Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents

Article abstract of DOI:10.1016/S0014-827X(00)00029-X

The key intermediate octahydroquinazoline (1) was obtained in one pot synthesis by a modification of the Biginelli reaction. Compound 1 was allowed to react with phenacyl bromide and bromomalononitrile to furnish thiazolo[2,3-b]quinazoline 3 and 12, respectively. Interaction of compound 12 with formamide, formic acid and phenyl isothiocyanate yielded the corresponding pyrimidino[4',5':4,5]thiazolo[2,3-b] quinazolines 13, 14 and 17, respectively. The structure of the synthesized compounds were elucidated by elemental analyses and spectroscopic analyses. Some of the prepared compounds were tested for their antifungal activity in comparison with tioconazole as a reference fungicide. (C) 2000 Elsevier Sciences S.A.

Full text of DOI:10.1016/S0014-827X(00)00029-X

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 249–255
Synthesis and evaluation of some new fluorinated
hydroquinazoline derivatives as antifungal agents
M.M. Ghorab a,*, S.M. Abdel-Gawad b, M.S.A. El-Gaby c
a Department of Drug Radiation Research, National Centre for Radiation Research and Technology, PO Box 29, Nasr City, Cairo, Egypt
b Department of Chemistry, Faculty of Science (Girls), Al-Azhar Uni6ersity, Assiut 71524, Egypt
c Department of Chemistry, Faculty of Science, Al-Azhar Uni6ersity at Assiut, Assiut 71524, Egypt
Received 1 October 1999; accepted 16 February 2000
Abstract
The key intermediate octahydroquinazoline (1) was obtained in one pot synthesis by a modification of the Biginelli reaction.
Compound 1 was allowed to react with phenacyl bromide and bromomalononitrile to furnish thiazolo[2,3-b]quinazoline 3 and 12,
respectively. Interaction of compound 12 with formamide, formic acid and phenyl isothiocyanate yielded the corresponding
pyrimidino[4%,5%:4,5]thiazolo[2,3-b] quinazolines 13, 14 and 17, respectively. The structure of the synthesized compounds were
elucidated by elemental analyses and spectroscopic analyses. Some of the prepared compounds were tested for their antifungal
activity in comparison with tioconazole as a reference fungicide. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Quinazolines; Thiazoloquinazolines; Pyrimidinothiazoloquinazolines and antifungal activity
The phenacylthio derivative 2 was prepared via reac-
tion of compound 1 with phenacyl bromide in anhy-
1. Introduction
drous acetone/K2CO3,which was cyclized by a simple
acid cyclodehydration in 98% H2SO4 to give compound
3. The thiazoloquinazoline derivative 3 was obtained
also in one step via reaction of 1 with phenacyl bromide
in boiling ethanol (Scheme 2). When compound 1 was
treated with POCl3/DMF at room temperature (r.t.) [8],
intermediate 4 was readily formed, which upon hydrol-
ysis gave the formyl derivative 5. Condensation of
Quinazoline and its synthetic analogues have been
found to exhibit a broad spectrum as biologically active
compounds. Quinazolines, in particular, as antimicro-
bial agents has attracted a special interest [1–5]. In the
meantime, many thiazole derivatives are known to ex-
hibit antifungal activity [6–11]. It was, therefore,
thought worthwhile to incorporate the thiazole, pyrim-
idinothiazole and triazinothiazole moieties with the hy-
compound 5 with malononitrile caused cyclization to
give thiazinoquinazoline derivative 6.
Refluxing of compound 1 with acetic anhydride leads
droquinazoline nucleus in one molecule to evaluate
their effect as anticipated active antifungal compounds.
to the formation of corresponding 3-acetyl derivative 7.
1
The site of acetylation in 7 was supported by H NMR
spectrum. The signal for C4 proton collapsed from a
2. Chemistry
doublet in compound 1 to a singlet in compound 7.
Reaction of compound 1 with methyl iodide in acetone
in the presence of anhydrous K2CO3 produced com-
4-(4%-Fluorophenyl)-2-thioxo-1,2,3,4,5,6,7,8-octahy-
droquinazolin-5 -one (1) was obtained by a modifica-
tion of the Biginelli reaction [12] employing a three
component system comprising 1,3-cyclohexanedione
with 4-fluorobenzaldehyde and thiourea (Scheme 1).
pound 8, instead of the expected product 9. This result
1
was proved using H NMR data, which showed two
singlets at 2.9 and 3.1 ppm due to SCH3 and N3-methyl
protons [13]. Compound 1 reacted with acrylonitrile to
give the 3-(2-cyanoethyl) derivative 10 rather than 11,
which is in agreement with previous works [14]. This is
* Corresponding author. Fax: +202-2749298.
E-mail address: ghorabmoustafa@hotmail.com (M.M. Ghorab).
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00029-X

250
M.M. Ghorab et al. / Il Farmaco 55 (2000) 249–255
1
also approved by H NMR which revealed a signal for
C4 proton converted from a doublet in compound 1 to
a singlet in compound 10 due to N3-cyanoethylation.
When a solution of 1 in ethanolic potassium hydroxide
was treated with cold bromomalononitrile, 3-amino-2-
cyano - 5 - (4% - fluorophenyl) - 5,6,7,8,9-pentahydrothia-
zolo[2,3-b]quinazolin-6-one (12) was obtained in good
yield (Scheme 3). The reaction of compound 12 with
formamide gave pyrimidinothiazoloquinazoline (13).
Compound 12 gave characteristic reactions for enami-
nonitriles. Thus, when 12 was heated under reflux with
formic acid it gave pyrimidinothiazolo-quinazoline
derivative 14. Interaction of 12 with malononitrile in
ethanol in presence of piperidine furnished the corre-
sponding pyridothiazolo-quinazoline derivative 15.
Compound 12 reacted with hydroxylamine hydrochlo-
ride in boiling ethanolic sodium ethoxide [15] to give
pyrazolothiazoloquinazoline derivative 16, its IR spec-
trum showed the absence of (CꢀN) band and presence
of (NH, NH2) bands. Compound 12 was reacted with
phenyl isothiocyanate in pyridine to give 4-amino-3-
phenyl-11-(4-fluorophenyl)-2-thioxo-2,7,8,9,10,11-hexa-
hydroquinazolin-10-one (17). In addition compound 12
reacted with acetic anhydride, for which two products
18 and 19 seemed possible. Structure 19 was ruled out
due to presence of (CꢀN) band in the IR spectrum.
Compound 12 when stirred with concentrated H2SO4
at r.t. [16] for 2 h, afforded 3-amino-2-carboxamido
derivative 20. The formation of the amide 20 was
confirmed by IR, which showed the disappearance of
the cyano (CꢀN) group and exhibited a carbonyl stretch
at 1650 cm−1 along with characteristic amino (NH2)
and carboxamido (CONH2) bands at 3410, 3320, 3250,
3180 cm−1 (Scheme 4).
Condensation of compound 20 with acetic anhydride
furnished the corresponding 2-methyl-11-(4%-fluoro-
phenyl) - 3,4,7,8,9,10,11 - heptahydroquinazolin - 4,10-
dione (19). Heating compound 20 with formamide
yielded the pyrimidinothiazolo-quinazoline (14). Inter-
action of compound 20 with thionyl chloride yielded
the thiadiazinothiazoloquinazoline derivative 21.
Scheme 1.
Scheme 2.

M.M. Ghorab et al. / Il Farmaco 55 (2000) 249–255
251
Scheme 3.
Scheme 4.
Finally, reaction of compound 20 with nitrous acid
3.1. 4-(4%-Fluorophenyl)-2-thioxo-1,2,3,4,5,6,7,8-octa-
gave the triazinothiazoloquinazoline derivative 22.
hydroquinazolin-5-one (1)
A mixture of thiourea (0.005 mol), 4-fluorobenzalde-
hyde (0.005 mol), 1,3-cyclohexanedione (0.007 mol),
abs. C2H5OH (20 ml) and 37% HCl (4 drops) was
heated under reflux for 3 h and the reaction solution
was allowed to cool, filtered off and crystallized from
C2H5OH to give 1 (Table 1).
3. Experimental
All melting points are uncorrected and were deter-
mined on a Stuart melting point apparatus. IR spectra
(cm−1) were recorded on a Pye-Unicam spectrophoto-
1
meter type 1200 using KBr Wafer technique. H NMR
spectra were recorded on a Varian EM-390 (90 MHz)
spectrometer using TMS as an internal standard and
DMSO-d6 as solvent. Chemical shifts were expressed in
l (ppm) values. Mass spectra were run using HP
Model: MS-5988. Elemental analysis were determined
using Perkin–Elmer 240 C Microanalyser.
3.2. 4-(4%-Fluorophenyl)2-(phenacylthio)-
3,4,5,6,7,8-hexahydroquinazolin-5-one (2)
A solution of 1 (0.005 mol), phenacyl bromide (0.005
mol) in anhydrous acetone in presence of (1 g) anhy-
drous K2CO3 was refluxed for 10 h. The reaction

Table 1
Physical and spectral data of the synthesized compounds 1–22
Compd
no.
M.p. (°C)
yield (%)
Molecular formula
(Mol. Wt)
Elemental analyses
calculated/found
IR w (cm−1
)
1H NMR l (ppm) (DMSO-d6)
C%
H%
N%
1 a
276–278
81
C14H13N2OSF
(276.31)
60.85
60.50
4.73
4.90
10.13
10.40
3280, 3200 (2NH), 1700
(CꢁO), 1500, 1220 (CꢁS)
1.8–2.5 (6H, m, CH2-6, CH2-7, CH2-8), 5.2
(1H, d, H-4), 7.2–7.8 (4H, m, arom); 9.7
(1H, s, N1-H), 10.7 (1H, s, N3-H).
2
104–106 69 C22H19N2O2SF
(394.44)
235–237 58 C22H17N2OSF
(376.43)
66.99
67.20
70.19
70.50
59.20
59.40
61.35
61.10
60.36
60.10
63.14
63.30
61.99
61.70
4.85
4.60
4.54
4.70
4.30
4.60
3.71
3.50
4.74
4.50
5.62
5.40
4.89
4.60
7.10
7.40
7.44
7.10
9.20
9.30
15.89
15.60
8.79
8.60
9.20
9.50
12.75
12.50
3410 (NH), 1710, 1655 (2CꢁO), 1600 (CꢁN)
1650 (CꢁO), 1600 (CꢁN).
1.4–2.6 (6H, m, CH2-6, CH2-7, CH2-8), 4.2 (2H, s, SCH2),
5.2 (1H, d, H-4), 7.2–7.8 (9H, m, arom), 9.8 (1H, s, N3-H).
1.7–2.7 (6H, m, CH2-7, CH2-8, CH2-9), 6.4 (1H, s, H-5),
7.1–7.6 (9H, m, arom), 8.1 (1H, s, H-2)
1.6–2.6 (6H, m, CH2-6, CH2-7, CH2-8), 6.6 (1H, s, H-4),
7.0–7.6 (4H, m, arom), 8.3 (1H, s, CHO), 9.4 (1H, s, N1-H).
3
5
129–131 71
C15H13N2O2SF
3250 (NH), 1700, 1650 (2CꢁO), 1520, 1240
(304.32)
167–169 64 C18H13N4OSF
(352.37)
(CꢁS)
6
3320 (NH), 2220 (CꢀN), 1655 (CꢁO), 1600
(CꢁN)
7
210–212 66
C
16H15N2O2SF
3200 (NH), 1730, 1680 (2CꢁO), 1510, 1250
(CꢁS)
1.8–2.6 (6H, m, CH2-6, CH2-7, CH2-8), 2.7 (3H, s, COCH3),
6.4 (1H, s, H-4), 7.0–7.4 (4H, m, arom), 11.9 (1H, s, N1-H)
1.6–2.5 (6H, m, CH2-6, CH2-7, CH2-8), 2.9 (3H, s, SCH3),
3.1 (3H, s, N-CH3), 6.7 (1H, s, H-4), 7.0–7.4 (4H, m, arom).
1.4–2.5 (6H, m, CH2-6, CH2-7, CH2-8), 4.2 (2H, t, CH2CN),
5.2 (2H, t, N-CH2), 6.2 (1H, s, H-4), 7.0–7.6 (4H, m, arom),
9.8 (1H, s, N1-H).
1.6–2.5 (6H, m, CH2-7, CH2-8, CH2-8, CH2-9); 5.7 (2H, s, NH2),
6.4 (1H, s, H-4), 7.1–7.6 (4H, m, arom).
1.4–2.6 (6H, m, CH2-7, CH2-8, CH2-9); 5.7 (2H, s, NH2),
6.6 (1H, s, H-11), 7.1–7.6 (4H, m, arom), 8.3 (1H, s, H-2).
1.6–2.6 (6H, m, CH2-7, CH2-8, CH2-9); 6.5 (1H, s, H-11),
7.2–7.6 (4H, m, arom), 8.2 (1H, s, H-2), 9.6 (1H, s, NH).
(318.35)
8
\300 53
C16H17N2OSF
(304.36)
1660 (CꢁO), 1600 (CꢁN)
/
10
260–262 49
C17H16N3OSF
3260 (NH), 2950 (CH aliph), 2240 (CꢀN),
1640 (CꢁO), 1540, 1210 (CꢁS)
(329.37)
12 a
13
235–237 92 C17H13N4OSF
(340.36)
59.99
60.20
58.84
58.60
58.69
58.90
59.10
59.30
57.45
57.10
60.61
60.30
59.67
59.80
59.67
59.40
56.97
56.70
50.48
50.20
55.28
55.10
3.84
3.60
3.83
3.90
3.55
3.30
3.71
3.40
3.96
3.60
3.81
3.70
3.95
3.70
3.95
3.60
4.21
4.40
3.23
3.10
3.27
3.50
16.46
16.20
19.06
19.30
15.20
15.50
20.67
20.40
19.70
19.80
14.72
14.40
14.65
14.50
14.65
14.90
15.63
15.90
13.85
13.50
18.95
18.70
3300, 3180 (NH2), 2200 (CꢀN), 1650 (CꢁO)
3310, 3170 (NH2), 1690 (CꢁO), 1600 (CꢁN)
3280, (NH), 1695, 1650 (2CꢁO), 1600 (CꢁN)
\300 78
C18H14N5OSF
(367.38)
(
14
252–254 68 C18H13N4O2SF
(368.37)
287–289 66 C20H15N6OSF
(406.42)
249
15
3400, 3320, 3270, 3190 (2NH2), 2200 (CꢀN),
1600 (CꢁN)
3415, 3260, 3200 (NH, NH2), 1600 (CꢁO),
1610 (CꢁN)
3250, 3210 (NH2), 1660 (CꢁO), 1600 (CꢁN)
255
16
\300 53
152–154 68
\300 59
C17H14N5OSF
(355.37)
1.5–2.6 (6H, m, CH2-6, CH2-7, CH2-8); 5.6 (2H, s, NH2),
6.8 (1H, s, H-10), 7.1–7.6 (4H, m, arom), 9.4 (1H, s, NH).
1.4–2.5 (6H, m, CH2-7, CH2-8, CH2-9); 5.7 (2H, s, NH2),
6.8 (1H, s, H-11), 7.2–7.9 (9H, m, arom)
1.3–2.4 (6H, m, CH2-7, CH2-8, CH2-9); 2.6 (3H, s, COCH3),
6.5 (1H, s, H-5), 7.0–7.6 (4H, m, arom), 9.1 (1H, s, NH)
1.4–2.5 (6H, m, CH2-7, CH2-8, CH2-9); 2.2 (3H, s, CH3),
6.5 (1H, s, H-11), 7.1–7.7 (4H, m, arom), 9.3 (1H, s, NH)
17
C
24H18N5OS2F
(475.54)
19H15N4O2SF
(382.39)
18
C
3360, (NH), 2930 (CH aliph), 2210 (CꢀN),
1710, 1670 (2CꢁO), 1605 (CꢁN)
3340 (NH), 1700, 1600 (2CꢁO), 1610 (CꢁN)
19
150–152 76 C19H15N4O2SF
(382.39)
20
274–276 81
\300 62
\300 51
C
17H15N4O2SF
3410, 3320, 3250, 3180 (2NH2), 1660, 1650
(2CꢁO), 1600 (CꢁN)
3360, 3280 (2NH), 1720, 1690 (2CꢁO), 1610
(CꢁN)
3290 (NH), 1695, 1670 (2CꢁO), 1610 (CꢁN)
(358.37)
C17H13N4O3S2F
(404.42)
21 a
22 a
C
17H12N5O2SF
(369.36)
a MS: m/z (%) for compound 1: 276 (57.82, M+, 277 (12.57, M+1), 278 (3.34, M+2), 122 (100); 12: 340 (3.65, M+), 341 (0.85, M+1), 25 g (100); 21: 404 (9.14, M+), 157 (100); 22: 369 (6.05,
M+), 69 (100).

M.M. Ghorab et al. / Il Farmaco 55 (2000) 249–255
253
mixture was concentrated under reduced pressure. The
3.8. 3-(2-Cyanoethyl)-4-(4%-fluorophenyl)-2-
separated solid was filtered off and crystallized from
thioxo-1,2,3,4,5,6,7,8,-octahydroquinazolin-5-one (10)
C2H5OH to give 2.
A mixture of 1 (0.005 mol) and acrylonitrile (0.005
mol) in pyridine (20 ml) was refluxed for 4 h. Then it
was cooled and poured into an ice–HCl mixture. The
separated solid was filtered off, washed with H2O, dried
and crystallized from C2H5OH to give 10.
3.3. 3-Phenyl-5-(4-fluorophenyl)-5,6,7,8,9-
pentahydrothiazolo[2,3-b]quinazolin-6-one (3)
3.3.1. Method A
A suspension of 2 (0.005 mol) in 98% H2SO4 (5 ml)
was stirred for 2 h, then left at r.t. overnight. The solid
formed, pouring the clear solution in ice-water (100 ml)
under stirring, was collected, washed with water, dried
and crystallized from dioxane to give 3.
3.9. 3-Amino-2-cyano-5-(4%-fluorophenyl)-5,6,7,8,9-
pentahydrothiazolo[2,3-b]-quinazolin-6-one (12)
Compound 1 (0.005 mol) was dissolved in an
aqueous solution of KOH (0.005 mol). The solution
was stirred at r.t., subsequently a solution of bromoma-
lononitrile (0.005 mol) in ethanol was added dropwise
over a period of 30 min. The reaction mixture was
stirred for a further 2 h at r.t. and the resulting precip-
itate was collected by filtration, washed with water
several times and dried. The crude product was crystal-
lized from C2H5OH to give 12.
3.3.2. Method B
To a solution of 1 (0.005 mol) in abs. C2H5OH
(50 ml), was added phenacyl bromide (0.005 mol).
The resulting mixture was refluxed for 24 h and
the obtained solid was crystallized from dioxane to give
3.
3.4. 3-Formyl-4-(4%-fluorophenyl)-2-thioxo-
1,2,3,4,5,6,7,8-octahydroquinazoline-5-one (5)
3.10. 4-Amino-11-(4%-fluorophenyl)- 7,8,9,10,11-
pentahydropyrimidino[4%,5%:4,5]-thiazolo[2,3-b]-
quinazolin-10-one (13)
To a solution of 1 (0.005 mol) in dry DMF (30 ml);
POCl3 (0.009 mol) was added under stirring in an-
ice-bath. Stirring was continued at r.t. for another
15 min and then the solution was poured into ice-
water, filtered, dried and crystallized from C2H5OH to
give 5.
A solution of 12 (0.005 mol) in formamide (20 ml)
was refluxed for 6 h. The reaction mixture was cooled,
diluted with water and the resulting precipitate was
collected by filtration and crystallized from C2H5OH to
give 13.
3.5. 2-Imino-3-cyano-6-(4%-fluorophenyl)-6,7,8,9,10-
pentahydro[1,3]thiazino[2,3-b]quinazolin-7-one (6)
3.11. 11-(4%-fluorophenyl)-3,4,7,8,9,10,11-
heptahydropyrimidino[4%,5%:4,5]thiazolo[2,3-b]-
quinazolin-4,10-dione (14)
To a solution of 5 (0.005 mol) in C2H5OH (25 ml),
malononitrile (0.005 mol), and triethylamine (0.5 ml)
were added; the mixture was refluxed for 6 h. Then the
reaction mixture was cooled and the solid obtained was
crystallized from C2H5OH to give 6.
3.11.1. Method A
A solution of 12 (0.005 mol) in formic acid (10 ml),
was refluxed for 4 h. The solid obtained was crystallized
from C2H5OH to give 14.
3.6. 3-Acetyl-4-(4%-fluorophenyl)-2-thioxo-
1,2,3,4,5,6,7,8-octahydroquinazolin-5-one (7)
3.11.2. Method B
A solution of 20 (0.005 mol) in formamide (20 ml)
was refluxed for 8 h. The obtained solid was crystallized
from C2H5OH to give 14.
To a solution of 1 (0.005 mol) in Ac2O (30 ml) was
refluxed for 2 h. The separated product was filtered off
and crystallized from C2H5OH to give 7.
3.12. 2,4-Diamino-3-cyano-11-(4-fluorophenyl)-
7,8,9,10,11-pentahydropyrido[2%,3%:4,5]thiazolo[2,3-b]-
quinazolin]-10-one (15)
3.7. 2,3-Dimethyl-4-(4%-fluoropheny)-
3,4,5,6,7,8,-hexahydroquinazolin-5-one (8)
A suspension of 12 (0.005 mol) in C2H5OH (20 ml)
containing a catalytic amount of triethylamine was
treated with malononitrile (0.005 mol). The reaction
mixture was refluxed for 10 h. The separated solid was
filtered off and crystallized from dioxane to give 15.
A mixture of 1 (0.005 mol) and methyl iodide (0.005
mol) in acetone (50 ml) in presence of (1 g) anhydrous
K2CO3 was refluxed for 24 h. The obtained solid was
crystallized from C2H5OH to give 8.

254
M.M. Ghorab et al. / Il Farmaco 55 (2000) 249–255
3.13. 3-Amino-10-(4-fluorophenyl)-1,6,7,8,9,10-
hexahydropyrazolo[3%,4%:4,5]-thiazolo[2,3-b]-
quinazolin-9-one (16)
3.19. 11-(4%-fluorophenyl)-3,4,7,8,9,10,11-
heptahydro[1,2,3]triazino[4,5%:4,5]-thiazolo[2,3-b]-
quinazolin-4,10-dione (22)
A solution of 12 (0.005 mol), hydroxylamine hy-
drochloride (0.005 mol) and sodium ethoxide (0.005
mol) in abs C2H5OH (50 ml) was refluxed for 8 h. The
separated solid was filtered and crystallized from
C2H5OH to give 16.
To a stirred suspension of 20 (0.005 ml) in a mixture
of acetic acid (8 ml) and water (4 ml) a solution of
sodium nitrite (0.005 mol) in water (6 ml) was added
dropwise at 0°C. The mixture was left in the refrigera-
tor for 12 h and the precipitate was collected by filtra-
tion and crystallized from C2H5OH to give 22.
3.14. 4-Amino-3-phenyl-2-thioxo-11-(4%-fluorophenyl)-
2,3,7,8,9,10,11-heptahydropyrimidino[4%,5%:4,5]-
thiazolo[2,3-b]quinazolin-10-one (17)
4. Antifungal activity
Most of the newly synthesized compounds were
tested for their antifungal activity against four species
of fungi namely, Aspergillus ochraceus Wilhelm
(AUCC-230), Penicillium chrysogenum Thom (AUCC-
530), Aspergillus fla6us Link (AUCC-164) and Candida
albicans Robin Berkho (AUCC- 1720), using the hole
cupplate agar diffusion method [17].
A mixture of 12 (0.005 mol), phenyl isothiocyanate
(0.005 mol) and pyridine (20 ml) was refluxed for 6 h.
The reaction mixture was cooled, diluted with water
and resulting solid was crystallized from dioxane to
give 17.
The tested compounds were dissolved in N,N-
dimethylformamide (DMF) to get a solution of 1000
mg/ml concentration. The fungi cultures were main-
tained on Czapek’s Dox agar medium. Dimethylfor-
mamide showed no inhibition zones. The minimum
inhibitory concentration (MIC) of the active com-
pounds were measured using the serial dilution method.
Five dilutions from the stock solution in DMF equiva-
lent to 100, 50, 40, 25 and 20 mg/ml, respectively were
used. The fungicide Trosyd (Tioconazole) was used as a
reference to evaluate the potency of the tested com-
pounds. Zone diameter of inhibition (mm) were mea-
sured in at the end of an incubation period of 48 h at
28°C. The results are illustrated in Table 2, compounds
3 and 14, were found to be the more active compounds,
nearly as Trosyd, against Aspergillus ochraceus and
Aspergillus fla6us (MIC values 40 mg/ml). On the other
hand compounds 10, 12, 14, 19 (MIC values 40 mg/ml)
and 17, 21 (MIC values 50 mg/ml) possess high activity,
nearly as Trosyd, against Penicillium Chrysogenum,
while only compound 12 (MIC values 40 mg/ml), exhib-
ited a high activity, nearly as Trosyd, against Candida
albicans.
3.15. 3-Acetylamino-2-cyano-5-(4%-fluorophenyl)-
5,6,7,8,9-pentahydrothiazolo-[2,3-b]quinazolin-6-one
(18)
A solution of 12 (0.005 mol) in Ac2O (10 ml) was
refluxed for 2 h. The obtained solid was crystallized
from C2H3OH to give 18.
3.16. 2-Methyl-11-(4%-fluorophenyl)-3,4,7,8,9,10,11-
heptahydropyrimidino[4%,5%:4,5]thiazolo[2,3-b]-
quinazolin-4,10-dione (19)
A solution of 20 (0.005 mol) in Ac2O (20 ml) was
refluxed for 6 h. The obtained solid was crystallized
from C2H5OH to give 19.
3.17. 3-Amino-2-carboxamido-5-(4%-fluorophenyl)-
5,6,7,8,9-pentahydrothiazolo[2,3-b]quinazolin-6-one (20)
Compound 12 (0.005 mol) was dissolved in conc.
H2SO4 (20 ml) and stirred at r.t. for 2 h.The reaction
mixture was diluted with ice–cold water and neutral-
ized with ammonium hydroxide. The resulting precipi-
tate was collected by filtration, dried and crystallized
from C2H3OH to give 20.
5. Discussion and conclusions
From the biological assay it was found that com-
pounds containing both the quinazoline and the pyrim-
idinothiazole moieties (13, 14, 17, 19) were found to be
the most active compounds against Aspergillus
ochraceus, Penicillium Chrysogenum and Aspergillus
fla6us compared to Trosyd, while compounds contain-
ing both the quinazoline and thiazole moieties (3, 12)
were found to be the most active compounds against
3.18. 11-(4%-fluorophenyl)-2-sulfoxido-
1,3,4,7,8,9,11-heptahydro[1,2,6]thiadiazino[4%,5%:4,5]-
thiazolo[2,3-b]quinazolin-4,10-dione (21)
A solution of 20 (0.005 mol) in thionyl chloride (10
ml) was refluxed for 4 h. The obtained solid was
crystallized from C2H5OH to give 21.

M.M. Ghorab et al. / Il Farmaco 55 (2000) 249–255
255
Table 2
Antifungal activity of some quinazoline derivatives
Compd. no.
Aspergillus ochraceus Wilhelm Penicillium chrysogenum
Aspergillus fla6us Link
Candida albicans (Robin)
(AUCC-230)
Thom (AUCC-530)
(AUCC-164)
Berkho (AUCC-1720)
Diameter
(mm)
MIC
(mg/ml)
Diameter
(mm)
MIC
(mg/ml)
Diameter
(mm)
MIC
(mg/ml)
Diameter
(mm)
MIC
(mg/ml)
1
2
3
5
8
10
12
13
14
17
18
19
12
18
30
12
12
20
18
20
30
18
18
18
18
8
10
20
18
18
20
30
30
20
30
28
16
30
28
12
30
8
8
16
30
10
14
20
20
28
30
18
18
16
18
8
18
20
8
40
40
40
18
20
30
18
18
18
18
18
16
8
40
40
40
50
40
40
50
40
50
21
22
Trosyd a
30
32
34
a Manufactured by Pfizer-Egypt, S.A.E., Cairo, A.R.E. under authority of Pfizer INC., USA.
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We thank Dr M.M. Afifi, Microbiology Department
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