, 3J ¼ 8.8 Hz), 8.20 (d, 1H, 3J ¼ 7.9 Hz), 8.34 (s, 1H, NH),8.67 (s, 1H), 8.81 (s, 1H), 11.10 (s, 1H, NH); 13C-NMR (DMSO-d6):108.74, 116.56, 122.66, 126.02, 128.29, 128.65, 129.80, 129.97,130.33, 132.09, 132.45, 133.24, 134.84, 138.85, 141.55, 146.49,156.02 (C––O), 163.53 (C––NH); IR: 3468, 3052, 1653, 1640,1619, 1592. MS: 351, 208, 176, 165, 133. Anal. calcd. (%) forC18H13N3O3S: C 61.53; H 3.73; N 11.96: Found: C 59.99; H 3.48;N 11.58. HPLC: 6.8 min, 96.6%.

4-Amino-6-[(4-isopropylphenyl)sulfonyl]-2(1H)-

quinazolinone (22e)Yield: 15%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 1.18(s, 3H, CH3), 1.19 (s, 3H, CH3), 2.96 (m, 1H, CH), 7.24 (d, 1H,3J ¼ 8.8 Hz), 7.49 (d, 2H, 3J ¼ 8.3 Hz), 7.88 (d, 2H, 3J ¼ 8.3 Hz),8.00 (s, 1H, NH), 8.04 (d, 1H, 3J ¼ 8.8 Hz), 8.32 (s 1H, NH), 8.73(s, 1H), 11.09 (s, 1H, NH). IR: 3347, 3053, 2963, 2871, 1673, 1650,1624, 1593. MS: 343, 328, 208, 176, 165, 133. Anal. calcd. (%)for C17H17N3O3S: C 59.46; H 4.99; N 12.24. Found: C 59.53; H 5.13;N 12.11.

6-(4-Chlorophenylsulfonyl)-2,4(1H,3H)-quinazolinedione

(22f)Yield: 11%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.32(d, 1H, 3J ¼ 8.7 Hz), 7.70 (d, 2H, 3J ¼ 8.2 Hz), 7.99 (d, 2H,3J ¼ 8.2 Hz), 8.16 (d, 1H, 3J ¼ 8.6 Hz), 8.33 (s, 1H), 11.62 (s, 2H,NH); 13C-NMR (DMSO-d6): 115.25, 117.49, 127.48, 129.64, 130.38,133.69, 134.19, 139.23, 140.23, 145.17, 150.41, 162.13; IR: 3450,3058, 1727, 1680, 1618. MS: 336/338, 209, 166, 161, 111/113.Anal. calcd. (%) for C14H9ClN2O4S: C 49.93; H2.69; N 8.32. Found:C 49.99; H 2.91; N 8.11. HPLC: 5.3 min, 97.7%.

6-(4-Tolylsulfonyl)-2,4(1H,3H)-quinazolindione (22g)Yield: 20%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 2.37(s, 3H), 7.30 (d, 1H, 3J ¼ 8.7 Hz), 7.43 (d, 2H, 3J ¼ 8.2 Hz), 7.84(d, 2H, 3J ¼ 8.2 Hz), 8.13 (d, 1H, 3J ¼ 8.7 Hz), 8.29 (s, 1H), 11.59



(s, 2H, NH). IR: 3259, 3040, 1720, 1675, 1616. MS: 316, 230, 209,166,139. Anal. calcd. (%) for C15H12N2O4S: C 56.95; H 3.82; N 8.86.Found: C 57.21; H 3.66; N 8.99.

The authors like to thank the staff members of the Department of Healthand Human Services, NCI, Bethesda, MD, USA for carrying out theanticancer screening of the novel compounds.

The authors have declared no conflict of interest.

References

[1] K. Poreba, A. Opolski, J. Witrzuk, Arch. Pharm. 2001, 334,4097–4098.

[2] A. Gangjee, O. Adaira, S. F. Queener, Bioorg. Med. Chem 2001,9, 2929–2935.

[3] S. Huang, R. Lin, Y. Yu, et al., Bioorg. Med. Chem. Lett. 2007, 17,1243–1245.

[4] A. Maloney, P. Workman, Expert. Opin. Biol. Ther. 2002, 2, 3–24.

[5] L. Zhu, X. Xu, J. Chromatogr. A 2003, 991, 151–158.

[6] S. Sarno, M. Salvi, R. Battistutta, et al., Biochim. Biophys. Acta,Proteins Proteomics 2005, 1754, 263–270.

[7] S. Sarno, M. Ruzzene, P. Frascella, et al., Mol. Cell Biochem.2005, 274, 69–76.

[8] L. Wright, X. Barril, B. Dymock, et al., Chem. Biol. 2004, 11,775–785.

[9] A. Kreusch, S. Han, A. Brinker, et al., Bioorg. Med. Chem. Lett.2005, 15, 1475–1478.

[10] S. S. Kulp, M. J. McGee, J. Org. Chem. 1983, 4097–4098.

[11] Y. Suzuki, S. Ota, Y. Fukuta, et al., J. Org. Chem. 2008, 2420–2423.

[12] Z. Vejdelek, J. Holubek, M. Budesınsky, et al., Collect. Czech.Chem. Commun. 1988, 361–372.

[13] Y. Liu, Y. Lu, M. Prashad, et al., Adv. Synth. Catal. 2005, 217–219.

[14] M. Gopalakrishnan, P. Sureshkumar, V. Kanagarajan, J.Thanusu, Catal. Communi. 2005, 753–756.

[15] L. Fullhart Jr, Iowa State College J. Sci. 1947, 27–28.

[16] I. Ivanov, Synth. Commun. 2006, 1405–1411.

[17] R. B. Davis, D. D. Carlos, G. S. Mattingly, J. Org. Chem. 1965,2607–2609.

[18] W. A. Waters, J. Chem. Soc. 1929, 2106–2111.

[19] L. Friedman, H. Shechter, J. Org. Chem. 1961, 2522–2524.[20] A. V. Narender, A. Kamal, P. B. Sattur, Synth. Commun.1988, 525–530.

[20] (a) F. Y. Kwong, S. L. Buchwald, Org. Lett. 2002, 3517-3520;(b) E. Sperotto, G. P. M. van Klink, J. G. de Vries, G. van Koten,J. Org. Chem. 2008, 5625-5628; (c) W. T. Ashton, J. B. Hynes,J. Med. Chem. 1973, 1233–1237.

[21] M. R. Grever, S. A. Schepartz, B. A. Chabner, Semin. Oncol.1992, 19, 622–638.

[22] M. R. Boyd, K. D. Paull, Drug Rev. Res. 1995, 34, 91–109.

[23] A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, et al., J. Natl.Cancer Inst. 1991, 83, 757–766.



synthesis, molecular modelling and biological evaluation of 4-amino-2(1h)-quinazolinone and...

Documents