Synthesis of new furothiazolo pyrimido quinazolinones from visnagenone or khellinone and antimicrobial activity

Article abstract of DOI:10.3390/molecules23112793

Substituted-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-ones (5a,b) were synthesized from condensation of visnagenone (2a) or khellinone (2b) with 6-amino-thiouracil (3) in dimethylformamide or refluxing of (4a) or (4b) in dimethylformamide. Hence, compounds (5a,b) were used as the starting materials for preparing many new heterocyclic compounds such as; furo[3,2-g]pyrimido[1,6-a]quinazoline (6a,b), furo[3,2-g]thiazolo[20,30:2,3] pyrimido[1,6-a]quinazolinone (7a,b), substituted-benzylidene-furo[3,2-g]thiazolo[20,30:2,3]pyrimido [1,6-a]quinazoline-3,5-dione (8a-f), 3-oxo-furo[3,2-g]pyrimido[1,6-a]quinazoline-pentane-2,4-dione (9a,b), 1-(pyrazole)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (10a,b), 2-(oxo or thioxo)-pyrimidinefuro[ 3,2-g]pyrimido[1,6-a]quinazolinone (11a-d), 1-(methylthio)-furo[3,2-g]pyrimido[1,6-a] quinazolinone (12a,b), 1-(methyl-sulfonyl)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (13a,b) and 6-methyl-1-((piperazine) or morpholino)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14a-d). The structures of the prepared compounds were elucidated on the basis of spectral data (IR, 1H-NMR, 13C-NMR, MS) and elemental analysis. Antimicrobial activity was evaluated for the synthesized compounds against Gram-positive, Gram-negative bacteria and fungi. The new compounds, furothiazolo pyrimido quinazolines 8a-f and 11a-d displayed results excellent for growth inhibition of bacteria and fungi.

Full text of DOI:10.3390/molecules23112793

molecules
Article
Synthesis of New Furothiazolo Pyrimido
Quinazolinones from Visnagenone or Khellinone
and Antimicrobial Activity
Ameen Ali Abu-Hashem 1,2
1
Photochemistry Department (Heterocyclic Unit), National Research Centre, Dokki, Giza1 2622, Egypt;
aminaliabuhashem@yahoo.com; Tel.: +2-01225211700 or +966-591363915; Fax: + 202-33370931
Chemistry Department, Faculty of Science, Jazan University, 2097 Jazan, Saudi Arabia
2
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Josef Jampilek
Received: 5 October 2018; Accepted: 24 October 2018; Published: 27 October 2018
Abstract: Substituted-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-
ones (5a ) were synthesized from condensation of visnagenone (2a) or khellinone (2b) with 6-
amino-thiouracil ( ) in dimethylformamide or refluxing of (4a) or (4b) in dimethylformamide.
Hence, compounds (5a ) were used as the starting materials for preparing many new heterocyclic
compounds such as; furo[3,2-g]pyrimido[1,6-a]quinazoline (6a
), furo[3,2-g]thiazolo[20,30:2,3]
pyrimido[1,6-a]quinazolinone (7a
), substituted-benzylidene-furo[3,2-g]thiazolo[20,30:2,3]pyrimido
[1,6-a]quinazoline-3,5-dione (8a ), 3-oxo-furo[3,2-g]pyrimido[1,6-a]quinazoline-pentane-2,4-dione
9a ), 1-(pyrazole)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (10a ), 2-(oxo or thioxo)-pyrimidine-
furo[3,2-g]pyrimido[1,6-a]quinazolinone 11a ), 1-(methylthio)-furo[3,2-g]pyrimido[1,6-a]
quinazolinone (12a ), 1-(methyl-sulfonyl)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (13a ) and
).
,b
3
,
b
,
b
,
b
–f
(
,b
,b
(
–d
,b
,b
6-methyl-1-((piperazine) or morpholino)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14a–d
The structures of the prepared compounds were elucidated on the basis of spectral data (IR, 1H-NMR,
13C-NMR, MS) and elemental analysis. Antimicrobial activity was evaluated for the synthesized
compounds against Gram-positive, Gram-negative bacteria and fungi. The new compounds,
furothiazolo pyrimido quinazolines 8a–f and 11a–d displayed results excellent for growth inhibition
of bacteria and fungi.
Keywords: visnagenone; khellinone; quinazolinone; pyrimidine; thiazole; pyrazole; furane;
antimicrobial activity
1. Introduction
Physicians confirm the usefulness of adding many naturally occurring drugs. Furochromones
(visnagin and khellin) compounds are natural products extracted from the plant of Ammi visnaga
Lam. and visnagin and khellin are used as therapy for kidney, bladder stones, diuretic infusions [
and are considered essential components of many drugs [ ]. As well, furochromone derivatives
are reported as anti-atherosclerotic, antineoplastic, anti-gastric, anti-anaphylactic and are used in
the treatment of urolithiasis, hypertriglyceridemia [ ] and vitiligo [ ]. Also, the visnaginone
derivatives were synthesized using different procedures and elucidated efficient antimicrobial
activities [ ]. Furthermore, furochromones have been used to treat pain in the renal colic [
and possesses coronary vasodilating activity [10 11]. Moreover, khellin and visnagin have been
1,2]
3
4,
5
6
7,
8
9]
,
used in the photo-chemotherapeutic treatment of vitiligo and psoriasis [12], photoreaction with
DNA [13] and Khellin displayed important epidermal growth factor receptor (EGFR) inhibitory
activity [14]. Benzofurans and furochromones [15–18] are very exciting heterocycles, which are
omnipresent in nature and display a wide range of pharmacological activities. Recently, furochromones
Molecules 2018, 23, 2793; doi:10.3390/molecules23112793
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2793
2 of 20
and benzofurans derivatives are used as in antiviral and anticancer activities [19
,20]. When fused of
furochromones with pyrimidine, quinoxaline and pyrazole derivatives showed anti-inflammatory and
analgesic activities [21], the cytotoxic activity [22] and used in the protection of DNA [23]. Additionally,
some of the moieties heterocyclic such as, chalcones [24], thiazolidinones [25], Mannich bases [26],
sulfonamides [27], and isoxazole [28], too, showed several of biological activity with benzofuran
derivatives (visnagenone, khellinone) (Figure 1).
Figure 1. Chemical structure of furochromone derivatives.
An extension of our work on the preparation of novel heterocyclic compounds resultant from the
naturally occurring visnagin and khellin [21–23,29], we synthesized and described several derivatives
which contained a benzofuran moiety (visnaginone, khellinone) incorporated with thiazole, pyrimidine,
pyrazole, and quinazolinone derivatives. The antimicrobial activity of the prepared compounds
were evaluated.
2. Results and Discussion
2.1. Synthesis
In the present work, the natural furochromones (visnagin 1a or khellin 1b) are highly sensitive
to alkali. Hence, aqueous alkaline hydrolysis of 1a and 1b using potassium hydroxide with heating
and stirring at 40–50 ◦C for 1–2 h lead to form visnagenone 2a or khellinone 2b, respectively [22
,
23].
Moreover, heating under reflux cyclic alfa, beta-unsaturated ketones (visnagenone 2a or khellinone
2b) with 6-aminothiouracil ( ) in dimethylformamide solution [21 22] with stirring for 4–6 h
or 14–16 h under (TLC) afforded new compounds respectively, 6-((1-(6-hydroxy-(4-methoxy or
4,7-dimethoxy)-benzofuran-5-yl)ethylidene)amino)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (4a
and (7-methoxy or 7,11-dimethoxy)-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]
quinazolin-3-one (5a ) in good yield obtained. Also, another method, stirring under reflux of 4a
3
,
,b)
,
b
or 4b in dimethylformamide solution for 8–10 h afforded the same products 5a and 5b, respectively.
The 1H-NMR spectrum of compound 4a showed three singlet broad signal at 10.80, 11.19 and 16.11 ppm
corresponding to the three protons of the (2NH) and one (OH) groups, which were D2O exchangeable
and 1H-NMR spectrum of compound 5a showed one singlet broad signal at 11.20 ppm conforming
to the one proton of the one (NH) group (D2O exchangeable) and the mass spectra of 4a, 4b, 5a and
5b showed molecular ion peaks at m/z 331 (M+, 100%) and 361 (M+, 100%), 313 (M+, 100%), 343 (M+,
100%) respectively (Scheme 1).

Molecules 2018, 23, 2793
3 of 20
Scheme 1. Synthesis of furopyrimido quinazolinones from visnagenone and khellinone derivatives.
In this research, simple and convenient methods to the syntheses of furopyrimido quinazoline,
furothiazolo pyrimido quinazolinone and furothiazolo pyrimido quinazolinone benzylidene
derivatives [30]. Thus, refluxing of 5a or 5b with chloroacetic acid in glacial acetic acid/acetic anhydride
and anhydrous sodium acetate for 3–5 h or 13–15 h with control via (TLC) to give new compounds
followed by, 2-(((7-methoxy or 7,11-dimethoxy)-6-methyl-3-oxo-3H-furo[3,2-g]pyrimido[1,6-a]
quinazolin-1-yl)thio)acetic acid (6a
,
b
) and (9-methoxy or 9,13-dimethoxy)-8-methyl-2-hydro-5H,14aH-
furo[3,2-g]thiazolo[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (7a
,b) in high yields. Moreover,
the boiling of 6a or 6b in dimethylformamide solution resulted in the same formation of 7a and
7b. The IR spectrum of compounds 6a and 6b exposed the presence of broad band absorption
at 3340–3350 cm−1 indicative of one (OH) group and 6a = 1745, 1684 cm−1 and 6b = 1748,
1
1681 cm−1 of the two carbonyl groups. The H-NMR spectrum of 6a showed a singlet broad
signal at 13.70 ppm corresponding to the one protons of the one (OH) group, which were D2O
1
exchangeable. Also, H-NMR spectrum of 7b displayed a five singlet signal at
δ 2.33, 3.97, 4.24,
5.62 and 7.39 ppm conforming to the thirteen protons of the methyl, two methoxy, (CH2), (CH,
thiazole) and (CH, pyrimidine) groups, respectively. As well as using one-pot synthesis as follows:
when a ternary mixture of 5a or 5b, chloroacetic acid and a proper aldehyde namely; benzaldehyde,
4-chlorobenzaldehyde or 4-methoxybenzaldehyde respectively, was heated under reflux in a mixture of
acetic acid and acetic anhydride in the presence of anhydrous sodium acetate afforded the conforming
2-(substituted-benzylidene)-9,(substituted)-methoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo
[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8a
–f) in high yields. In another route, we obtained on
the same compounds (8a
–
f
) via refluxing of 7a or 7b with appropriate aromatic aldehyde in dioxane
1
solution containing a catalyst amount of piperidine for 10–12 h. H-NMR spectrum of 8a showed six
singlets at 2.30, 3.91, 5.59, 7.32, 7.85 and 8.05 ppm conforming to the 10 protons of the methyl, methoxy,
thiazole proton, pyrimidine proton, phenyl proton and (CH) proton groups, respectively and two
doublet signals at 6.75, 7.72 ppm of the two protons (J = 2.30 Hz, furan). The structures assignments
for compounds were established on their elemental analysis and spectral (IR, 1H, 13C-NMR, and MS)
data are shown in the experimental section (Scheme 2).

Molecules 2018, 23, 2793
4 of 20
Scheme 2. Synthesis of furothiazolopyrimidoquinazolinone derivatives.
Alkylation of an ethanolic potassium hydroxide solution of 5a or 5b with 3-chloro-pentane-
2,4-dione (3-chloroacetylacetone) [30], yielded the 3-(((7-methoxy or 7,11-dimethoxy)-6-methyl-3-oxo-3H-
furo[3,2-g]pyrimido[1,6-a]quinazolin-1-yl)thio)pentane-2,4-dione (9a,b) in high yield. The IR spectra
of 9a and 9b showed a strong absorption bands at 9a = 1725, 1721, 1682 cm−1 and 9b = 1728, 1722,
1684 cm−1 characteristic to three carbonyl groups, respectively. The 13C-NMR (DMSO-d6, ppm) of
9a showed signals at 68.2, 91.3 and 96.5 for three carbon atoms of (CH), (CH, phenyl) and (CH,
pyrimidine) and signals at 168.6, 184.5 and 188.2 three carbon atoms of the three carbonyl groups,
and the molecular ion peaks of 9a and 9b at m/z 411 (95%) and 441 (90%), respectively. On the other
hand, compounds 9a and 9b, as a typical 1,3-diketone condensation with each of hydrazine hydrate,
urea and thiourea to afford the corresponding 1-((3,5-dimethyl-1H-pyrazol-4-yl)thio)-(7-methoxy or
7,11-dimethoxy)-6-methyl-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (10a,b) and 1-((4,6-dimethyl-
2-(oxo or thioxo)-1,2-dihydropyrimidin-5-yl)thio)-(7-methoxy or 7,11-dimethoxy)-6-methyl-3H-furo[3,2-g]
pyrimido[1,6-a]quinazolin-3-one (11a–d), respectively. IR spectrum of 10a and 10b showed absorption
of a broad band at 3380–3360 cm−1 corresponding to NH group. Also, the compounds 11a
–
d
exhibited
1
absorption bands at 3390–3370 cm−1 for NH group were detected in the IR spectrum. H-NMR spectrum
of 10a showed one singlet at 11.50 ppm corresponding to the one proton of NH group and compound 11a
revealed one singlet at 10.60 ppm for one proton of NH group (D2O exchangeable). All new compounds

Molecules 2018, 23, 2793
5 of 20
were proven by elemental and spectral analysis (IR, 1H, 13C-NMR and MS) which is mentioned in the
experimental part (Scheme 3).
Scheme 3. Synthesis of pyrazole, pyrimidine, -furopyrimido quinazolinone derivatives.
Alkylation of an ethanolic potassium hydroxide solution of 5a or 5b with methyl-iodide
yielded the (7-methoxy or 7,11-dimethoxy)-6-methyl-1-(methylthio)-3H-furo[3,2-g]pyrimido[1,6-a]
quinazolin-3-one (12a,b). Assignment of structures 12a and 12b to the reaction products is based
on correct elemental analysis and IR, NMR spectroscopy are in agreement with the structure. Thus,
1H-NMR spectrum of 12a or 12b showed one singlet signal at 2.80 or 2.88 ppm indicative of three
protons to (SCH3) group and the molecular ion peaks of 12a or 12b displayed at m/z 327 (M+, 100%)
and 357 (M+, 100%), respectively. Moreover, oxidation of 12a or 12b with hydrogen peroxide in
acetic acid yielded the (7-methoxy or 7,11-dimethoxy)-6-methyl-1-(methylsulfonyl)-3H-furo[3,2-g]
pyrimido[1,6-a]quinazolin-3-one (13a
,
b
). The IR spectrum of 13a exposed the presence of two
1
bands at 1162, 1340 cm−1 corresponding to (SO2) group, and H-NMR spectrum of 13a exhibited
one singlet at 2.95 agreeing to the three protons of (SO2CH3) group. Furthermore, heating under
refluxing compounds 12a or 12b with secondary aliphatic amines [21
,22,30], namely piperazine or
morpholine in methanol, produced the (7-methoxy or 7,11-dimethoxy)-6-methyl-1-((piperazin-1-yl) or
morpholino)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14a–d). IR spectrum of 14a displayed
absorption bands at 3390, 1687 cm−1 conforming to NH and carbonyl group, respectively. Additionally,
the 1H-NMR spectrum of 14c displayed a singlet broad signal at 10.35 ppm conforming to the one
proton of the one (NH) group, which was D2O exchangeable. The mass spectrum of 13a, 13b, 14a, 14b,
14c and 14d revealed molecular ion peaks at m/z 359 (M+, 84%), 389 (M+, 80%), 365 (M+, 83%), 366 (M+,
78%), 395 (M+, 76%) and 396 (M+, 74%), respectively (Scheme 4).

Molecules 2018, 23, 2793
6 of 20
Scheme 4. Synthesis of piperazine, morpholine, -furopyrimido-quinazolinone derivatives.
2.2. Biological Screening
The antimicrobial activity of the compounds was tested in vitro and the results are shown in
Tables 1 and 2. Some of these compounds indicated highest antimicrobial activity, comparable
to cefotaxime sodium (MIC = 2–5
potent antimicrobial activity against Gram-positive bacteria; Staphylococcus aureus (ATCC®6538
Streptococcus pyogenes (ATCC®19615™) and Gram-negative bacteria; Escherichia coli (ATCC®25922™),
Klebsiella pneumoniae (ATCC® 10031
). Also, another compounds; 14a 7a and 9a exhibited
moderate antimicrobial activities. The MIC values in
mol mL−1 of these compounds were as
the following, 8a (1–8), 11 a (6–10), 10a (9–12). Compounds 8a and 11a exposed too
higher antifungal activity with MIC in (2–9) and 11a (7–12) whose results
mol/cm3 of 8a
were comparable with the positive control, nystatin (MIC 2-4
mol mL−1). Some of compounds
revealed moderate anti-fungal activity when compared with the nystatin (MIC 2–4
mol mL−1):
10a (10–14), 14a (12–18), 7a (15–20) and 9a (17–22). The tested fungi were Aspergillus niger
(ATCC® 16888 ), Alternaria alternate, Curvularia lunata and Candida albicans (ATCC®10231
). Thru
µ
mol mL−1). Compounds 8a
–
f
,
11a
–
d
and 10a
–
b
displayed
™),
™
–
d,
–
b
–b
µ
–
f
–
d
–
b
–f
–d
µ
–
f
–d
µ
µ
–
b
–
d
–
b
–b
™
™
comparing the observed antimicrobial activities of the furopyrimido quinazolinones, furothiazolo
pyrimido quinazolinones obtained in this study to their structures, the (SAR’s) were suggested; the
presence of the functional groups linked with visnagenone 2a or khellinone 2b derivatives, such as
thioxo, methyl, hydroxyl, methoxy, amino, chloro, substituted-benzylidene, thiazole, quinazoline,
pyrimidine, pyrazole, methylsulfonyl, piperazine and morpholine moieties. Remainder the compounds
demonstrated a weak activity compared to the antimicrobial activity of the standard drugs (cefotaxime
sodium and nystatin). The thiazolopyrimidine derivatives possessing verified to be effective
as antimicrobial agents in previous articles [
aureus, E. coli, and Klebsiella pneumoniae [ 31] and they were also effective against Streptococcus
pyogenes and species of fungi, namely, Aspergillus niger, Candida albicans [ 32]. In this work and
previous reports, most bacteria and fungi types effected susceptible to this class of heterocyclic
compounds [33 35]. Moreover, previous results and our findings corroboration the promising
7,8]. Also, they were active against Staphylococcus
7,
7,
–
antimicrobial activity of furothiazolopyrimidoquinazolinone derivatives which can be developed
to higher antimicrobial activities

Molecules 2018, 23, 2793
7 of 20
Table 1. A minimum inhibitory concentration of the compounds against bacteria.
−1
MIC (µmol mL
Microorganisms
Gram-Positive Bacteria Gram-Negative Bacteria
Staphylococcus Streptococcus
Aureus Pyogenes
)
Compounds
Klebsiella
Pneumoniae
E. coli
1a
1b
2a
2b
3
4a
4b
5a
5b
6a
6b
7a
7b
8a
34
33
31
30
37
29
28
27
26
23
22
17
16
8
33
32
30
29
35
28
27
26
25
22
21
16
15
7
31
30
29
28
34
27
26
25
24
21
20
15
14
7
30
29
28
27
33
26
25
24
23
20
19
14
13
5
8b
8c
5
7
4
6
3
5
2
4
8d
8e
7
4
7
3
6
2
4
1
8f
9a
9b
10a
10b
11a
11b
6
5
4
3
19
18
12
11
10
9
18
17
11
11
10
8
17
16
10
10
9
16
15
10
9
8
7
7
11c
11d
10
8
9
8
8
7
7
6
12a
12b
13a
13b
14a
14b
14c
25
24
21
20
14
15
13
14
5
24
23
20
19
13
14
12
14
4
23
22
19
18
12
14
11
13
3
22
21
18
17
11
12
10
12
2
14d
Cefotaxime sodium
Negative control
NI
NI
NI
NI
DMSO was used as the negative control and as the solvent for test compounds and the reference drug.
NI–No inhibition.
Table 2. A minimum inhibitory concentration of the compounds against fungi.
−1
MIC (µmol mL
)
Microorganisms
Compounds
Aspergillus
Niger
Alternaria Curvularia Candida
Alternata
Lunata
Albicans
1a
1b
2a
2b
39
38
35
33
38
36
34
32
37
34
33
31
36
33
32
30

Molecules 2018, 23, 2793
8 of 20
Table 2. Cont.
−1
MIC (µmol mL
)
Microorganisms
Compounds
Aspergillus
Niger
Alternaria Curvularia Candida
Alternata
Lunata
Albicans
3
4a
4b
5a
5b
6a
6b
7a
7b
42
31
30
29
29
26
25
20
19
9
40
30
29
28
27
24
23
18
17
8
39
29
27
26
26
23
22
17
16
8
38
28
26
25
25
22
21
16
15
4
8a
8b
8c
6
8
5
7
4
6
3
5
8d
8e
9
5
8
4
7
3
5
2
8f
9a
9b
7
6
5
4
22
21
14
13
12
10
11
9
28
27
24
23
16
18
15
17
4
20
19
13
12
11
9
19
18
12
11
10
8
18
17
11
10
9
8
8
7
24
23
20
19
13
15
12
14
2
10a
10b
11a
11b
11c
11d
12a
12b
13a
13b
14a
14b
14c
14d
Nystatin
10
9
9
8
26
25
22
21
15
16
14
16
3
25
24
21
20
14
15
13
15
2
Negative control
NI
NI
NI
NI
DMSO was used as the negative control and as the solvent for test compounds and the reference drug.
NI–No inhibition.
3. Experimental Section
3.1. General Information
All melting points were taken on an Electrothermal IA 9100 series digital melting point apparatus
(Shimadzu, Tokyo, Japan). Elemental analyses were performed on Vario EL (Elementar, Langenselbold,
Germany). Microanalytical data were processed in the microanalytical center, Faculty of Science, Cairo
University and National Research Centre. The IR spectra (KBr disc) were recorded using a Perkin-Elmer
1650 spectrometer (Waltham, MA, USA). NMR spectra were determined using JEOL 270 MHz and
JEOL JMS-AX 500 MHz (JEOL, Tokyo, Japan) spectrometers with Me4Si as an internal standard. Mass
spectra were recorded on an EI Ms-QP 1000 EX instrument (Shimadzu, Japan) at 70 eV. Biological
evaluations were done by the antimicrobial unit, Department of Chemistry of Natural and Microbial
Products, National Research Centre, Egypt. All starting materials and solvents were purchased from
Sigma-Aldrich (Saint Louis, MO, USA).

Molecules 2018, 23, 2793
9 of 20
3.2. General Procedure for Synthesis of 6-((1-(6-Hydroxy-(4-methoxy or 4,7-dimethoxy)-benzofuran-5-yl)
ethylidene)amino)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (4a,b)
A mixture of visnaginone 2a (2.06 g, 0.01 mol) or khellinone 2b (2.36 g, 0.01 mol) with 6-amino-
2-thioxo-2,3-dihydropyrimidin-4(1H)-one
3 (1.43 g, 0.01 mol) in dimethylformamide (40 mL) was
refluxed for 4–6 h. The solid formed was filtered off, dried, and crystallized from the proper solvent to
give 4a and 4b, respectively.
3.3. Synthesis of 6-((1-(6-Hydroxy-4-methoxybenzofuran-5-yl)ethylidene)amino)-2-thioxo-2,3-dihydro
pyrimidin-4(1H)-one (4a)
The compound was obtained from the reaction of visnaginone (2a) with 6-amino-thiouracil (
as yellow crystals, crystallized from methanol in 90% yield, m.p. 231 ◦C. IR ( , cm−1) KBr: 3370 (brs,
2NH), 3030 (CH-aryl), 2960 (CH-aliph), 1685 (CO, amide), 1630 (C=N). 1H-NMR (DMSO-d6, ppm)
3)
ν
δ
2.38 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 6.79 (d, 1H, J = 2.35 Hz, furan), 7.80 (d, 1H, J = 2.38 Hz, furan),
7.92 (s, 1H, phenyl), 7.94 (s, 1H, pyrimidine), 10.80, 11.19 (br, 2H, 2NH, D2O exchangeable), 16.11 (br,
1H, OH, D2O exchangeable); 13C-NMR (DMSO-d6)
δ 21.3 (1C, CH3), 61.7 (1C, OCH3), 93.1 (1C, CH,
pyrimidine), 98.9 (1C, CH, phenyl), 100.5, 104.5, 108.9, 146.6, 146.9, 154.5, 160.9, 163.2, (8C, Ar-C), 164.1
(1C, C=N-ph), 168.1(1C, C=O), 173.5 (1C, C=S); MS (70 eV, %) m/z 331 (M+, 100%); Anal. Calc. (Found)
for C15H13N3O4S (331.35): C, 54.37 (54.30); H, 3.95 (3.91); N, 12.68(12.60).
3.4. Synthesis of 6-((1-(6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)amino)-2-thioxo-2,3-dihydro
pyrimidin-4(1H)-one (4b)
The compound was obtained from the reaction of khellinone (2b) with 6-amino-thiouracil (
yellowish crystals, crystallized from dioxane in 84% yield, m.p. 211 ◦C. IR ( , cm−1) KBr: 3371(brs,
2NH), 3032 (CH-aryl), 2965 (CH-aliph), 1682 (CO, amide), 1631 (C=N). 1H-NMR (DMSO-d6, ppm)
2.39 (s, 3H, CH3), 3.94 (s, 6H, 2OCH3), 6.80 (d, 1H, J = 2.34 Hz, furan), 7.83 (d, 1H, J = 2.37 Hz,
furan), 7.95 (s, 1H, pyrimidine), 10.81,11.20 (br, 2H, 2NH, D2O exchangeable), 16.12 (br, 1H, OH, D2O
exchangeable); 13C-NMR (DMSO-d6)
21.4 (1C, CH3), 61.6 (2C, OCH3), 93.2 (1C, CH, pyrimidine),
3) as
ν
δ
δ
100.5, 104.7, 109.9, 129.3, 146.2, 147.1, 153.8, 158.9, 164.7, (9C, Ar-C), 165.2 (1C, C=N-ph), 167.9 (1C,
C=O), 173.8 (1C, C=S); MS (70 eV, %) m/z 361 (M+, 100%); Anal. Calc. (Found) for C16H15N3O5S
(361.37): C, 53.18 (53.23); H, 4.18 (4.13); N, 11.63 (11.68).
3.5. General Procedure for Synthesis of (7-Methoxy or 7,11-dimethoxy)-6-methyl-1-thioxo-1,2-dihydro-
3H-furo[3,2-g]pyrimido [1,6-a]quinazolin-3-one (5a,b)
Method A: A mix of visnaginone 2a (2.06 g, 0.01 mol) or khellinone 2b (2.36 g, 0.01 mol) with
6-amino-2-thiouracil (3) in DMF (40 mL) was refluxed for 14–16 h. The product precipitated was
filtered off and washed with 100 mL water, dried and crystallized from the proper solvent to give 5a
and 5b, respectively. Method B: A refluxing of 4a (3.31 g, 0.01 mol) or 4b (3.61 g, 0.01 mol) in DMF
(40 mL) was refluxed for 8–10 h under control (TLC). The final precipitated was filtered off and washed
with 50 mL ethanol, dried, and crystallized from the proper solvent to give 5a and 5b, respectively.
3.6. Synthesis of 7-Methoxy-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-
3-one (5a)
The compound was obtained from the reaction of visnaginone (2a) with 6-aminothiouracil (3)
or compound (4◦a) in dimethylformamide, as yellowish crystals, crystallized from benzene in 85%
yield, m.p. 271 C. IR (ν
, cm−1) KBr: 3350 (brs, NH), 3028 (CH-aryl), 2955 (CH-aliph), 1680 (CO,
amide), 1635 (C=N). 1H-NMR (DMSO-d6, ppm)
J = 2.33 Hz, furan), 7.33 (s, 1H, pyrimidine), 7.80 (d, 1H, J = 2.36 Hz, furan), 8.29 (s, 1H, phenyl), 11.20
(br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6)
24.5 (1C, CH3), 61.8 (1C, OCH3), 79.7 (1C,
CH, pyrimidine), 99.1 (1C, CH, phenyl), 104.9, 108.9,116.6, 140.9, 146.6, 148.9, 160.1, 161.2, 164.1 (9C,
δ 2.32 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 6.75 (d, 1H,
δ

Molecules 2018, 23, 2793
10 of 20
Ar-C), 168.2 (1C, C=O), 173.6 (1C, C=S); MS (70 eV, %) m/z 313 (M+, 100%); Anal. Calc. (Found) for
C15H11N3O3S (313.33): C, 57.50 (57.58); H, 3.54 (3.59); N, 13.41(13.50).
3.7. Synthesis of 7,11-Dimethoxy-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]
quinazolin-3-one (5b)
The compound was obtained from the reaction of khellinone (2b) with 6-amino-thiouracil (
compound (4b) in dimethylformamide, as yellow crystals, crystallized from toluene in 82% yield, m.p.
251 ◦C. IR ( , cm−1) KBr: 3352 (brs, NH), 3029 (CH-aryl), 2957 (CH-aliph), 1681 (CO, amide), 1633
(C=N). 1H-NMR (DMSO-d6, ppm)
2.35 (s, 3H, CH3), 3.95 (s, 6H, 2OCH3), 6.77 (d, 1H, J = 2.31 Hz,
furan), 7.30 (s, 1H, pyrimidine), 7.82 (d, 1H, J = 2.37 Hz, furan), 11.25 (br, 1H, NH, D2O exchangeable);
13C-NMR (DMSO-d6)
24.6 (1C, CH3), 61.9 (2C, 2OCH3), 80.2 (1C, CH, pyrimidine), 105.1, 109.2, 115.9,
3) or
ν
δ
δ
125.8, 137.5, 142.8, 146.5, 149.2, 161.7, 164.8 (10C, Ar-C), 168.4 (1C, C=O), 173.8 (1C, C=S); MS (70 eV, %)
m/z 343 (M+, 100%); Anal. Calc. (Found) for C16H13N3O4S (343.36): C, 55.97 (55.90); H, 3.82 (3.75); N,
12.24 (12.29).
3.8. General Procedure for Synthesis of 2-(((7-Methoxy or 7,11-dimethoxy)-6-methyl-3-oxo-3H-furo[3,2-g]
pyrimido[1,6-a]quinazolin-1-yl)thio) Acetic Acid (6a,b)
A mixture from 5a (3.13 g, 0.01 mol) or 5b (3.43 g, 0.01 mol), chloroacetic acid (0.94 g, 0.01 mol)
and (0.02 mol) of anhydrous sodium acetate was stirred under reflux in 40 mL of glacial acetic acid
and 20 mL of acetic anhydride for 3–5 h. The reaction mixture was cooled and poured into cold water
(100 mL). The deposited precipitate was filtered off, and crystallized from appropriate solvent to
produce 6a and 6b, respectively.
3.9. Synthesis of 2-((7-Methoxy-6-methyl-3-oxo-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-1-yl)thio)
Acetic Acid (6a)
The compound was obtained from the reaction of (5a) with chloroacetic acid, as brownish crystals,
crystallized from hexane in 88% yield, m.p. 294 ◦C. IR ( , cm−1) KBr: 3340 (brs, OH), 3025 (CH-aryl),
ν
2950 (CH-aliph), 1745 (CO, acid), 1684 (CO, amide), 1631 (C=N). 1H-NMR (DMSO-d6, ppm)
δ 2.30 (s,
3H, CH3), 3.91 (s, 3H, OCH3), 4.27 (s, 2H, CH2), 6.77 (d, 1H, J = 2.32 Hz, furan), 7.35 (s, 1H, pyrimidine),
7.78 (d, 1H, J = 2.35 Hz, furan), 7.90 (s, 1H, phenyl), 13.70 (br, 1H, OH, D2O exchangeable); 13C-NMR
(DMSO-d6)
δ 23.6 (1C, CH3), 32.8 (1C, CH2), 61.7 (1C, OCH3), 97.2 (1C, CH, phenyl), 100.6 (1C, CH,
pyrimidine), 103.4, 105.3, 108.5, 143.7, 146.5, 152.2,158.4, 160.6, 163.9,164.8 (10C, Ar-C), 169.1, 172.8 (2C,
2C=O); MS (70 eV, %) m/z 371 (M+, 100%); Anal. Calc. (Found) for C17H13N3O5S (371.37): C, 54.98
(54.91); H, 3.53 (3.58); N, 11.32(11.40).
3.10. Synthesis of 2-((7,11-Dimethoxy-6-methyl-3-oxo-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-1-yl)thio)
Acetic Acid (6b)
The compound was obtained from the reaction of (5b) with chloroacetic acid, as yellowish crystals,
crystallized from ethanol in 86% yield, m.p. 283 ◦C. IR ( , cm−1) KBr: 3345 (brs, OH), 3027 (CH-aryl),
ν
2952 (CH-aliph), 1748 (CO, acid), 1681 (CO, amide), 1632 (C=N). 1H-NMR (DMSO-d6, ppm)
3H, CH3), 3.95 (s, 6H, 2OCH3), 4.25 (s, 2H, CH2), 6.79 (d, 1H, J = 2.35 Hz, furan), 7.38 (s, 1H, pyrimidine),
7.80 (d, 1H, J = 2.35 Hz, furan), 13.75 (br, 1H, OH, D2O exchangeable); 13C-NMR (DMSO-d6)
23.4 (1C,
δ 2.31 (s,
δ
CH3), 32.6 (1C, CH2), 61.3 (2C, 2OCH3), 100.1 (1C, CH, pyrimidine), 101.2, 105.4, 108.8, 124.1, 130.1,
146.2, 146.7, 150.5, 160.1, 164.4, 166.9 (11C, Ar-C), 169.5, 172.9 (2C, 2C=O); MS (70 eV, %) m/z 401 (M+,
100%); Anal. Calc. (Found) for C18H15N3O6S (401.39): C, 53.86 (53.80); H, 3.77 (3.71); N, 10.47 (10.42).
3.11. General Procedure for Synthesis of (9-Methoxy or 9,13-dimethoxy)-8-methyl-2-hydro-5H,14aH-
furo[3,2-g]thiazolo[20,30:2,3] pyrimido[1,6-a]quinazoline-3,5-dione (7a,b)
Method A: A mixture from 5a (3.13 g, 0.01 mol) or 5b (3.43 g, 0.01 mol), chloroacetic acid (0.94 g,
0.01 mol) and (0.02 mol) of anhydrous sodium acetate was stirred under reflux in 40 mL of glacial acetic

Molecules 2018, 23, 2793
11 of 20
◦
acid and 20 mL of acetic anhydride on a water bath (60–70 C) for 13–15 h (TLC). The reaction mixture
was allowed to cool to room temperature and poured into water (100 mL). The solid precipitate was
filtered off, and crystallized from appropriate solvent to produced 7a and 7b in good yields, respectively.
Method B: A mixture of 6a (3.71 g, 0.01 mol) or 6b (4.01 g, 0.01 mol) in dimethylformamide (35 mL)
was refluxed for 6–8 h with (TLC). The final product was filtered off, dried and crystallized from the
proper solvent to give 7a and 7b, respectively.
3.12. Synthesis of 9-Methoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo[20,30:2,3]pyrimido[1,6-a]
quinazoline-3,5-dione (7a)
The compound was obtained from the reaction of (5a) with chloroacetic acid or compound (6a) in
DMF, as white crystals, crystallized from dioxane in 82% yield, m.p. 338 ◦C. IR (
ν
, cm−1) KBr: 3035
2.37 (s,
3H, CH3), 3.93 (s, 3H, OCH3), 4.21 (s, 2H, CH2), 5.57 (s, 1H, CH, thiazole), 6.78 (d, 1H, J = 2.34 Hz, furan),
7.38 (s, 1H, pyrimidine), 7.75 (d, 1H, J = 2.32 Hz, furan), 7.88 (s, 1H, phenyl); 13C-NMR (DMSO-d6)
(CH-aryl), 2962 (CH-aliph), 1688, 1680 (2CO, amide), 1635 (C=N). 1H-NMR (DMSO-d6, ppm)
δ
δ
23.3 (1C, CH3), 32.6 (1C, CH2), 61.8 (1C, OCH3), 76.1 (1C, CH, thiazole), 94.5 (1C, CH, phenyl), 98.8
(1C, CH, pyrimidine), 101.2, 105.5, 107.9, 142.2, 146.4, 153.5, 159.7, 160.4, 164.5 (9C, Ar-C), 166.4, 170.1
(2C, 2C=O); MS (70 eV, %) m/z 355 (M+, 90%); Anal. Calc. (Found) for C17H13N3O4S (355.37): C, 57.46
(57.40); H, 3.69 (3.62); N, 11.82 (11.88).
3.13. Synthesis of 9,13-Dimethoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo[20,30:2,3]pyrimido[1,6-a]
quinazoline-3,5-dione (7b)
The compound was obtained from the reaction of (5b) with chloroacetic acid or compound (6b
in DMF, as yellowish crystals, crystallized from methanol in 80% yield, m.p. 303 ◦C. IR ( , cm−1) KBr:
3038 (CH-aryl), 2966 (CH-aliph), 1685, 1682 (2CO, amide), 1632 (C=N). 1H-NMR (DMSO-d6, ppm)
2.33 (s, 3H, CH3), 3.97 (s, 6H, 2OCH3), 4.24 (s, 2H, CH2), 5.62 (s, 1H, CH, thiazole), 6.74 (d, 1H, J = 2.33
Hz, furan), 7.39 (s, 1H, pyrimidine), 7.77 (d, 1H, J = 2.31 Hz, furan); 13C-NMR (DMSO-d6)
23.1 (1C,
)
ν
δ
δ
CH3), 32.3 (1C, CH2), 61.7 (2C, 2OCH3), 76.4 (1C, CH, thiazole), 97.5 (1C, CH, pyrimidine), 101.4, 105.6,
108.2, 123.6, 127.8, 146.3, 146.8, 152.9, 160.1, 164.7 (10C, Ar-C), 166.2, 170.5 (2C, 2C=O); MS (70 eV, %)
m/z 385 (M+, 95%); Anal. Calc. (Found) for C18H15N3O5S (385.39): C, 56.10 (56.18); H, 3.92 (3.85); N,
10.90 (10.98).
3.14. General Procedure for Synthesis of 2-(Substituted-benzylidene)-9,(substituted)-methoxy-8-methyl-2-
hydro-5H,14aH-furo[3,2-g] thiazolo[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8a–f)
Method A: One pot synthesis: A mixture from 5a (3.13g, 0.01 mol) or 5b (3.43 g, 0.01 mol),
chloroacetic acid (0.94 g, 0.01 mol), the appropriate aromatic aldehyde (10 mmol) and (0.02 mol) of
anhydrous sodium acetate was stirred under reflux in 40 mL of glacial acetic acid and 20 mL of acetic
anhydride for 24–26 h. The reaction mixture was cooled and poured into ice water. The deposited
precipitate was filtered off, and crystallized from appropriate solvent to give (8a–f).
Method B: A mixture of compound 7a (3.55 g, 10 mmol) or 7b (3.85 g, 10 mmol) and the appropriate
aromatic aldehyde (10 mmol) in dioxane (40 mL) containing a catalyst amount of piperidine (0.5 mL)
was stirred and heated under reflux for 10–12 h (TLC control). The reaction mixture was cooled, the
formed precipitate filtered off, dried and recrystallized from the appropriate solvent to afford (8a–f).
3.15. Synthesis of 2-Benzylidene-9-methoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo[20,30:2,3]
pyrimido[1,6-a]quinazoline-3,5-dione (8a)
The compound was obtained from the reaction of (5a) and benzaldehyde (1.06 g, 10 mmol)
with chloroacetic acid or compound (7a) with benzaldehyde, as yellowish crystals, crystallized from
dimethylformamide in 75% yield, m.p. > 350 ◦C. IR (
ν
, cm−1) KBr: 3050 (CH-aryl), 2945 (CH-aliph),
2.30 (s, 3H, CH3), 3.91 (s, 3H, OCH3),
5.59 (s, 1H, CH, thiazole), 6.75 (d, 1H, J = 2.31 Hz, furan), 7.32 (s, 1H, pyrimidine), 7.40–7.67(m, 5H,
1685, 1672 (2CO, amide), 1630 (C=N). 1H-NMR (DMSO-d6, ppm)
δ

Molecules 2018, 23, 2793
12 of 20
phenyl), 7.72 (d, 1H, J = 2.30 Hz, furan), 7.85 (s, 1H, phenyl), 8.05 (s, 1H, CH); 13C-NMR (DMSO-d6)
23.1 (1C, CH3), 61.6 (1C, OCH3), 77.5 (1C, CH, thiazole), 90.8 (1C, CH, phenyl), 92.9 (1C, CH,
δ
pyrimidine), 100.7, 104.8, 105.6, (3C, benzofurane), 121.9 (1C, CH), 127.2, 128.1, 128.7, 133.9 (6C,
phenyl), 137.5 (1C, thiazole), 140.3, 146.4, 153.8, 160.1, 160.4, 164.2 (6C, pyrimidobenzo furane), 165.6,
168.4 (2C, 2C=O); MS (70 eV, %) m/z 443 (M+, 88%); Anal. Calc. (Found) for C24H17N3O4S (443.48): C,
65.00 (65.10); H, 3.86 (3.80); N, 9.48 (9.41).
3.16. Synthesis of 2-(4-Chlorobenzylidene)-9-methoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo
[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8b)
The compound was obtained from the reaction of (5a) and 4-chlorobenzaldehyde (1.40 g, 10 mmol)
with chloroacetic acid or compound (7a) with 4-chloro-benzaldehyde, as yellow crystals, crystallized
from dioxane in 80% yield, m.p. > 350 ◦C. IR (
ν
, cm−1) KBr: 3052 (CH-aryl), 2948 (CH-aliph), 1687,
2.31 (s, 3H, CH3), 3.90 (s, 3H, OCH3),
1674 (2CO, amide), 1631 (C=N). 1H-NMR (DMSO-d6, ppm)
δ
5.60 (s, 1H, CH, thiazole), 6.74 (d, 1H, J = 2.32 Hz, furan), 7.33 (s, 1H, pyrimidine), 7.45–7.50 (dd, 2H,
J = 7.60, 7.64 Hz, 4-chlorophenyl), 7.55–7.60 (dd, 2H, J = 7.62, 7.66 Hz, 4-chloro phenyl),7.70 (d, 1H,
J = 2.34 Hz, furan), 7.83 (s, 1H, phenyl), 8.08 (s, 1H, CH); 13C-NMR (DMSO-d6)
δ 23.2 (1C, CH3), 61.4
(1C, OCH3), 77.8 (1C, CH, thiazole), 90.2 (1C, CH, phenyl), 92.1 (1C, CH, pyrimidine), 100.3, 104.9,
105.5, (3C, benzofurane), 122.1 (1C, CH), 128.4, 129.2, 132.5, 132.8 (6C, 4-chlorophenyl), 137.9 (1C,
thiazole), 140.6, 146.3,153.5, 160.3, 160.7, 164.3 (6C, pyrimidobenzo furane), 165.8, 168.7 (2C, 2C=O);
MS (70 eV, %) m/z 477 (M+, 90%); Anal. Calc. (Found) for C24H16ClN3O4S (477.92): C, 60.32 (60.39); H,
3.37 (3.44); N, 8.79 (8.85).
3.17. Synthesis of 9-Methoxy-2-(4-methoxybenzylidene)-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo
[20,30:2,3]pyrimido [1,6-a]quinazoline-3,5-dione (8c)
The compound was obtained from the reaction of (5a) and 4-methoxy-benzaldehyde (1.36 g,
10 mmol) with chloroacetic acid or compound (7a) with 4-methoxybenzaldehyde, as brownish crystals,
◦
crystallized from ethanol in 78% yield, m.p. > 350 C. IR (
ν
, cm−1) KBr: 3054 (CH-aryl), 2944
2.29 (s, 3H, CH3), 3.92
(CH-aliph), 1683, 1671 (2CO, amide), 1636 (C=N). 1H-NMR (DMSO-d6, ppm)
δ
(s, 3H, OCH3), 4.10 (s, 3H, OCH3), 5.59 (s, 1H, CH, thiazole), 6.71 (d, 1H, J = 2.32 Hz, furan), 7.28 (s,
1H, pyrimidine), 7.48–7.53 (dd, 2H, J = 7.61, 7.65 Hz, 4-methoxyphenyl), 7.58–7.63 (dd, 2H, J = 7.63,
7.67 Hz, 4-methoxyphenyl), 7.69 (d, 1 H, J = 2.37 Hz, furan), 7.86 (s, 1 H, phenyl), 8.06 (s, 1H, CH);
13C-NMR (DMSO-d6)
δ 23.4 (1C, CH3), 58.5 (1C, OCH3), 61.7 (1C, OCH3), 77.2 (1C, CH, thiazole), 90.5
(1C, CH, phenyl), 92.4 (1C, CH, pyrimidine), 100.4, 105.1, 105.5, (3C, benzofurane), 122.6 (1C, CH),
123.1, 127.7, 130.1, 155.5 (6C, 4-methoxyphenyl), 137.4 (1C, thiazole), 140.8, 146.2,153.6, 160.1, 160.4,
164.3 (6C, pyrimidobenzofurane), 165.1, 168.6 (2C, 2C=O); MS (70 eV, %) m/z 473 (M+, 87%); Anal. Calc.
(Found) for C25H19N3O5S (473.50): C, 63.42 (63.49); H, 4.04 (4.12); N, 8.87 (8.95).
3.18. Synthesis of 2-Benzylidene-9,13-dimethoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo
[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8d)
The compound was obtained from the reaction of (5b) and benzaldehyde (1.06 g, 10 mmol) with
chloroacetic acid or compound (7b) with benzaldehyde, as yellow crystals, crystallized from acetone
◦
in 79% yield, m.p. > 350 C. IR (
amide), 1638 (C=N). 1H-NMR (DMSO-d6, ppm)
CH, thiazole), 6.74 (d, 1H, J= 2.30 Hz, furan), 7.34 (s, 1H, pyrimidine), 7.45–7.65 (m, 5H, phenyl), 7.74
(d, 1H, J = 2.35 Hz, furan), 8.02 (s, 1H, CH); 13C-NMR (DMSO-d6)
23.5 (1C, CH3), 61.8 (2C, 2OCH3),
ν
, cm−1) KBr: 3060 (CH-aryl), 2950 (CH-aliph), 1688, 1678 (2CO,
δ
2.33 (s, 3H, CH3), 3.97 (s, 6H, 2OCH3), 5.60 (s, 1H,
δ
77.7 (1C, CH, thiazole), 91.7 (1C, CH, pyrimidine), 101.4, 105.3, 108.8, 120.7 (4C, benzo furane), 122.2
(1C, CH), 126.1 (1C, pyrimidine), 127.7, 128.3, 128.8, 134.6 (6C, phenyl), 137.7 (1C, thiazole), 146.2, 146.7,
151.9, 160.6, 164.8 (5C, pyrimidobenzofurane), 165.1, 168.3 (2C, 2C=O); MS (70 eV, %) m/z 473 (M+,
84%); Anal. Calc. (Found) for C25H19N3O5S (473.50): C, 63.42 (63.50); H, 4.04 (4.10); N, 8.87 (8.80).

Molecules 2018, 23, 2793
13 of 20
3.19. Synthesis of 2-(4-Chlorobenzylidene)-9,13-dimethoxy-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo
[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8e)
The compound was obtained from the reaction of (5b) and 4-chlorobenzaldehyde (1.40 g, 10 mmol)
with chloroacetic acid or compound (7b) with 4-chlorobenzaldehyde, as yellowish crystals, crystallized
from methanol in 88% yield, m.p. > 350 ◦C. IR (
ν
, cm−1) KBr: 3055 (CH-aryl), 2945 (CH-aliph), 1686,
2.30 (s, 3H, CH3), 3.98 (s, 6H, 2OCH3),
1674 (2CO, amide), 1634 (C=N). 1H-NMR (DMSO-d6, ppm)
δ
5.59 (s, 1H, CH, thiazole), 6.73 (d, 1H, J = 2.31 Hz, furan), 7.35 (s, 1H, pyrimidine), 7.47–7.52 (dd, 2H,
J = 7.68, 7.62 Hz, 4-chlorophenyl), 7.57–7.62 (dd, 2H, J = 7.61, 7.65 Hz, 4-chloro phenyl), 7.75 (d, 1H,
J = 2.36 Hz, furan), 8.04 (s, 1H, CH); 13C-NMR (DMSO-d6)
δ 23.7 (1C, CH3), 61.9 (2C, 2OCH3), 77.6 (1C,
CH, thiazole), 91.2 (1C, CH, pyrimidine), 100.5, 105.6, 108.4, 120.8 (4C, benzo furane), 122.4 (1C, CH),
126.3 (1C, pyrimidine), 128.2, 128.8, 131.5, 131.9 (6C, 4-chloro phenyl), 137.5 (1C, thiazole), 146.3, 146.9,
150.8, 160.4, 164.9 (5C, pyrimidobenzofurane), 165.3, 168.1 (2C, 2C=O); MS (70 eV, %) m/z 507 (M+,
98%); Anal. Calc. (Found) for C25H18ClN3O5S (507.94): C, 59.12 (59.22); H, 3.57 (3.50); N, 8.27 (8.35).
3.20. Synthesis of 9,13-Dimethoxy-2-(4-methoxybenzylidene)-8-methyl-2-hydro-5H,14aH-furo[3,2-g]thiazolo
[20,30:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8f)
The compound was obtained from the reaction of (5b) and 4-methoxy-benzaldehyde (1.36 g,
10 mmol) with chloroacetic acid or compound (7b) with 4-methoxybenzaldehyde, as brownish crystals,
◦
crystallized from benzene in 73% yield, m.p. > 350 C. IR (
ν
, cm−1) KBr: 3052 (CH-aryl), 2944
2.28 (s, 3H, CH3), 3.95
(CH-aliph), 1685, 1672 (2CO, amide), 1630 (C=N). 1H-NMR (DMSO-d6, ppm)
δ
(s, 6H, 2OCH3), 4.12 (s, 3H, OCH3), 5.55 (s, 1H, CH, thiazole), 6.71 (d, 1H, J= 2.32 Hz, furan), 7.37 (s, 1H,
pyrimidine), 7.49–7.54 (dd, 2H, J = 7.65, 7.61 Hz, 4-methoxyphenyl), 7.58–7.63 (dd, 2H, J = 7.62, 7.66 Hz,
4-methoxyphenyl), 7.76 (d, 1H, J = 2.35 Hz, furan), 8.06 (s, 1H, CH); 13C-NMR (DMSO-d6)
δ 23.4 (1C,
CH3), 58.2 (1C, OCH3), 61.8 (2C, 2OCH3), 77.3 (1C, CH, thiazole), 91.5 (1C, CH, pyrimidine), 100.2,
105.5, 108.6, 120.5 (4C, benzofurane), 122.7 (1C, CH), 126.1 (1C, pyrimidine), 127.2, 128.4, 129.1, 152.2
(6C, 4-methoxyphenyl), 137.8 (1C, thiazole), 146.1, 146.7, 150.6, 160.5, 164.8 (5C, pyrimidobenzo furane),
165.7, 168.2 (2C, 2C=O); MS (70 eV, %) m/z 503 (M+, 91%); Anal. Calc. (Found) for C26H21N3O6S
(503.53): C, 62.02 (62.10); H, 4.20 (4.28); N, 8.35 (8.27).
3.21. General Procedure for Synthesis of 3-(((7-Methoxy or 7,11-dimethoxy)-6-methyl-3-oxo-3H-furo[3,2-g]
pyrimido[1,6-a] quinazolin-1-yl)thio)pentane-2,4-dione (9a,b)
To a warmed ethanolic potassium hydroxide solution (prepared by dissolving 10 mmol of KOH
in 50 mL ethanol) was added each of 5a (3.13 g, 0.01 mol) or 5b (3.43 g, 0.01 mol), the heating was
continued for 40 min and the mixture was allowed to cool to room temperature, and the proper
3-chloro-pentane-2,4-dione (3-chloroacetylacetone, 1.12 mL, 0.01 mol) was added. The mixture was
stirred under reflux for 6–8 h (control TLC), and then cool to room temperature, poured into cold water
(100 mL). The solid product precipitated was filtered off, washed with 100 mL water; the product was
dried and crystallized from the suitable solvent to afford 9a and 9b in good yields, respectively.
3.22. Synthesis of 3-((7-Methoxy-6-methyl-3-oxo-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-1-yl)thio)pentane-
2,4-dione (9a)
The compound was obtained from the reaction of (5a) with 3-chloro-pentane-2,4-dione
◦
(3-chloroacetylacetone), as white crystals, crystallized from hexane in 92% yield, m.p. > 350 C.
IR (
(C=N). 1H-NMR (DMSO-d6, ppm)
(s, 1H, CH), 6.73 (d, 1H, J = 2.31 Hz, furan), 7.37 (s, 1H, pyrimidine), 7.62 (s, 1H, phenyl), 7.75 (d, 1H,
J = 2.33 Hz, furan), 13C-NMR (DMSO-d6)
23.8(1C, CH3), 26.5 (2C, 2COCH3), 61.6 (1C, OCH3), 68.2
ν
, cm−1) KBr: 3035 (CH-aryl), 2945 (CH-aliph), 1725, 1721 (2CO, acetyl), 1682 (CO, amide), 1638
δ
2.26 (s, 6H, 2COCH3), 2.34 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 4.08
δ
(1C, CH), 91.3 (1C, CH, phenyl), 96.5 (1C, CH, pyrimidine), 100.1, 105.3, 108.5, 142.6, 146.1, 153.5, 157.4,
160.3, 163.8, 165.7 (10C, Ar-C), 168.6, 184.5, 188.2 (3C, 3C=O); MS (70 eV, %) m/z 411 (M+, 95%); Anal.
Calc. (Found) for C20H17N3O5S (411.43): C, 58.39 (58.32); H, 4.16 (4.10); N, 10.21 (10.16).

Molecules 2018, 23, 2793
14 of 20
3.23. Synthesis of 3-((7,11-Dimethoxy-6-methyl-3-oxo-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-1-yl)thio)
pentane-2,4-dione (9b)
The compound was obtained from the reaction of (5b) with 3-chloro-pentane-2,4-dione
(3-chloroacetylacetone), as white crystals, crystallized from dioxane in 90% yield, m.p. 348 ◦C. IR (
ν,
cm−1) KBr: 3038 (CH-aryl), 2949 (CH-aliph), 1728, 1722 (2CO, acetyl), 1684 (CO, amide), 1636 (C=N).
1H-NMR (DMSO-d6, ppm)
2.28 (s, 6H, 2COCH3), 2.37 (s, 3H, CH3), 3.98 (s, 6H, 2OCH3), 4.15 (s,
δ
1H, CH), 6.72 (d, 1H, J = 2.34 Hz, furan), 7.35 (s, 1H, pyrimidine), 7.79 (d, 1H, J = 2.37 Hz, furan),
13C-NMR (DMSO-d6) δ 23.4 (1C, CH3), 26.1 (2C, 2COCH3), 61.9 (2C, 2OCH3), 68.5 (1C, CH), 97.1 (1C,
CH, pyrimidine), 100.2, 105.7, 108.9, 122.5, 130.2, 146.3, 146.8, 150.7, 159.6, 164.2, 166.4 (11C, Ar-C),
168.8, 185.1, 188.7 (3C, 3C=O); MS (70 eV, %) m/z 441 (M+, 90%); Anal. Calc. (Found) for C21H19N3O6S
(441.46): C, 57.14 (57.20); H, 4.34 (4.39); N, 9.52 (9.60).
3.24. General Procedure for Synthesis of 1-((3,5-Dimethyl-1H-pyrazol-4-yl)thio)-(7-methoxy or 7,11-
dimethoxy)-6-methyl-3H-furo [3,2-g]pyrimido[1,6-a]quinazolin-3-one (10a,b)
A mixture of 9a (4.11 g, 0.01 mol) or 9b (4.41 g, 0.01 mol), and hydrazine hydrate (99–100%) in
dioxane (30 mL) and ethanol (20 mL) was stirred under reflux for 13–15 h. The reaction mixture was
allowed to cool to room temperature, poured into cold water (100 mL). The deposited precipitate
was filtered off, dried, and crystallized from the proper solvent to give 10a and 10b in good
yields, respectively.
3.25. Synthesis of 1-((3,5-Dimethyl-1H-pyrazol-4-yl)thio)-7-methoxy-6-methyl-3H-furo[3,2-g]pyrimido [1,6-a]
quinazolin-3-one (10a)
The compound was obtained from the reaction of (9a) with hydrazine hydrate, as yellow crystals,
crystallized from dimethylformamide in 95% yield, m.p. > 350 ◦C. IR ( , cm−1) KBr: 3375 (brs, NH),
ν
3030 (CH-aryl), 2940 (CH-aliph), 1684 (CO, amide), 1633 (C=N). 1H-NMR (DMSO-d6, ppm)
δ 2.28 (s,
3H, CH3), 2.38 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 6.75 (d, 1H, J = 2.32 Hz, furan),
7.32 (s, 1H, pyrimidine), 7.60 (s, 1H, phenyl), 7.72 (d, 1H, J = 2.37 Hz, furan), 11.50 (brs, NH, D2O
exchangeable); 13C-NMR (DMSO-d6)
δ 20.1, 20.3, 23.2 (3C, 3CH3), 61.4 (1C, OCH3), 91.1 (1C, CH,
phenyl), 96.3 (1C, CH, pyrimidine), 100.2, 105.1, 107.2, 108.4, 142.3, 144.5, 146.6, 154.1, 158.2, 160.5,
164.4, 166.3 (13C, Ar-C), 168.8 (1C, C=O); MS (70 eV, %) m/z 407 (M+, 100%); Anal. Calc. (Found) for
C20H17N5O3S (407.45): C, 58.96 (58.88); H, 4.21 (4.15); N, 17.19 (17.10).
3.26. Synthesis of 1-((3,5-Dimethyl-1H-pyrazol-4-yl)thio)-7,11-dimethoxy-6-methyl-3H-furo[3,2-g]pyrimido
[1,6-a]quinazolin-3-one (10b)
The compound was obtained from the reaction of (9◦b) with hydrazine hydrate, as yellowish
crystals, crystallized from dioxane in 91% yield, m.p. > 350 C. IR (ν
, cm−1) KBr: 3370 (brs, NH), 3032
(CH-aryl), 2943 (CH-aliph), 1682 (CO, amide), 1635 (C=N). 1H-NMR (DMSO-d6, ppm)
δ 2.30 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 2.41 (s, 3H, CH3), 3.98 (s, 6H, 2OCH3), 6.77 (d, 1H, J = 2.36 Hz, furan), 7.38
(s, 1H, pyrimidine), 7.79 (d, 1H, J = 2.34 Hz, furan), 11.55 (brs, NH, D2O exchangeable); 13C-NMR
(DMSO-d6)
δ 20.4, 20.6, 23.5 (3C, 3CH3), 61.9 (2C, 2OCH3), 96.7 (1C, CH, pyrimidine), 100.3, 105.6,
107.8, 108.5, 122.5, 130.4, 144.8, 146.1, 146.8, 151.4, 160.5, 164.2, 166.6 (14C, Ar-C), 168.9 (1C, C=O); MS
(70 eV, %) m/z 437 (M+, 100%); Anal. Calc. (Found) for C21H17N5O4S (437.47): C, 57.66 (57.72); H, 4.38
(4.30); N, 16.01 (16.10).
3.27. General Procedure for Synthesis of 1-((4,6-Dimethyl-2-(oxo or thioxo)-1,2-dihydropyrimidin-5-yl)thio)-
(7-methoxy or 7,11-dimethoxy)-6-methyl-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (11a–d)
A mixture of 9a (4.11 g, 0.01 mol) or 9b (4.41 g, 0.01 mol), and urea (0.60 g, 0.01 mol) or thiourea
(0. 76 g, 0.01 mol) was stirred under reflux in dioxane (40 mL) in the presence of catalytic amount of
piperidine (1 mL) for 16–18 h. The reaction mixture was allowed to cool to room temperature, poured

Molecules 2018, 23, 2793
15 of 20
into water (100 mL), the deposited precipitate was filtered off, washed with ethanol (40 mL), dried and
crystallized from proper solvent to afford (11a–d).
3.28. Synthesis of 1-((4,6-Dimethyl-2-oxo-1,2-dihydropyrimidin-5-yl)thio)-7-methoxy-6-methyl-3H-
furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (11a)
The compound was obtained from the reaction of (9a) with urea, as yellowish crystals, crystallized
◦
from dioxane in 86% yield, m.p. > 350 C. IR (
ν
, cm−1) KBr: 3380 (brs, NH), 3032 (CH-aryl), 2942
(CH-aliph), 1685, 1680 (2C=O, amide), 1635 (C=N). 1H-NMR (DMSO-d6, ppm)
δ
2.11 (s, 3H, CH3),
2.28 (s, 3H, CH3), 2.37 (s, 3H, CH3), 3.94 (s, 3H, OCH3), 6.72 (d, 1H, J = 2.31 Hz, furan), 7.36 (s, 1H,
pyrimidine), 7.63 (s, 1H, phenyl), 7.79 (d, 1H, J = 2.38 Hz, furan), 10.60 (brs, NH, D2O exchangeable);
13C-NMR (DMSO-d6)
δ 20.6, 20.9, 23.5 (3C, 3CH3), 61.8 (1C, OCH3), 85.4 (1C, pyrimidine), 91.5 (1C,
CH, phenyl), 97.7 (1C, CH, pyrimidine), 100.4, 105.7, 108.2, 143.1, 146.1, 153.6, 158.5, 160.4, 163.8, 164.7,
165.2, 166.8 (12C, Ar-C), 169.2, 172.5 (2C, 2C=O); MS (70 eV, %) m/z 435 (M+, 92%); Anal. Calc. (Found)
for C21H17N5O4S (435.46): C, 57.92 (57.85); H, 3.94 (3.99); N, 16.08 (16.15).
3.29. Synthesis of 1-((4,6-Dimethyl-2-thioxo-1,2-dihydropyrimidin-5-yl)thio)-7-methoxy-6-methyl-3H-
furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (11b)
The compound was obtained from the reaction of (9a) with thiourea, as yellow crystals,
◦
crystallized from dimethylformamide in 82% yield, m.p. > 350 C. IR (
NH), 3035 (CH-aryl), 2944 (CH-aliph), 1681 (C=O, amide), 1632 (C=N). 1H-NMR (DMSO-d6, ppm)
2.10 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 6.70 (d, 1H, J = 2.30 Hz,
furan), 7.34 (s, 1H, pyrimidine), 7.61 (s, 1H, phenyl), 7.78 (d, 1H, J = 2.36 Hz, furan), 12.30 (brs, NH,
D2O exchangeable); 13C-NMR (DMSO-d6)
21.4, 21.8, 23.7 (3C, 3CH3), 61.7 (1C, OCH3), 84.6 (1C,
ν
, cm−1) KBr: 3385 (brs,
δ
δ
pyrimidine), 91.8 (1C, CH, phenyl), 98.2 (1C, CH, pyrimidine), 100.2, 105.8, 108.1, 143.7, 146.3, 153.8,
158.9, 160.5, 163.9, 164.2, 165.8, 169.6 (12C, Ar-C), 170.1 (1C, C=O), 177.8 (1C, C=S); MS (70 eV, %) m/z
451 (M+, 90%); Anal. Calc. (Found) for C21H17N5O3S2 (451.52): C, 55.86 (55.78); H, 3.80 (3.88); N,
15.51 (15.60).
3.30. Synthesis of 1-((4,6-Dimethyl-2-oxo-1,2-dihydropyrimidin-5-yl)thio)-7,11-dimethoxy-6-methyl-3H-
furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (11c)
The compound was obtained from the reaction of (9b) with urea, as yellow crystals, crystallized
from methanol in 80% yield, m.p. > 350 ◦C. IR ( , cm−1) KBr: 3377 (brs, NH), 3039 (CH-aryl), 2937
ν
(CH-aliph), 1687, 1683 (2C=O, amide), 1638 (C=N). 1H-NMR (DMSO-d6, ppm)
δ 2.09 (s, 3H, CH3),
2.27 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.99 (s, 6H, 2OCH3), 6.75 (d, 1H, J = 2.32 Hz, furan), 7.38 (s, 1H,
pyrimidine), 7.76 (d, 1H, J = 2.37 Hz, furan), 10.74 (brs, NH, D2O exchangeable); 13C-NMR (DMSO-d6)
δ
20.5, 20.7, 23.7 (3C, 3CH3), 61.9 (2C, 2OCH3), 87.1(1C, pyrimidine), 98.9 (1C, CH, pyrimidine), 100.2,
105.4, 108.8, 122.3, 130.5, 146.1, 146.9, 152.1, 158.2, 164.1, 164.5, 166.2, 168.5 (13C, Ar-C), 169.8, 171.4
(2C, 2C=O); MS (70 eV, %) m/z 465 (M+, 88%); Anal. Calc. (Found) for C22H19N5O5S (465.48): C, 56.77
(56.70); H, 4.11 (4.05); N, 15.05 (15.14).
3.31. Synthesis of 1-((4, 6-Dimethyl-2-thioxo-1,2-dihydropyrimidin-5-yl)thio)-7,11-dimethoxy-6-methyl-3H-
furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (11d)
The compound was obtained from the rea◦ction of (9b) with thiourea, as yellowish crystals,
crystallized from dioxane in 80% yield, m.p. > 350 C. IR (
2945 (CH-aliph), 1683 (C=O, amide), 1630 (C=N). H-NMR (DMSO-d6, ppm)
ν
, cm−1) KBr: 3388 (brs, NH), 3034 (CH-aryl),
1
δ 2.13 (s, 3H, CH3),
2.25 (s, 3H, CH3), 2.32 (s, 3H, CH3), 4.01 (s, 6H, 2OCH3), 6.73 (d, 1H, J = 2.34 Hz, furan), 7.36 (s, 1H,
pyrimidine),7.80 (d, 1H, J = 2.38 Hz, furan), 12.50 (brs, NH, D2O exchangeable); 13C-NMR (DMSO-d6)
δ
21.5, 21.9, 23.8 (3C, 3CH3), 62.01 (2C, 2OCH3), 86.1 (1C, pyrimidine), 99.3 (1C, CH, pyrimidine), 100.4,
105.2, 108.7, 122.7, 130.4, 146.3, 146.7, 151.9, 159.1, 164.3, 164.5, 166.9, 168.2 (13C, Ar-C), 169.8(1C, C=O),

Molecules 2018, 23, 2793
16 of 20
178.5 (1C, C=S); MS (70 eV, %) m/z 481 (M+, 86%); Anal. Calc. (Found) for C22H19N5O4S2 (481.54): C,
54.87 (54.95); H, 3.98 (3.90); N, 14.54 (14.47).
3.32. General Procedure for Synthesis of (7-Methoxy or 7,11-dimethoxy)-6-methyl-1-(methylthio)-3H-
furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (12a,b)
To a warmed ethanolic KOH solution (prepared by dissolving 10 mmol of KOH in 50 mL ethanol)
was added each of 5a (3.13 g, 0.01 mol) or 5b (3.43 g, 0.01 mol), the heating was continued for 30 min
and the mixture was allowed to cool to room temperature, and methyl iodide (0.62 mL, 0.01 mol) was
added. The mixture was stirred under reflux for 5–7 h, then cool to room temperature, poured into
cold water (100 mL). The solid product precipitated was filtered off, washed with water; the product
was dried and crystallized from the proper solvent to produce 12a and 12b, respectively.
3.33. Synthesis of 7-Methoxy-6-methyl-1-(methylthio)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (12a)
The compound was obtained from the reaction of (5a) with methyl iodide, as yellow crystals,
◦
crystallized from methanol in 90% yield, m.p. 329 C. IR (
1685 (CO, amide), 1630 (C=N). 1H-NMR (DMSO-d6, ppm)
(s, 3H, OCH3), 6.73 (d, 1H, J = 2.31 Hz, furan), 7.34 (s, 1H, pyrimidine), 7.64 (s, 1H, phenyl), 7.78 (d, 1H,
J = 2.35 Hz, furan); 13C-NMR (DMSO-d6)
18.9 (1C, SCH3), 23.8 (1C, CH3), 61.4 (1C, OCH3), 92.7 (1C,
ν
, cm−1) KBr: 3035 (CH-aryl), 2962 (CH-aliph),
2.30 (s, 3H, CH3), 2.80 (s, 3H, SCH3), 3.90
δ
δ
CH, phenyl), 98.9 (1C, CH, pyrimidine), 100.3, 105.2, 108.5, 145.2, 146.4, 153.7, 158.3, 160.9, 164.6, 167.8
(10C, Ar-C), 169.1 (1C, C=O); MS (70 eV, %) m/z 327 (M+, 100%); Anal. Calc. (Found) for C16H13N3O3S
(327.36): C, 58.71 (58.78); H, 4.00 (4.10); N, 12.84 (12.90).
3.34. Synthesis of 7,11-Dimethoxy-6-methyl-1-(methylthio)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-
3-one (12b)
The compound was obtained from the reaction of (5b) with methyl iodide, as yellowish crystals,
◦
crystallized from ethanol in 86% yield, m.p. 311 C. IR (
1683 (CO, amide), 1633 (C=N). 1H-NMR (DMSO-d6, ppm)
(s, 6H, 2OCH3), 6.78 (d, 1H, J=2.32 Hz, furan), 7.38 (s, 1H, pyrimidine), 7.80 (d, 1H, J = 2.34 Hz, furan);
13C-NMR (DMSO-d6)
19.2 (1C, SCH3), 23.6 (1C, CH3), 61.8 (2C, 2OCH3), 99.4 (1C, CH, pyrimidine),
ν
, cm−1) KBr: 3038 (CH-aryl), 2965 (CH-aliph),
δ
2.35 (s, 3H, CH3), 2.88 (s, 3H, SCH3), 3.97
δ
100.1, 105.7, 108.2, 122.7, 130.5, 146.1, 146.8, 151.5, 159.7, 164.4, 168.2 (11C, Ar-C), 169.7 (1C, C=O); MS
(70 eV, %) m/z 357 (M+, 100%); Anal. Calc. (Found) for C17H15N3O4S (357.38): C, 57.13 (57.22); H, 4.23
(4.28); N, 11.76 (11.66).
3.35. General Procedure for Synthesis of (7-Methoxy or 7,11-dimethoxy)-6-methyl-1-(methylsulfonyl)-3H-
furo[3,2-g]pyrimido[1,6-a] quinazolin-3-one (13a,b)
A mixture of 12a (3.27 g, 0.01 mol) or 12b (3.57 g, 0.01 mol), and excess amount of hydrogen
peroxide (5 mL) in acetic acid (40 mL) was heated gently with stirring for 12–14 h with (TLC).
◦
The reaction mixture was allowed to cool to 0 C. The deposited precipitate was filtered off, and
crystallized from the proper solvent to afford 13a and 13b, respectively.
3.36. Synthesis of 7-Methoxy-6-methyl-1-(methylsulfonyl)-3H-furo [3,2-g]pyrimido[1,6-a]quinazolin-
3-one (13a)
The compound was obtained from the reaction of (12a) with hydrogen peroxide, as yellowish
crystals, crystallized from benzene in 75% yield, m.p. 241 ◦C. IR (
(CH-aliph), 1687 (CO, amide), 1632 (C=N), 1162, 1340 (SO2). H-NMR (DMSO-d6, ppm)
ν
, cm−1) KBr: 3032 (CH-aryl), 2920
1
δ
2.34 (s, 3H,
CH3), 2.95 (s, 3H, SO2CH3), 3.92 (s, 3H, OCH3), 6.76 (d, 1H, J = 2.36 Hz, furan), 7.37 (s, 1H, pyrimidine),
7.61 (s, 1H, phenyl), 7.81 (d, 1H, J = 2.32 Hz, furan); 13C-NMR (DMSO-d6)
δ
23.5 (1C, CH3), 35.6 (1C,
SO2CH3), 61.3 (1C, OCH3), 93.5 (1C, CH, phenyl), 99.4 (1C, CH, pyrimidine), 100.2, 105.4, 108.7, 140.3,
145.5, 146.2, 153.9, 160.8, 164.4, 168.1 (10C, Ar-C), 169.5 (1C, C=O); MS (70 eV, %) m/z 359 (M+, 84%);
Anal. Calc. (Found) for C16H13N3O5S (359.36): C, 53.48 (53.40); H, 3.65 (3.57); N, 11.69 (11.61).

Molecules 2018, 23, 2793
17 of 20
3.37. Synthesis of 7,11-Dimethoxy-6-methyl-1-(methylsulfonyl)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-
3-one (13b)
The compound was obtained from the reaction of (12b) with hydrogen peroxide, as yellow
crystals, crystallized from toluene in 75% yield, m.p. 221 ◦C. IR ( , cm−1) KBr: 3029 (CH-aryl), 2918
ν
(CH-aliph), 1684 (CO, amide), 1628 (C=N), 1160, 1342(SO2). 1H-NMR (DMSO-d6, ppm)
3H, CH3), 2.97 (s, 3H, SO2CH3), 4.01 (s, 6H, 2OCH3), 6.80 (d, 1H, J = 2.30 Hz, furan), 7.31 (s, 1H,
pyrimidine), 7.75 (d, 1H, J = 2.33 Hz, furan); 13C-NMR (DMSO-d6)
23.3 (1C, CH3), 35.8 (1C, SO2CH3),
δ 2.29 (s,
δ
61.9 (2C, 2OCH3), 99.8 (1C, CH, pyrimidine), 100.4, 105.7, 108.9, 122.4, 130.1, 140.6, 146.3, 146.8, 151.5,
164.7, 168.5(11C, Ar-C), 169.5 (1C, C=O); MS (70 eV, %) m/z 389 (M+, 80%); Anal. Calc. (Found) for
C17H15N3 O6S (389.38): C, 52.44 (52.50); H, 3.88 (3.80); N, 10.79 (10.71).
3.38. General Procedure for Synthesis of (7-Methoxy or 7,11-dimethoxy)-6-methyl-1-((piperazin-1-yl) or
morpholino)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14a–d)
In a warm solution of 12a (3.27 g, 0.01 mol) or 12b (3.57 g, 0.01 mol), in methanol (50 mL) was
added the freshly distilled 2nd amine, namely piperazine (0.95 mL, 0.01 mol) or morpholine (0.86 mL,
0.01 mol). The reaction mixture was stirred under reflux for 7–9 h, then allowed to cool to 0 ◦C for
14 h and the solid obtained was filtered, washed with water (100 mL) dried and recrystallized from
appropriate solvent to produce (14a–d).
3.39. Synthesis of 7-Methoxy-6-methyl-1-(piperazin-1-yl)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-
3-one (14a)
The compound was obtained from the reaction of (12a) with piperazine, as pale yellow crystals,
crystallized from dioxane in 79% yield, m.p. 202 ◦C. IR ( , cm−1) KBr: 3390 (br, NH), 3044 (CH-aryl),
ν
2940 (CH-aliph), 1687 (CO, amide), 1620 (C=N). 1H-NMR (DMSO-d6, ppm)
(m, 8H, piperazine), 3.92 (s, 3H, OCH3), 6.78 (d, 1H, J = 2.36 Hz, furan), 7.38 (s, 1H, pyrimidine), 7.66 (s,
1H, phenyl), 7.81 (d, 1H, J = 2.37 Hz, furan), 10.30 (brs, NH, D2O exchangeable); 13C-NMR (DMSO-d6)
δ 2.29 (s, 3H, CH3), 2.82–2.91
δ
23.2 (1C, CH3), 48.3 (2C, 2CH2, piperazine), 52.5 (2C, 2CH2, piperazine), 61.7 (1C, OCH3), 91.8 (1C, CH,
phenyl), 98.4 (1C, CH, pyrimidine), 100.1, 105.3, 108.2, 144.6, 146.1, 153.8, 154.9, 160.3, 164.4, 168.1(10C,
Ar-C), 169.3 (1C, C=O); MS (70 eV, %) m/z 365 (M+, 83%); Anal. Calc. (Found) for C19H19N5O3 (365.39):
C, 62.46 (62.55); H, 5.24 (5.18); N, 19.17 (19.24).
3.40. Synthesis of 7-Methoxy-6-methyl-1-morpholino-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14b)
The compound was obtained from the reaction of (12a) with morpholine, as yellow crystals,
◦
crystallized from methanol in 75% yield, m.p. 171 C. IR (
ν
, cm−1) KBr: 3040 (CH-aryl), 2936 (CH-aliph),
2.30 (s, 3H, CH3), 3.14–3.23 (m, 8H,
1
1685 (CO, amide), 1622 (C=N). H-NMR (DMSO-d6, ppm)
δ
morpholine), 3.90 (s, 3H, OCH3), 6.76 (d, 1H, J = 2.34 Hz, furan), 7.33 (s, 1H, pyrimidine), 7.64 (s,
1H, phenyl), 7.80 (d, 1H, J = 2.35 Hz, furan); 13C-NMR (DMSO-d6)
δ
23.1 (1C, CH3), 51.5 (2C, 2CH2,
morpholine), 55.8 (2C, 2CH2, morpholine), 61.9 (1C, OCH3), 91.5 (1C, CH, phenyl), 99.5 (1C, CH,
pyrimidine), 100.7, 105.6, 108.4, 144.7, 146.3, 153.9, 155.2, 160.7, 164.8, 168.9 (10C, Ar-C), 169.8 (1C,
C=O); MS (70 eV, %) m/z 366 (M+, 78%); Anal. Calc. (Found) for C19H18N4O4 (366.38): C, 62.29 (62.37);
H, 4.95 (4.88); N, 15.29 (15.22).
3.41. Synthesis of 7,11-Dimethoxy-6-methyl-1-(piperazin-1-yl)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-
3-one (14c)
The compound was obtained from the reaction of (12b) with piperazine, as yellowish crystals,
ν
crystallized from ethanol in 74% yield, m.p. 184 ◦C. IR ( , cm−1) KBr: 3395 (br, NH), 3048 (CH-aryl),
2944 (CH-aliph), 1689 (CO, amide), 1624 (C=N). 1H-NMR (DMSO-d6, ppm)
(m, 8H, piperazine), 3.97 (s, 6H, 2OCH3), 6.81 (d, 1H, J = 2.32 Hz, furan), 7.36 (s, 1H, pyrimidine), 7.84
(d, 1H, J = 2.30 Hz, furan), 10.35 (brs, NH, D2O exchangeable); 13C-NMR (DMSO-d6)
23.5 (1C, CH3),
48.6 (2C, 2CH2, piperazine), 52.8 (2C, 2CH2, piperazine), 61.8 (2C, 2OCH3), 99.6(1C, CH, pyrimidine),
δ 2.31 (s, 3H, CH3), 2.85–2.94
δ

Molecules 2018, 23, 2793
18 of 20
100.5, 105.7, 108.9, 122.3, 130.2, 146.4, 146.5, 151.8, 154.1, 164.8, 168.5 (10C, Ar-C), 169.7(1C, C=O); MS
(70 eV, %) m/z 395 (M+, 76%); Anal. Calc. (Found) for C20H21N5O4 (395.42): C, 60.75 (60.82); H, 5.35
(5.43); N, 17.71 (17.78).
3.42. Synthesis of 7,11-Dimethoxy-6-methyl-1-morpholino-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-
3-one (14d)
The compound was obtained from the reac◦tion of (12b) with morpholine, as yellowish crystals,
crystallized from n-hexane in 72% yield, m.p. 156 C. IR (
1683 (CO, amide), 1626 (C=N). H-NMR (DMSO-d6, ppm)
ν
, cm−1) KBr: 3039 (CH-aryl), 2934 (CH-aliph),
1
δ 2.32 (s, 3H, CH3), 3.16–3.25 (m, 8H,
morpholine), 3.97 (s, 6H, 2OCH3), 6.79 (d, 1H, J = 2.33 Hz, furan), 7.37 (s, 1H, pyrimidine), 7.82 (d,
1H, J = 2.37 Hz, furan); 13C-NMR (DMSO-d6) δ 23.7 (1C, CH3), 53.8 (2C, 2CH2, morpholine), 57.6 (2C,
2CH2, morpholine), 61.9 (2C, 2OCH3), 99.8 (1C, CH, pyrimidine), 100.4, 105.3, 108.7, 122.6, 130.1, 146.2,
146.8, 151.3, 154.2, 164.5, 168.6 (11C, Ar-C), 169.4 (1C, C=O); MS (70 eV, %) m/z 396 (M+, 74%); Anal.
Calc. (Found) for C20H20N4O5 (396.40): C, 60.60 (60.68); H, 5.09 (5.16); N, 14.13 (14.20).
3.43. Biological Screening
The antimicrobial activity of the newly prepared compounds was tested in vitro against
Gram-positive bacteria Staphylococcus aureus (ATCC®6538 ), Streptococcus pyogenes (ATCC®19615
™ ™),
Gram-negative bacteria Escherichia coli (ATCC®25922
and the fungi Aspergillus niger (ATCC® 16888
), Alternaria alternate, Curvularia lunata and Candida
albicans (ATCC®10231
). The newly prepared compounds were dissolved in dimethyl sulfoxide
(DMSO) and tested for their antimicrobial activity by the agar disk diffusion technique. Cefotaxime
sodium and nystatin [34 35] were used as the standard drugs for antibacterial and antifungal assays,
respectively. A solution of 100
g mL−1 of the tested compound was practical and microplate-wells,
™ ™)
), Klebsiella pneumoniae (ATCC® 10031
™
™
,
µ
1 cm in diameter, were used. Zones of inhibition were measured with calipers or automated
scanners and were paralleled with those of the standards. Cefotaxime sodium (0.15 µmol mL−1) and
nystatin (0.037 µ
mol mL−1) were used as the standard drugs for antibacterial and antifungal activity,
respectively. Compound-impregnated disks were placed on an agar plate containing a standard
suspension of microorganisms. The plate was incubated for 24 h at 37 ◦C. For the assessment of the
minimum inhibitory concentration (MIC) by the serial plate dilution way [34,35], 5 mg of each tested
compound was dissolved in 1 mL of DMSO separately to prepare stock solutions. Serial dilutions
◦
were prepared from each stock solution. The plates were incubated at 37 C for 24 h. MIC is defined as
the lowest concentration (µ
mol mL−1) of the tested compound that results in no visible growth on
the plates. DMSO was used as the solvent control to ensure that the solvent had no effect on bacterial
growth. The results are shown in Tables 1 and 2.
4. Conclusions
In this work, we synthesized novel heterocyclic compounds with potent antimicrobial activity
starting from furochromones (visnagenone 2a or khellinone 2b). New derivatives were prepared in
good yields such as; furopyrimido quinazolinones, furothiazolo pyrimido quinazolinones, substituted-
benzyliden-furothiazolo pyrimido quinazolinones, pyrazolo furopyrimido quinazolin-ones, oxo
or thioxo-pyrimidin-furopyrimido quinazolinones and methylthio, methylsulfonyl, piperazino or
morpholino-furopyrimido quinazolinones. Some new prepared compounds such as substituted-
benzylidene-furothiazolo pyrimido quinazolinones 8a–f showed higher activity against the tested
microorganisms (bacteria and fungi).
Funding: This research received no external funding.
Acknowledgments: The author is extremely grateful to Department of Chemistry of Natural and Microbial
Products, National Research Centre for helping us to screen the newly synthesized compounds for
antimicrobial activity.

Molecules 2018, 23, 2793
19 of 20
Conflicts of Interest: The author a declare no conflict of interest.
References
1.
2.
3.
Trease, G.E.; Evans, W.C. Pharmacognosy, 12th ed.; Bailliere Tindall: Eastbourne, UK, 1983; p. 385.
Wallis, T.E. Textbook of Pharmacognosy, 5th ed.; Whitefriars: London, UK, 1967; p. 244.
El-Domiaty, M.M. Improved high-performance liquid chromatographic determination of khellin and
visnagin in Ammi visnaga fruits and pharmaceutical formulations. J. Pharm. Sci. 1992, 81, 475–478.
[CrossRef] [PubMed]
4.
5.
6.
Bhagavathula, A.S.; Al-Khatib, A.J.M.; Elnour, A.A.; Kalbani, N.M.S.A.; Shehab, A. Ammi visnaga in
treatment of urolithiasis and hypertriglyceridemia. Pharmacogn. Res. 2015, 7, 397–400. [CrossRef]
Gammill, R.B.; Day, C.E.; Schurr, P.E. Khellin analogues. 1. General topological requirements for lipid-altering
activity in furochromones. J. Med. Chem. 1983, 26, 1672–1674. [CrossRef] [PubMed]
De Leeuw, J.; Assen, Y.; Van Der Beek, N.; Bjerring, P.; Martino Neumann, H. Treatment of vitiligo with
khellin liposomes, ultraviolet light and blister roof transplantation. J. Eur. Acad. Dermatol. Venereol. 2011, 25,
74–81. [CrossRef] [PubMed]
7.
8.
9.
Abdou, S.E.; El-Qusy, S.M.; Ghabrial, S.S.; Haggag, M.I. Reactions with visnaginone: Synthesis, cyclisation
and microbial evaluation of some visnaginone thiosemicarbazone derivatives. Mod. App. Sci. 2011, 5.
[CrossRef]
El-Nakkady, S.S.; Roaiah, H.F.; El-Serwy, W.S.; Soliman, A.M.; El-Moez, S.I.; Abdel-Rahman, A.A. Antitumor
and antimicrobial activities of some hetero aromatic benzofurans derived from naturally occurring visnagin.
Acta Pol. Pharm. 2012, 69, 645–655. [PubMed]
Kandil, A.; Gobran, W.; Samaan, H.A.; Abu-Shady, H. The spasmolytic potential of a new khellin derivative.
J. Drug Res. 1977, 9, 35.
10. Oguro, K.; Kubota, K.; Kimura, T.; Hashimoto, K. Effects of various coronary vasodilators on myocardial
oxygen consumption. Jpn. J. Pharmacol. 1973, 23, 459–466. [CrossRef] [PubMed]
11. Oguro, K.; Hashimoto, K. Quanttative and comparative studies of pharma-cological features in the coronary,
femoral and renal circulations with different coronary vasodilators. Jpn. J. Pharmacol. 1974, 24, 227–233.
[CrossRef] [PubMed]
12. Vedaldi, D.; Caflleri, S.; Dall’Acqua, F.; Andrea, L.; Bovalini, L.; Martelli, P. Khellin, a naturally occurring
furochromone, used for the photochemotherapy of skin diseases: Mechanism of action. Farmaco 1988, 4,
333–346.
13. Trabalzini, L.; Martelli, P.; Bovalini, L.; Dall’Acqua, F.; Sage, E. Photosensitization of DNA of defined sequence
by furochromones, Khellin and Visnagen. J. Photochem. Photobiol. B 1990, 7, 317–336. [CrossRef]
14. Elgazwy Abdel-Sattar, S.H.; Edrees Mastoura, M.; Ismail Nasser, S.M. Molecular modeling study bioactive
natural product of khellin analogues as a novel potential pharmacophore of EGFR inhibitors. J. Enzym. Inhib.
Med. Chem. 2013, 28, 1171–1181. [CrossRef] [PubMed]
15. Melzig, L.; Rauhut, C.B.; Knochel, P. 2, 3-Functionalization of furans, benzofurans and thiophenes via
magnesiation and sulfoxide-magnesium exchange. Chem. Commun. 2009, 3536–3538. [CrossRef] [PubMed]
16. Mustafa, A. Furochromones. In Furopyrans and Furopyrones; John Wiley and Sons: London, UK; New York,
NY, USA; Sydney, Australia, 1967; pp. 102–159.
17. Gammill, R.B.; Hyde, B.R. Total synthesis of the lipid-altering and antiatherosclerotic furochromone khellin.
The furoic acid route to highly functionalized benzofurans. J. Org. Chem. 1983, 48, 3863–3865. [CrossRef]
18. Galal, S.A.; Abd EL-All, A.S.; Abdallah, M.M.; EL-Diwani, H.I. Synthesis of potent antitumor and antiviral
benzofuran derivatives. Bioorg. Med. Chem. Lett. 2009, 19, 2420–2428. [CrossRef] [PubMed]
19. Kim, S.; Salim, A.A.; Swanson, S.M.; Kinghorn, A.D. Potential of cyclopenta[b]benzofurans from Aglaia
species in cancer chemotherapy. Anticancer Agents Med. Chem. 2006, 6, 319–345. [CrossRef] [PubMed]
20. Hudson, J.B.; Towers, G.H.N. Phytomedicines as antivirals. Drugs Future 1999, 24, 295–320. [CrossRef]
21. Abu-Hashem, A.A.; Youssef, M.M. Synthesis of new visnagen and khellin furochromone pyrimidine
derivatives and their anti-inflammatory and analgesic activity. Molecules 2011, 16, 1956–1972. [CrossRef]
[PubMed]
22. Abu-Hashem, A.A.; El-Shazly, M. Synthesis of new quinoxaline, pyrimidine, and pyrazole furochromone
derivatives as cytotoxic agents. Monatsh. Chem. 2017, 148, 1853–1863. [CrossRef]

Molecules 2018, 23, 2793
20 of 20
23. Keshk, E.M.; Abu-Hashem, A.A.; Girges, M.M.; Abdel-Rahman, A.H.; Badria, F.A. Synthesis of
benzo[1,2-b:5,4-b]difuranyl-triazoles, oxadiazoles, thiazolidione, thiadiazoles, and the use of DNA in
evaluation of their biological activity. Phosphorus Sulufur Silicon Relat. Elem. 2004, 179, 1577–1593. [CrossRef]
24. Kamal, A.; Shankaraiah, N.; Prabhakar, S.; Reddy, C.R.; Markandeya, N.; Reddy, K.L.; Devaiah, V. Solid-phase
synthesis of new pyrrolobenzo diazepine-chalcone conjugates: DNA-binding affinity and anticancer activity.
Bioorg. Med. Chem. Lett. 2008, 18, 2434–2439. [CrossRef] [PubMed]
25. Abd Elhafez, O.M.; El Khrisy Eel, D.; Badria, F.; Fathy Ael, D. Synthesis and biological investigation of
new thiazolidinone and oxadiazoline coumarin derivatives. Arch. Pharm. Res. 2003, 26, 686–696. [CrossRef]
[PubMed]
26. Wenzel, N.I.; Chavain, N.; Wang, Y.; Friebolin, W.; Maes, L.; Pradines, B.; Lanzer, M.; Yardley, V.;
Brun, R.; Herold-Mende, C.; et al. Antimalarial versus cytotoxic properties of dual drugs derived from
4-aminoquinolines and Mannich bases: Interaction with DNA. J. Med. Chem. 2010, 53, 3214–3226. [CrossRef]
[PubMed]
27. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C.T. Anticancer and antiviral sulfonamides. Curr. Med.
Chem. 2003, 10, 925–953. [CrossRef] [PubMed]
28. Rescifina, A.; Chiacchio, M.A.; Corsaro, A.; De Clercq, E.; Iannazzo, D.; Mastino, A.; Piperno, A.; Romeo, G.;
Romeo, R.; Valveri, V. Synthesis and biological activity of isoxazolidinyl polycyclic aromatic hydrocarbons:
Potential DNA intercalators. J. Med. Chem. 2006, 49, 709–715. [CrossRef] [PubMed]
29. Abu-Hashem, A.A.; El-Shazly, M. Synthesis, reactions and biological activities of furochromones: A review.
Eur. J. Med. Chem. 2015, 90, 633–665. [CrossRef] [PubMed]
30. El-Gazzar, A.B.A.; Youssef, A.M.S.; Youssef, M.M.; Abu-Hashem, A.A.; Badria, F.A. Design and synthesis of
azolopyrimidoquinolines, pyrimidoquinazolines as anti-oxidant, anti-inflammatory and analgesic activities.
Eur. J. Med. Chem. 2009, 44, 609–624. [CrossRef] [PubMed]
31. Riyadh, S.M.; Farghaly, T.A.; Gomha, S.M. Novel polyazaheterocyclic systems: Synthesis, antitumor, and
antimicrobial activities. Arch. Pharm. Res. 2010, 33, 1721–1728. [CrossRef] [PubMed]
32. Ali, T.E.; Ibrahim, M.A. Synthesis and Antimicrobial Activity of Chromone-linked 2-Pyridone Fused with
1,2,4-Triazoles, 1,2,4-Triazines and 1,2,4-Triazepines Ring Systems. J. Braz. Chem. Soc. 2010, 21, 1007–1016.
[CrossRef]
33. Khalil, A.M.; Berghot, M.A.; Gouda, M.A. Synthesis and antibacterial activity of some new heterocycles
incorporating phthalazine. Eur. J. Med. Chem. 2009, 44, 4448–4454. [CrossRef] [PubMed]
34. Jain, S.R.; Kar, A. The antibacterial activity of some essential oils and their combinations. Planta Med. 1971
,
20, 118–123. [CrossRef] [PubMed]
35. Abu-Hashem, A.A. Synthesis and biological activity of pyrimidines, quinolines, thiazines and pyrazoles
bearing a common thieno moiety. Acta Pol. Pharm. Drug Res. 2018, 75, 59–70.
Sample Availability: Samples of the synthesized compounds are available from the authors.
©
2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).