Synthesis of novel 1,3-disubstituted pyrrolo[1,2-a]pyrazine derivatives and antiproliferative effects on glioblastoma cell line

Article abstract of DOI:10.1007/s00706-021-02761-3

Novel pyrrolopyrazine derivatives were synthesized according to a very simple protocol starting from N-propargylated-2-acyl-pyrroles. These derivatives were obtained in good to excellent yields (68–94%) in the presence of ammonium acetate and Cs₂CO₃, and then subjected to cytotoxicity testing against glioblastoma cell line T98G. Among the tested molecules, those that cause 68.9%, 59.1%, and 37.5% cell death, were identified as lead compounds. The structure–activity relationship (SAR) study revealed that conformation, π–π interactions, and halogen bonds could be important for efficiency. Finally, theoretical ADMET studies on pyrrolopyrazine derivatives demonstrated that pharmacokinetic phases are suitable. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-021-02761-3

Monatshefte für Chemie - Chemical Monthly (2021) 152:513–522
https://doi.org/10.1007/s00706-021-02761-3
ORIGINAL PAPER
Synthesis of novel 1,3‑disubstituted pyrrolo[1,2‑a]pyrazine derivatives
and antiproliferative efects on glioblastoma cell line
Meltem Tan Uygun1
Received: 14 January 2021 / Accepted: 29 March 2021 / Published online: 14 April 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
Novel pyrrolopyrazine derivatives were synthesized according to a very simple protocol starting from N-propargylated-2-acyl-
pyrroles. These derivatives were obtained in good to excellent yields (68–94%) in the presence of ammonium acetate and
Cs2CO3, and then subjected to cytotoxicity testing against glioblastoma cell line T98G. Among the tested molecules, those
that cause 68.9%, 59.1%, and 37.5% cell death, were identifed as lead compounds. The structure–activity relationship (SAR)
study revealed that conformation, π–π interactions, and halogen bonds could be important for efciency. Finally, theoretical
ADMET studies on pyrrolopyrazine derivatives demonstrated that pharmacokinetic phases are suitable.
Graphic abstract
Keywords Alkyne cyclization · Allene · Pyrrole · Glioblastoma
Introduction
Glioblastoma (GB) is the most lethal brain tumor with
median patients’ survival of 10–14 months [17]. The
standard treatment for glioblastoma patients is currently
surgical resection followed by radiotherapy and/or chemo-
therapy [18]. Many cancer cells express activated onco-
genes or lack key tumor suppressors, and this can make
these cancer cells prone to dysregulated phases of DNA
replication, which in turn cause DNA damage [19]. Ataxia
telangiectasia and Rad3 (ATR)-related protein is a master
regulator of the DDR (DNA damage response), and once
activated, ATR phosphorylates multiple substrates, includ-
ing the Chk1 kinase, to regulate cell-cycle progression,
replication fork stability, and DNA repair [20]. Accord-
ingly, ATR inhibitors may be useful for cancer treatment,
either used alone or in combination with DNA damaging
agents, because they shut down a DNA repair mechanism
that is more important for cellular survival in many can-
cer cells than in healthy normal cells [19]. Some pyrro-
lopyrazine compounds that are useful as inhibitors of ATR
protein kinase for cancer treatment have been recently pat-
ented [19]. Some pharmacologically active pyrrolo[1,2-a]
Heterocyclic compounds that include two nitrogen atoms
have various biological activities. In particular nitrogen-
fused bicyclic compounds such as imidazo[1,2-b]pyri-
dazine, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine, and
imidazo[1,2-a]pyrimidine have interesting biological activi-
ties such as antiplasmodial, anti HCV, and anticancer activi-
ties [1–5]. Beside these compounds, pyrrolo[1,2-a]pyrazines
have neuroleptic, cardiovaskular [6], immunosuppressive,
antibacterial, anti-insect defensive properties [7] and are
also a potent and selective 5-HT2C receptor agonists [8] and
selective 5-HT3 receptor agonists [9]. Furthermore, some
clinically used drugs for lung [10], prostate [11, 12], and
breast cancer [13], tuberculosis treatment [14], or inhibitors
of glycogen synthase kinase-3β (GSK-3) [15] and protein
kinase B1 [16], have nitrogen-fused scafolds.
* Meltem Tan Uygun
meltemtan@yyu.edu.tr
1
Pharmaceutical Chemistry Section, Van Yuzuncu Yil
University, 65080 Van, Turkey
Vol.:(0123456789)
1 3

514
M. Tan Uygun
Fig. 1 Pharmacologically active pyrrolopyrazine and imidazolopyridine derivatives
pyrazines are disclosed in the literature, as shown in Fig. 1.
Various imidazopyridine derivatives show cytotoxic activ-
ity against glioblastoma cell line (LN-405) [18].
Scheme 1
R
O
O
N
N
N
N
However, in the literature, there are only few methods
for the synthesis of pyrrolo[1,2-a]pyrazine compounds.
The synthesis of pyrrolo[1,2-a]pyrazines, starting from
the N-alkylation of pyrrole-2-carboxaldehyde and dehy-
drative cyclization in the presence of ammonium ace-
tate, was presented by Kim et al. [21]. Also, 3-substi-
tuted 1-methylpyrrolo[1,2-a]pyrazines were achieved by
Abbiati et al. by intramolecular cyclization of 2-acetyl-
N-propargylpyrroles in the presence of ammonia under
microwave heating using TiCl4 [22]. Balci et al. reported
that the reaction of pyrrole-2-carbaldehyde having a pro-
pargyl group attached to the nitrogen atom, with ammo-
nia in the presence of Cs2CO3 led to the formation of
3-methylpyrrolo[1,2-a]pyrazine [23]. Interestingly, the
same group also obtained the same cyclization product
from the reaction of N-propargyl-pyrrole-2-carbaldehyde
with allylamine and propargylamine. Another similar
study, which is the cyclization reaction of N-propar-
gylated-2-acylindole and 2 M ammonia, was presented by
Abbiati et al. [24]. Besides the addition of TiCl4 to the
reaction medium, microwave or conventional heating in a
sealed tube shortened the reaction time.
R
H
R
cyclisation
propargylation
1
2
3
Results and discussion
Chemistry
2-Acylpyrrole compounds 1a–1i were commercially avail-
able at Saf Chemical Reagent-SAFF CHEMICAL. The
starting materials, N-propargylated-2-acyl pyrroles 2a–2i
were formed by reaction of corresponding 2-acyl pyrroles
1a–1i with propargyl bromide in the presence of K2CO3
(Scheme 2) at room temperature.
To optimize the cyclization conditions, 2a was used as a
model substrate (Table 1). Based on the literature informa-
tion, 2a was reacted with 4 equiv. of ammonium acetate
in i-PrOH at 83 °C. No product was observed after 24 h
(entry 1). Then, 2a was reacted with 4 equiv. of ammo-
nia (25% solution in water) in the presence of Cs2CO3 in
i-PrOH. Allene 4a isomer of compounds 2a and 5a was
obtained after 3 h (entry 2). It has been reported from Balcı
et al. that the propargyl group isomerize to allene under
basic conditions [25]. Moreover, the addition of water to
4a followed by the formation of 5a proved the presence
of allene compound (see supp. info for NMR data). The
formation of the allene gave important information about
For the reasons described above, we became interested
in the synthesis of novel pyrrolo[1,2-a]pyrazines 3 through
cyclization of compound 2 in the presence of Cs2CO3 and
ammonium acetate (Scheme 1), and then in the evaluation
of their biological activity against a glioblastoma cell line
(T98G).
1 3

Synthesis of novel 1,3-disubstituted pyrrolo[1,2-a]pyrazine derivatives and…
515
Scheme 2
O
O
Br
N
N
H
R
R
,
K
rt
2CO3
DMF,
-
Ph
-CH3
2f
1a-1i
R=p
2a
(90%)
(92%)
R=p
-Cl-Ph (92%)
R=2-Thienyl (74%)
p
2g
R= -F-Ph
2b
(95%)
2h R=Cyclohexyl
2c
(89%)
R=Ph
β
(62%)
R=2-Furyl
(90%)
(96%)
-Ph
-Napthyl
2i
R=
2d
2e
R=p
-NO2
the reaction mechanism (Scheme 3). Then, 2a was reacted
with Cs2CO3 and 4 equiv. of NH4OAc. However, no reac-
tion was observed after 3 h and even after the addition of
an excess of Cs2CO3 and prolonged heating (24 h) (entry
3). We have determined that when cesium carbonate and
ammonium acetate are present in the reaction medium at
the same time, they somehow prevent the formation of
allene. Hence, the 2a derivative and cesium carbonate
were heated in i-PrOH for 30 min. After the allen isomer-
ization was determined by TLC monitoring, the amine
source was added to the reaction fask. In the experiments
given in Table 1, entries 4–10 were carried out in this way.
An excess of ammonium acetate (6 eq.) resulted in the
isolation of 3a and 4a both in 44% yield (entry 4). 30 Eq.
of NH4OAc increased the yield of 3a up to 91%, (entry
5). For comparison, 20 equiv. ammonia were used and the
target compound was obtained 24% yield after 76 h beside
4a and 5a (entry 6). Same conditions were applied in a
closed system [24] to improve reaction efciency and time.
Allene isomer initially occurred from 2a with conventional
system in half an hour, and then, allene and NH4OAc were
reacted in a sealed tube for 24 h, and 3a was obtained
Table 1 Reaction optimization of intramolecular cyclization of 2a
Entry
Cs2CO3
Amine
Time/h
Yieldd/%
c
(NH3 /NH4OAc)
3a
4a
5a
1
2
3
4
5
6
7
8
9
10
–
–/4
4/–
–/4
–/6
–/30
20/–
–/10
–/20
–/10
–/20
24
3
–
–
–
44
91
24
25
38
30
84
–
80
–
44
–
33
–
62
–
16
–
10
–
12
9
33
75
–
1a
1a
1b
1b
1b
1b
1b
1b
1b
24
30
96
76
24
24
96
96
70
–
a1 equiv. of 2a, 1 equiv. of Cs2CO3, and coresponding equiv. amount of amine in i-propanol simultaneously at 83 °C
b1 equiv. of 2a and 1 equiv. of Cs2CO3 in i-propanol for 0.5 h at 83 °C, then coresponding equiv. amount of amine
cAmmonia solution 25%
dIsolated yields
1 3

516
M. Tan Uygun
Scheme 3
Cl
O
O
HO
N
NH
Cl
N
Cl
Cl
N
NH2
6a
Cl
Cl
-H
2O
2a
a
c
Cs2CO3
OA
4
NH
H+
NH3
O
b
N
N
b
4OAc
N
N
NH
6b
N
NH
Cl
c
3a
N
OA
4
O
O
2
O
NH
-H
c
4a
H
a
NH3
2
c
O
H
2O
N
N
Cl
O
Cl
OH
5a
Table 2 Preparation of pyrrolo[1,2-a]pyrazines 3a–3i
Comp.
R
Yield/%
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-Cl-Ph
2-Thienyl
Ph
β-Naphthyl
p-NO2-Ph
p-CH3-Ph
p-F-Ph
Cyclohexyl
2-Furyl
91
68
92
86
76
78
77
72
94
in 25% yield (entry 7). The reaction was continued for
96 h to understand efect of the time to the reaction yield.
Cyclization compound was obtained in 30% yield (entry
8). Finally, the amount of base was doubled to increase the
reaction yield. The cyclization compound was obtained
in 38% after 24 h (entry 9). The yield increased to 84%
after heating for 96 h (entry 10). The reaction conditions
reported in entry 5 for the synthesis of 3a were chosen to
investigate the scope of the reaction.
The reaction scope was further examined with N-pro-
pargylated-2-acyl-pyrrole compounds 2b–2i as shown in
Table 2. Pyrrolo[1,2-a]pyrazines 3a–3i were obtained in
good to excellent yields (68–94%).
1 3

Synthesis of novel 1,3-disubstituted pyrrolo[1,2-a]pyrazine derivatives and…
517
Fig. 2 Antiproliferative efecta
of synthesized molecules on
T98G at 24 hb (a: Numbers
show percentage of cell viability
(living cancer cells after treat
with compounds), b: concentra-
tion of molecules was 100 µM
in DMSO)
Based on the optimization fndings, we proposed three
diferent reaction pathways, as shown in Scheme 3. All
proposed mechanisms encompass the initial base catalyzed
formation of allene 4a. In pathway a, after formation of
allene 4a, ammonium acetate attacks the central carbon
atom of the allene unit giving rise to amine intermediate
6a. The condensation reaction between amino and car-
bonyl groups followed by proton shift forms the cyclization
product 3a. In pathway b, from 4a and ammonium acetate,
imine 6b is formed. Then, the initially formed imine nitro-
gen atom attacks the central carbon atom of the allene unit,
and fnal proton shift afords the cyclization product 3a.
Another reaction mechanism begins with the addition of
water to the allene compound 4a to form 5a. The intramo-
lecular condensation reaction of ammonium acetate with
5a results in the formation of compound 3a.
Table 3 Some of ADMET
Entry Log P Caco2 Intest VDss
Fu
CYPs
Total C OCT2 hERG Skin sensitive
parameters for synthesized
Ab./%
I–II
molecules (for explanation of
abbreviation in the table, please
see supporting information)
3a
3b
3c
3.96
3.37
3.31
1.57
1.74
1.72
96
96
98
0.12 0.35 CYP1A2
CYP2C19
0.02 0.36 CYP1A2
0.32
0.35
0.91
No
No
No
No
No
No
No
No
No
CYP2C19
0.06 0.35 CYP1A2
CYP3A4
CYP2C19
3d
3e
3f
4.46
3.22
3.62
1.68
1.33
1.44
98
96
99
0.28 0.31 CYP3A4
0.87
0.65
1.0
No
No
No
No
No
No
No
No
No
CYP1A2
CYP2C19
CYP2C9
0.09 0.28 CYP3A4
CYP1A2
CYP2C19
CYP2C9
0.34 0.31 CYP1A2
CYP3A4
CYP2C19
3g
3h
3.45
3.69
1.52
1.71
97
95
0.15 0.41 CYP1A2
0.60
1.15
No
No
No
No
No
No
CYP2C19
0.57 0.28 CYP3A4
CYP1A2
CYP2C19
3i
2.90
1.74
100
−0.18 0.48 CYP1A2
0.68
No
No
No
1 3

518
M. Tan Uygun
predicted fraction that would be unbound in plasma [26].
Decrease of this value means that the molecule’s binding
rates to plasma proteins increase. The pyrrolopyrazine
derivative with the cyclohexyl moiety (compound 3h) has
the lowest Fu value (Fu: 0.28; Table 3). The synthesized
molecules are not OCT2 substrate and it means that they
have no potential for disposition and clearance efect. Total
Clearance of synthesized molecules is between 0.32 and
1.0 log(cm3/min). Another important parameter for drugs
is the inhibition of HERGI/II. İnhibition of hERG channels
has resulted in the withdrawal of many substances from the
pharmaceutical market. Calculations show that molecules
do not inhibit hERGI/II, and molecules have not allergic
reaction on skin. Theoretical ADMET information shows
that the synthesized molecules are likely to have suitable
pharmacokinetic parameters.
Cytotoxicity assay
The antiproliferative efect of nine diferent pyrrolo[1,2-a]-
pyrazine derivatives synthesized in this study was investi-
gated because pyrrolopyrazine compounds are considered
as inhibitors of ATR protein kinase. The antiproliferative
efects of compounds 3a–3i on the T98G (glioblastoma cell
line) were examined using the MTT method at 24 and 48 h,
and the results are given in Fig. 2.
Among the molecules, 3h, 3d, and 3g, which cause
68.9%, 59.1%, and 37.5% death of cancer cells, respec-
tively, have been identifed as the most promising compunds
for further evaluations. The substituent patterns around
these molecules give usefull information for the design of
novel compounds. The most efective molecule 3h has a
cyclohexyl ring on C-1 position. All other molecules contain
aromatic groups on this position. As known, cyclohexane
has two possible conformations (chair and boat), whereas
aromatic rings are fat. This structural diference may reduce
the distances for active site interactions and the synthesized
molecule. The other most efective compound 3d has a
naphthalene group as a substituent. Aromatic rings show
their efects via π–π interactions. It is not surprising that
this interaction is greater at 3d due to the presence of two
condensed aromatic benzene rings. While the activities of
the derivatives having both chlorine atom and methyl group
in the para position were low, the antiproliferative efect of
the derivative containing fuorine in the para position was
quite good. Flourobenzene containing compound 3g show
its efect via π–π interactions, and also, fuorine atoms can
form halogen bonds and/or hydrogen bonds at the relevant
position.
Conclusion
In conclusion, we have found a simple route to novel diverse
1,3-disubstituted pyrrolo[1,2-a]pyrazines by employing pro-
pargylation and intramolecular cyclization. The cyclization
reactions were carried out with N-propargylated-2-acyl-
pyrroles and ammonium acetate in the presence of cesium
carbonate. The antiproliferative efect of all synthesized
molecules was tested on a glioblastoma cell line (T98G).
Compound 3d, 3g, and 3h show an antiproliferative efect at
a concentration of 100 µM. Theoretical ADMET parameters
showed that compounds have good pharmacokinetic param-
eters and these results are promising for further studies.
Theoretical pharmacokinetic study for synthesized
molecules
Experimental
All reagents were used as purchased from commercial sup-
pliers without further purifcation. Proton nuclear magnetic
resonance spectra (1H NMR) were recorded on an instru-
ment 400 MHz, and chemical shifts are reported in parts
per million (ppm) downfeld from TMS, using CDCl3 as
an internal standard. Proton-decoupled carbon nuclear mag-
netic resonance spectra (13C NMR) spectra were recorded
on an instrument 100 MHz. Column chromatography was
performed on silica gel (60-mesh). TLC was carried out on
0.2 mm silica gel 60 F254 analytical aluminum plates. High-
resolution mass spectra were using by THERMO ITQ900
LC/MS spectrometer with ESI method. Melting points were
measured using melting point apparatus. All spectroscopic
analyses were conducted at the Science Research and Appli-
cation Center of Van Yuzuncu Yil University.
Theoretical ADMET information of the molecular skeleton,
whose antiproliferative efect was determined, was also cal-
culated. To calculate some important ADMET parameters,
the pkCSM program was used [26]. The results are shown
in Table 3. Caco-2 permeability and small intestinal absorp-
tion, which are the absorption parameter, were calculated.
The obtained results showed that all synthesized molecules
have proper Caco-2 permeability. Small intestinal absorp-
tion, which is desired to be high, was also calculated between
95 and 100%. Log P values were found to be between a suit-
able range when Lipinski rules were considered (2.90–4.46).
The VDss values of the molecules are not very high (−0.18
to 0.57 log L/kg). The higher the VD is, the more of a drug
is distributed in tissue rather than plasma [26]. According
to the results, the molecules obtained in this study will be
found in plasma rather than in tissues. Fu value means the
1 3

Synthesis of novel 1,3-disubstituted pyrrolo[1,2-a]pyrazine derivatives and…
519
7.95–7.89 (m, 4H, Ar-H), 7.61–7.53 (m, 2H, Ar-H), 7.34
(dd, J=1.8, 2.5 Hz, 1H, Pyr-H), 6.87 (dd, J=1.8, 4.1 Hz,
1H, Pyr-H), 6.27 (dd, J=2.5, 4.1 Hz, 1H, Pyr-H), 5.36 (d,
J=2.6 Hz, 2H, –CH2–), 2.50 (t, J=2.6 Hz, 1H, –CH) ppm;
13C NMR (100 MHz, CDCl3): δ = 186.1, 136.8, 134.9,
132.3, 130.4, 130.0, 129.8, 129.2, 128.1, 127.9, 127.8,
126.7, 125.6, 123.7, 108.9, 78.4, 74.2, 38.7 ppm; LC–MS/
MS: m/z calcd. for C18H13NNaO ([M + Na]+) 282.0889,
found 282.0894.
General procedure for the synthesis
of the compounds 2a–2i
To a stirred mixture of 2-acylpyrroles 1a–1i (1 mmol) in 10
cm3 DMF was added K2CO3 (2 mmol) at 0 °C. The reaction
mixture was stirred at 0 °C for 20 min, and then propargyl
bromide (1.4 mmol) in 5 cm3 DMF was added to the reac-
tion fask dropwise over a period of 10 min. After stirring for
16 h at room temperature, the resulting mixture was diluted
with 20 cm3 water and extracted with ethyl acetate (3×20
cm3). The combined extracts were washed with brine (4×10
cm3), dried with MgSO4, and fltered. The solvent was evap-
orated, and the crude product was purifed over silica gel
eluting with hexane/EtOAc (5:1) to give 2a–2i.
(4‑Nitrophenyl)[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl]metha‑
none (2e, C14H10N2O3) Light brown solid; m.p.: 149–150 °C;
yield: 96%; 1H NMR (400 MHz, CDCl3): δ=8.32–8.29 (m,
AA′BB′ system, 2H, Ar-H), 7.94–7.91 (m, AA′BB′ system,
2H, Ar-H), 7.38 (dd, J=1.7, 2.6 Hz, 1H, Pyr-H), 6.74 (dd,
J=1.7, 4.1 Hz, 1H, Pyr-H), 6.27 (dd, J=2.6, 4.1 Hz, 1H,
Pyr-H), 5.30 (d, J=2.6 Hz, 2H, –CH2–), 2.49 (t, J=2.6 Hz,
1H, –CH) ppm; 13C NMR (100 MHz, CDCl3): δ = 183.7,
145.0, 131.1, 130.8, 129.9, 129.0, 124.4, 123.4, 109.5,
(4‑Chlorophenyl)[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl]metha‑
none (2a, C14H10ClNO) White solid; m.p.: 89–91 °C; yield:
1
92%; H NMR (400 MHz, CDCl3): δ = 7.77–7.74 (m,
AA′BB′ system, 2H, Ar-H), 7.44–7.41 (m, AA′BB′ system,
2H, Ar-H), 7.31 (dd, J=1.7, 2.6 Hz, 1H, Pyr-H), 6.75 (dd,
J=1.7, 4.1 Hz, 1H, Pyr-H), 6.23 (dd, J=2.6, 4.1 Hz, 1H,
Pyr-H), 5.28 (d, J=2.6 Hz, 2H, –CH2–), 2.46 (t, J=2.6 Hz,
1H, CH) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.7,
137.9, 137.8, 130.6, 130.1, 129.4, 128.4, 123.5, 109.0,
78.1, 74.1, 38.7 ppm; HRMS: m/z calcd. for C14H10ClNO+
([M+H]+) 244.0529, found for C14H11ClNO+ ([M+H]+)
244.0501.
+
77.8, 74.4, 38.9 ppm; HRMS: m/z calcd. for C14H10N2O3
+
([M + H]+) 255.0770, found for C14H11N2O3 ([M + H]+)
255.0748.
[1‑(Prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl](p‑tolyl)methanone (2f,
1
C15H13NO) White solid; m.p.: 66–68 °C; yield: 90%; H
NMR (400 MHz, CDCl3): δ=7.76–7.70 (m, AA′BB′ system,
2H, Ar-H), 7.29 (dd, J=1.7, 2.6 Hz, 1H, Pyr-H), 7.26–7.24
(m, AA′BB′ system, 2H, Ar-H), 6.78 (dd, J = 1.7, 4.0 Hz,
1H, Pyr-H), 6.22 (dd, J=2.6, 4.0 Hz, 1H, Pyr-H), 5.29 (d,
J=2.6 Hz, 2H, –CH2–), 2.45 (t, J=2.6 Hz, 1H, CH), 2.43
(s, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ=186.0,
142.2, 136.9, 129.9, 129.5, 129.4, 128.7, 123.1, 108.6, 78.3,
73.9, 38.6, 21.5 ppm; HRMS: m/z calcd. for C15H13NO+
([M + H]+) 224.1075, found for C15H14NO+ ([M + H]+)
224.1041.
[1‑(Prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl](thiophen‑2‑yl)metha‑
none (2b, C12H9NOS) Dark brown viscous liquid; yield: 74%;
1H NMR (400 MHz, CDCl3): δ=7.75 (dd, J=1.2, 3.8 Hz,
1H, Thp-H), 7.60 (dd, J = 1.2, 5.0 Hz, 1H, Thp-H), 7.27
(dd, J=1.7, 2.6 Hz, 1H, Pyr-H), 7.14 (dd, J=3.8, 5.0 Hz,
1H, Thp-H), 7.08 (dd, J=1.7, 4.1 Hz, 1H, Pyr-H), 6.24 (dd,
J=2.6, 4.1 Hz, 1H, Pyr-H), 5.24 (d, J=2.6 Hz, 2H, CH2–),
2.44 (t, J = 2.6 Hz, 1H, –CH) ppm; 13C NMR (100 MHz,
CDCl3): δ=177.1, 144.4, 132.5, 132.3, 129.7, 129.4, 127.6,
121.7, 109.0, 78.2, 74.1, 38.5 ppm; LC–MS/MS: m/z calcd.
for C12H10NOS+ ([M+H]+) 216.0477, found 216.0482.
(4‑Fluorophenyl)[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl]metha‑
none (2g, C14H10FNO) White solid; m.p.: 87–89 °C; yield:
1
92%; H NMR (400 MHz, CDCl3): δ = 7.86–7.82 (m,
AA′BB′ system, 2H, Ar-H), 7.31–7.30 (m, 1H, Pyr-H),
7.16–7.10 (m, AA′BB′ system, 2H, Ar-H), 6.76–6.74 (m,
1H, Pyr-H), 6.24–6.22 (m, 1H, Pyr-H), 5.28 (d, J=2.5 Hz,
2H, –CH2–), 2.46 (t, J=2.5 Hz, 1H, –CH) ppm; 13C NMR
(100 MHz, CDCl3): δ=184.6, 164.9 (d, J=252.4 Hz), 135.8
(d, J=3.0 Hz), 131.6 (d, J=8.9 Hz), 129.9, 129.5, 123.3,
115.1 (d, J=21.8 Hz), 108.9, 78.2, 74.0, 38.6 ppm; HRMS:
m/z calcd. for C14H10FNO+ ([M+H]+) 228.0825, found for
C14H11FNO+ ([M+H]+) 228.0811.
Phenyl[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl]methanone (2c,
C14H11NO) Light brown viscous liquid [Ref. 25]; yield: 89%;
1H NMR (400 MHz, CDCl3): δ=7.83–7.79 (m, 2H, Ar-H),
7.56–7.52 (m, 1H, Ar-H), 7.47–7.42 (m, 2H, Ar-H), 7.31
(dd, J=1.7, 2.6 Hz, 1H, Pyr-H), 6.78 (dd, J=1.7, 4.1 Hz,
1H, Pyr-H), 6.23 (dd, J=2.6, 4.1 Hz, 1H, Pyr-H), 5.31 (d,
J=2.6 Hz, 2H, –CH2–), 2.46 (t, J=2.6 Hz, 1H, Ar-H) ppm;
13C NMR (100 MHz, CDCl3): δ=186.2, 139.6, 131.6, 129.8,
129.2, 128.1, 123.6, 108.8, 78.3, 74.0, 38.7 ppm.
Cyclohexyl[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl]methanone
(2h, C14H17NO) Dark yellow viscous liquid; yield: 95%; 1H
NMR (400 MHz, CDCl3): δ=7.18–7.17 (m, 1H, Ar-H), 6.99
(dd, J=1.7, 4.1 Hz, 1H, Pyr-H), 6.16 (dd, J=2.7, 4.1 Hz,
Naphthalen‑2‑yl[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl]metha‑
none (2d, C18H13NO) Yellow solid; m.p.: 126–128 °C; yield:
90%; 1H NMR (400 MHz, CDCl3): δ=8.35 (bs, 1H, Ar-H),
1 3

520
M. Tan Uygun
1H, Pyr-H), 5.19 (d, J=2.6 Hz, 2H, –CH2–), 2.99 (tt, J=3.2,
11.7 Hz, 1H, Cyhxl-H), 2.41 (t, J = 2.6 Hz, 1H, –CH),
1.83–1.78 (m, 4H, Cyhxl-H), 1.71–1.66 (m, 1H, Cyhxl-H),
1.55–1.45 (m, 2H, Cyhxl-H), 1.35–1.23 (m, 3H, Cyhxl-H)
ppm; 13C NMR (100 MHz, CDCl3): δ=195.1, 129.2, 129.1,
119.3, 108.4, 78.3, 73.9, 47.0, 38.9, 29.9, 29.8, 25.9 ppm;
HRMS: m/z calcd. for C14H17NO+ ([M + H]+) 216.1388,
found for C14H18NO+ ([M+H]+) 216.1367.
6.86 (dd, J = 2.5, 4.2 Hz, 1H, Pyr-H), 2.45 (d, J = 1.0 Hz,
3H, –CH3) ppm; 13C NMR (CDCl3): δ=146.1, 142.6, 135.0,
128.2, 127.7, 127.5, 124.3, 114.7, 114.6, 113.8, 103.4,
20.8 ppm; HRMS: m/z calcd. for C12H11N2S+ ([M + H]+)
215.0638, found 215.0639.
3 ‑ M e t hy l ‑ 1 ‑ p h e ny l py r ro l o [ 1 , 2 ‑ a] py ra z i n e ( 3 c,
C14H12N2) Colorless cyrstals; m.p.: 92–94 °C; yield: 92%;
1H NMR (CDCl3): δ=7.97–7.94 (m, 2H, Ar-H), 7.65–7.64
(m, 1H,=CH), 7.53–7.47 (m, 3H, Ar-H), 7.40 (dd, J=1.3,
2.5 Hz, 1H, Pyr-H), 6.87 (dt, J = 1.3, 4.2 Hz, 1H, PyrH),
6.83 (dd, J= 2.5, 4.2 Hz, 1H, Pyr-H), 2.48 (d, J = 1.0 Hz,
3H, –CH3) ppm; 13C NMR (CDCl3): δ=153.0, 138.5, 135.4,
129.4, 128.5, 128.4, 125.9, 114.6, 114.4, 113.8, 104.1,
Furan‑2‑yl[1‑(prop‑2‑yn‑1‑yl)‑1H‑pyrrol‑2‑yl])methanone
(2i, C12H9NO2) Yellow viscous liquid; yield: 62%; 1H NMR
(400 MHz, CDCl3): δ=7.62 (dd, J=0.8, 1.7 Hz, 1H, Fry-
H), 7.36 (dd, J = 1.7, 4.1 Hz, 1H, Pyr-H), 7.29–7.28 (m,
1H, Pyr-H), 7.25 (dd, J=0.8, 3.5 Hz, 1H, Fry-H), 6.55 (dd,
J=1.7, 3.5 Hz, 1H, Fry-H), 6.27 (dd, J=2.6, 4.1 Hz, 1H,
Pyr-H), 5.27 (d, J=2.6 Hz, 2H, –CH2–), 2.44 (t, J=2.6 Hz,
1H, –CH) ppm; 13C NMR (100 MHz, CDCl3): δ = 171.9,
153.1, 145.8, 129.8, 128.6, 121.8, 117.9, 111.9, 109.2, 78.2,
+
21.0 ppm; HRMS: m/z calcd. for C14H13N2 ([M + H]+)
209.1073, found 209.1075.
3‑Methyl‑1‑(naphthalen‑2‑yl)pyrrolo[1,2‑a]pyrazine (3d,
C18H14N2) Light brown solid; m.p.: 54–56 °C; yield: 86%;
1H NMR (CDCl3): δ = 8.50 (d, J = 1.0 Hz, 1H, Nap-H),
8.51 (dd, J=1.7, 8.5 Hz, 1H, Nap-H), 7.99 (d, J =8.5 Hz,
1H, Nap-H), 7.98–7.96 (m, 1H, Nap-H), 7.93–7.90 (m, 1H,
Nap-H), 7.64–7.63 (m, 1H,=CH), 7.56–7.54 (m, 2H, Nap-
H), 7.40 (dd, J=1.3, 2.5 Hz, 1H, Pyr-H), 6.98 (dt, J=1.3,
4.2 Hz, 1H, Pyr-H), 6.87 (dd, J=2.5, 4.2 Hz, 1H, Pyr-H),
2.52 (d, J = 1.1 Hz, 3H, –CH3) ppm; 13C NMR (CDCl3):
δ=152.9, 135.9, 135.4, 133.9, 133.2, 128.7, 128.3, 128.2,
127.8, 126.7, 126.3, 126.1, 126.0, 114.7, 114.6, 113.9, 104.2,
+
74.0, 38.8 ppm; LC–MS/MS: m/z calcd. for C12H10NO2
([M+H]+) 200.0712, found 200.0719.
General procedure for the synthesis
of the compounds 3a–3i
To a stirred mixture of N-propargylated-2-acylpyrroles
2a–2i (1 mmol) in 20 cm3 isopropanol was added Cs2CO3
(1 mmol) at room temperature. The reaction mixture
was then heated at refux for 0.5 h. Ammonium acetate
(30 mmol) was added to the reaction fask and refuxed
continued for 96 h, the resulting mixture was evaporated,
and the crude product was diluted with 20 cm3 water and
extracted with ethyl acetate (3 × 20 cm3). The combined
extracts were dried with MgSO4 and fltered. The solvent
was evaporated, and the crude product was purifed over
silica gel eluting with hexane/EtOAc (5:1) to give 3a–3i.
+
21.0 ppm; HRMS: m/z calcd. for C18H15N2 ([M + H]+)
259.1230, found 259.1231.
3‑Methyl‑1‑(4‑nitrophenyl)pyrrolo[1,2‑a]pyrazine (3e,
C14H11N3O2) Orange solid; m.p.: 162–165 °C; yield: 76%;
1H NMR (CDCl3): δ = 8.38–8.35 (AA′BB′ system, 2H,
Ar-H), 8.178.14 (AA′BB′ system, 2H, Ar-H), 7.72–7.71 (m,
1H, =CH), 7.46 (dd, J=1.1, 2.5 Hz, 1H, Pyr-H), 6.90 (dd,
J = 2.5, 4.2 Hz, 1H, Pyr-H), 6.84 (dt, J = 1.1, 4.2 Hz, 1H,
Pyr-H), 2.49 (d, J=0.9 Hz, 3H, –CH3), 2.44 (d, 3H, –CH3)
ppm; 13C NMR (CDCl3): δ = 150.4, 148.3, 144.5, 135.6,
129.5, 125.4, 123.7, 115.2, 115.1, 114.7, 103.7, 20.9 ppm;
HRMS: m/z calcd. for C14H12N3O2+ ([M+H]+) 254.0924,
found 254.0925.
1‑(4‑Chlorophenyl)‑3‑methylpyrrolo[1,2‑a]pyrazine (3a,
C14H11ClN2) Light green solid; m.p.: 121–123 °C; yield:
91%; 1H NMR (CDCl3): δ=7.93–7.90 (AA′BB′ system, 2H,
Ar-H), 7.61 (bs, 1H,=CH), 7.49–7.45 (AA′BB′ system, 2H,
Ar-H), 7.38 (t, J=2.0 Hz, 1H, Pyr-H), 6.82 (d, J=2.0 Hz,
2H, Pyr-H), 2.46 (d, J=1.1 Hz, 3H, –CH3) ppm; 13C NMR
(CDCl3): δ=151.6, 136.9, 135.4, 135.3, 129.8, 128.7, 125.6,
114.8, 114.6, 114.0, 103.9, 20.9 ppm; HRMS: m/z calcd. for
C14H12ClN2+ ([M+H]+) 243.0684, found 243.0689.
3‑Methyl‑1‑(p‑tolyl)pyrrolo[1, 2‑a]pyrazine (3f,
1
C15H14N2) Brown solid; m.p.: 70–72 °C; yield: 78%; H
NMR (CDCl3): δ=7.90–7.87 (AA′BB′ system, 2H, Ar-H),
7.617.60 (m, 1H,=CH), 7.37 (dd, J=1.3, 2.5 Hz, 1H, Pyr-
H), 7.34–7.31 (AA′BB′ system, 2H, Ar-H), 6.88 (dt, J=1.3,
4.2 Hz, 1H, Pyr-H), 6.82 (dd, J=2.5, 4.2 Hz, 1H, Pyr-H),
2.47 (d, J=1.1 Hz, 3H, –CH3), 2.44 (s, 3H, ArCH3) ppm;
13C NMR (CDCl3): δ = 153.0, 139.5, 135.7, 135.3, 129.2,
128.4, 125.9, 114.5, 114.3, 113.6, 104.1, 21.4, 21.0 ppm;
3‑Methyl‑1‑(thiophen‑2‑yl)pyrrolo[1,2‑a]pyrazine (3b,
1
C
12H10N2S) Green solid; m.p.: 62–64 °C; yield: 68%; H
NMR (CDCl3): δ = 7.90 (dd, J = 1.1, 3.7 Hz, 1H, Thp-H),
7.60–7.59 (m, 1H,=CH), 7.49 (dd, J=1.1, 5.1 Hz, 1H, Thp-
H), 7.37 (dd, J=1.2, 2.5 Hz, 1H, Pyr-H), 7.19 (dd, J=3.7,
5.1 Hz, 1H, Thp-H), 7.09 (dt, J=1.2, 4.2 Hz, 1H, Pyr-H),
1 3

Synthesis of novel 1,3-disubstituted pyrrolo[1,2-a]pyrazine derivatives and…
521
+
HRMS: m/z calcd. for C15H15N2 ([M + H]+) 223.1230,
(obtained from entry 2); 1H NMR (CDCl3): δ=7.747.71 (m,
AA′BB′ system, 2H, Ar-H), 7.44–7.40 (m, AA′BB′ system,
2H, Ar-H), 6.92 (dd, J=1.7, 2.5 Hz, 1H, Pyr-H), 6.81 (dd,
J=1.7, 4.1 Hz, 1H, Pyr-H), 6.28 (dd, J=2.5, 4.1 Hz, 1H,
Pyr-H), 5.11 (s, 2H, –CH2), 2.28 (s, 3H, –CH3) ppm; 13C
NMR (100 MHz, CDCl3): δ = 202.0, 184.9, 137.9, 137.7,
131.9, 130.5, 129.6, 128.4, 123.2, 109.2, 58.6, 27.1 ppm;
HRMS: m/z calcd. for C14H12ClNO2+ ([M+H]+) 262.0635,
found for C14H13ClNO2+ ([M+H]+) 262.0603.
found 223.1231.
1‑(4‑Fluorophenyl)‑3‑methylpyrrolo[1,2‑a]pyrazine (3g,
C14H11FN2) White solid; m.p.: 102–104 °C; yield: 77%;
1H NMR (CDCl3): δ = 7.99–7.94 (AA′BB′ system, 2H,
Ar-H), 7.62 (bs, 1H,=CH), 7.38 (t, J=1.9 Hz, 1H, Pyr-H),
7.22–7.16 (AA′BB′ system, 2H, Ar-H), 6.83 (d, J=1.9 Hz,
2H, Pyr-H), 2.46 (d, J=1.0 Hz, 3H, –CH3) ppm; 13C NMR
(CDCl3): δ = 163.6 (d, J = 248.8 Hz), 151.9, 135.3, 134.6
(d, J = 3.2 Hz), 130.4 (d, J = 8.4 Hz), 125.7, 115.5 (d,
J=21.6 Hz), 114.8, 114.5, 113.8, 103.9, 21.0 ppm; HRMS:
Cell viability assay (MTT)
+
m/z calcd. for C14H12FN2 ([M + H]+) 227.0979, found
Cell culture
227.0979.
The study material included commercially available glio-
blastoma T98G (ATCC® CRL-1690™) cells. The cells were
cultured in vitro in DMEM, high glucose (cat no: DMEM-
HA) with 10% FBS (cat no: FBS-HI12A), 1% l-glutamine,
1% penicillin/streptomycin and incubated at 37 °C in a 5%
CO2 and 95% humidifed atmosphere. Cells were placed in
96-well plates at a density of 6×103 cells/well in 100 mm3
medium for MTT. The cells were incubated overnight for
attachment to the surface of the plate.
1‑Cyclohexyl‑3‑methylpyrrolo[1,2‑a]pyrazine (3h,
C14H18N2) Yellow liquid, yield: 72%; H NMR (CDCl3):
1
δ=7.47 (bs, 1H, =CH), 7.25 (dd, J=1.5, 2.3 Hz, 1H, Pyr-
H), 6.766.75 (m, 1H, Pyr-H), 6.74 (dd, J=2.3, 4.1 Hz, 2H,
Pyr-H), 3.06 (t, J = 3.4, 11.8 Hz, 1H, Cychxl-H), 2.38 (d,
J=1.1 Hz, 3H, –CH3), 1.99–1.89 (m, 4H, Cychxl-H), 1.86–
1.77 (m, 3H, Cychxl-H), 1.49–1.36 (m, 3H, Cychxl-H) ppm;
13C NMR (CDCl3): δ = 159.9, 134.9, 126.1, 114.0, 113.2,
113.0, 101.6, 43.7, 31.2, 26.6, 26.1, 21.0 ppm; HRMS: m/z
calcd. for C14H19N2+ ([M+H]+) 215.1543, found 215.1547.
Preparation of solutions
1‑(Furan‑2‑yl)‑3‑methylpyrrolo[1,2‑a]pyrazine (3i,
C12H10N2O) Brown liquid; yield: 94%; 1H NMR (CDCl3):
δ = 7.67 (dd, J = 0.8, 1.8 Hz, 1H, Fry-H), 7.60–7.59 (m,
1H,=CH), 7.36 (dd, J=1.2, 2.5 Hz, 1H, Pyr-H), 7.28 (dd,
J = 0.8, 3.5 Hz, 1H, Fry-H), 7.20 (dt, J = 1.2, 4.2 Hz, 1H,
PyrH), 6.86 (dd, J = 2.5, 4.2 Hz, 1H, Pyr-H), 6.59 (dd,
J=1.8, 3.5 Hz, 1H, Fry-H), 2.45 (d, J=1.1 Hz, 3H, –CH3)
ppm; 13C NMR (CDCl3): δ = 152.2, 144.1, 142.5, 134.9,
123.6, 114.7, 114.5, 113.8, 111.9, 111.8, 103.9, 21.0 ppm;
HRMS: m/z calcd. for C12H11N2O+ ([M + H]+) 199.0866,
found 199.0869.
Synthesized compounds were used to induce toxicity. Stock
solutions of pyrrolo[1,2-a]pyrazines were prepared in
DMSO. Then, solutions of appropriate fnal concentration
(50, 100, 150, and 200 µM) were obtained by dilution with
the medium as mentioned in cell culture part. The concentra-
tion of DMSO was kept at a noncytotoxic level (≤0.05%0).
MTT assay
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) cell viability tests were conducted in the presence
of diferent concentrations of synthesized compounds to
determine relative cell growth. It was replicated three times
for each concentration.
(4‑Chlorophenyl)[1‑(propa‑1,2‑dien‑1‑yl)‑1H‑pyrrol‑2‑yl]‑
methanone (4a, C14H10ClNO) Light yellow liquid; yield:
1
80% (obtained from entry 2); H NMR (CDCl3): δ = 8.16
(t, J = 6.6 Hz, 1H, =CH), 7.77–7.73 (m, AA′BB′ system,
2H, Ar-H), 7.45–7.41 (m, AA′BB′ system, 2H, Ar-H),
7.27 (dd, J = 1.6, 2.7 Hz, 1H, Pyr-H), 6.75 (dd, J = 1.6,
4.0 Hz, 1H, Pyr-H), 6.26 (dd, J=2.7, 4.0 Hz, 1H, Pyr-H),
5.53 (d, J=6.6 Hz, 2H,=CH2) ppm; 13C NMR (100 MHz,
CDCl3): δ = 203.0, 184.9, 138.0, 137.9, 130.6, 129.3,
128.4, 127.9, 124.1, 110.2, 99.2, 87.1 ppm; HRMS: m/z
calcd. for C14H10ClNO+ ([M + H]+) 244.0529, found for
C14H11ClNO+ ([M+H]+) 244.0501.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s00706-021-02761-3.
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1 3