Synthesis and anticancer assessment of some new 2-amino-3-cyanopyridine derivatives

Article abstract of DOI:10.1080/00397911.2020.1870698

The 2-Aminonicotinonitrile derivative was reacted with different bi-functional reagents such as formamide, thiourea, acetic anhydride, and phthalic anhydride under optimized conditions to give pyrimidine, thiourea, acetamide, and isoindoline derivatives, respectively, When it was treated with active methylene reagents as malononitrile, phenacyl bromide, and ethyl bromoacetate under varied experimental modulation, it afforded 1, 8-naphthyridine, ethyl, and methylamino nicotinonitrile derivatives, respectively. Also, it was reacted with p-toluene sulfonyl chloride, chloroacetyl chloride, and benzoyl chloride to give sulfonamide, 2-chloro-N-acetamide, and benzamide derivatives, respectively. Likewise, it was reacted with diethyl malonate, ethyl cyanoacetate, and cyano acetic acid to give ethylpropanoate, naphthyridine, and cyano acetamide derivatives, respectively. However, treatment of ethylpropanoate and cyano acetamide derivatives with hydrazine hydrate gave pyrazole and 5-amino-pyrazole nicotinonitrile derivatives, respectively. In addition, it was reacted with p-anisaldehyde, phenyl isocyanate, and triethyl orthoformate to give benzylamino nicotinonitrile, phenyl urea, and N-formamide derivatives, respectively. Furthermore, it was reacted with nitrous acid then coupled with aniline; it was also reacted with isatine and 1,3- dibromo propane to give oxoindoline derivative, and the dimer. Elemental analyses, together with spectroscopic data including IR, ¹H-NMR in addition to ¹³C-NMR and mass spectra submit proofs for the chemical structures for all compounds.

Full text of DOI:10.1080/00397911.2020.1870698

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Synthesis and anticancer assessment of some new
2-amino-3-cyanopyridine derivatives
S. Y. Mansour, G. H. Sayed, M. I. Marzouk & S. S. Shaban
To cite this article: S. Y. Mansour, G. H. Sayed, M. I. Marzouk & S. S. Shaban (2021) Synthesis
and anticancer assessment of some new 2-amino-3-cyanopyridine derivatives, Synthetic
Communications, 51:8, 1160-1170, DOI: 10.1080/00397911.2020.1870698
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2021, VOL. 51, NO. 8, 1160–1170
https://doi.org/10.1080/00397911.2020.1870698
Synthesis and anticancer assessment of some new
2-amino-3-cyanopyridine derivatives
S. Y. Mansour, G. H. Sayed, M. I. Marzouk, and S. S. Shaban
Heterocyclic Synthetic Laboratory, Chemistry Department, Faculty of Science, Ain Shams University,
Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 20 October 2020
The 2-Aminonicotinonitrile derivative was reacted with different bi-
functional reagents such as formamide, thiourea, acetic anhydride,
and phthalic anhydride under optimized conditions to give pyrimi-
dine, thiourea, acetamide, and isoindoline derivatives, respectively,
When it was treated with active methylene reagents as malononitrile,
phenacyl bromide, and ethyl bromoacetate under varied experimen-
tal modulation, it afforded 1, 8-naphthyridine, ethyl, and methyla-
mino nicotinonitrile derivatives, respectively. Also, it was reacted
with p-toluene sulfonyl chloride, chloroacetyl chloride, and benzoyl
chloride to give sulfonamide, 2-chloro-N-acetamide, and benzamide
derivatives, respectively. Likewise, it was reacted with diethyl malon-
ate, ethyl cyanoacetate, and cyano acetic acid to give ethylpropa-
noate, naphthyridine, and cyano acetamide derivatives, respectively.
However, treatment of ethylpropanoate and cyano acetamide deriva-
tives with hydrazine hydrate gave pyrazole and 5-amino-pyrazole
nicotinonitrile derivatives, respectively. In addition, it was reacted
with p-anisaldehyde, phenyl isocyanate, and triethyl orthoformate to
give benzylamino nicotinonitrile, phenyl urea, and N-formamide
derivatives, respectively. Furthermore, it was reacted with nitrous
acid then coupled with aniline; it was also reacted with isatine and
1,3- dibromo propane to give oxoindoline derivative, and the dimer.
Elemental analyses, together with spectroscopic data including IR,
1H-NMR in addition to 13C-NMR and mass spectra submit proofs for
the chemical structures for all compounds.
KEYWORDS
Acetophenone; anisalde-
hyde; malononitrile;
microwave; pyridine
GRAPHICAL ABSTRACT
CONTACT S. S. Shaban
safashaban@ymail.com
Heterocyclic Synthetic Laboratory, Chemistry Department, Faculty
of Science, Ain Shams University, Cairo, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
ß 2021 Taylor & Francis Group, LLC

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Introduction
Studying cyano and/or amino pyridine heterocyclic derivatives as a six-member ring
containing nitrogen has attraced great attention because of its superior biological activ-
ities particularly in the medicinal field as antimicrobial active agents,[1–5] antiviral,[6]
antidiabetic,[4,6] antituberculosis,[7] antitumor drugs activity,[8–10] antiinflammatory,[11]
antioxidant,[12] proton pump inhibitors,[13] treatment of cardiovascular diseases as anti-
hypertensive agents.[14] Also, derivatives containing substituted phenyl moiety sitting at
positions 4- and 6- are of great importance as multiskilled scaffolds are used to con-
struct a diversity of heterocyclic compounds that have pronounced biological effects
and pharmaceutical applications.
The above-mentioned screening of biological activity facts motivates our con-
cern[14–17] for the preparation of various new heterocyclic products that comprise pyri-
dine moiety and were tested as anticancer agents against hepatocellular carcinoma
(liver) HepG2 and mammary gland breast MCF-7 cancer and as antimicrobial agents
against Gram-positive bacteria (Bacillus subtilis) and Gram-negative bacteria
(Escherichia coli). The antifungal activities of the compounds were tested against two
fungi (Candida albicans, Aspergillus flavus).
Result and discussion
The one-pot synthesis is a specific research methodology (multicomponent reactions) in
which three or more reactants are mixed in one flask, reacted with one another depend-
ing on their reactivity to produce the required product.[18,19] The one-pot (multicompo-
nent) approach presents a higher yield with less reaction time.
The reaction of acetophenone, anisaldehyde, and malononitrile in the presence of
ammonium acetate under microwave conditions using one-pot reaction produced
2-amino-4-(4-methoxyphenyl)-6-phenylnicotinonitrile (1) in an excellent yield[20]
(Scheme 1).
Compound 1 was reacted with formamide by different procedures; reflux and by irradi-
ating in the microwave for 4 min., producing pyrido pyrimidinone derivative 2. The second
procedure gave a higher yield. The IR spectrum of compound 2 showed bands at 3292 and
1
1695 cm–1 for NH and C¼O. The H-NMR spectrum showed singlet for NH at 7.34 ppm.
Scheme 1. Formation of compound 1.

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S. Y. MANSOUR ET AL.
Starting compound 1 was interacted with thiourea via losing of ammonia molecule
producing 3-cyano-pyridin-thiourea derivative 3. Compound 3 was alternatively pre-
pared through the reaction of compound 1 with ammonium thiocyanate to give the
same product (higher yield, shorter reaction time), the obtained products are identical
in all aspects (IR spectra, m.p and mixed m.p), the last reaction probably proceeds
through the following mechanism. Ammonium thiocyanate is stable in air, nevertheless,
upon heating, it isomerizes to thiourea. Then, the reaction proceeds via the attack of
the amino group on the C ¼ S group followed by the elimination of ammonia.
The suggested mechanism for the formation of compound 3
The thiourea derivative 3 underwent reaction with hydrazine hydrate/EtOH, giving
rise to nicotinonitrile derivative 4. Its infrared spectrum showed absorption bands at
3465, 3307, 3183, 2205, and 1639 cm–1 for NH2, NH, CꢀN, and C¼N, respectively.
1
However, its H-NMR spectrum showed correctly the characteristic exchangeable singlet
at d 6.91 and 7.22 ppm for (4H, 2NH2) and (1H, NH), respectively.
2-Amino-nicotinonitrile derivative 1 was reacted with acetic anhydride, giving the
monoacylated product 5 which when subjected to react with o-phenylene diamine,
imidazolo nicotinonitrile derivative 6 was obtained. The 1H-NMR spectrum of
compound 6 showed singlet at 10.82 ppm for 3H, 3NH (D2O exchangeable). Thereafter,
product 5 was reacted with hydrazine hydrate, gave the acetohydrazonamide
derivative 7.
The reaction of compound 1 with phthalic anhydride yielded the 1, 3-dioxoisoindo-
line product 8. The disappearance of the NH2 group from IR and1H-NMR spectra of 8,
besides the appearance of the two absorption bands at 1792 and 1734 cm–1 for two
carbonyl groups establish evidences for the structure of the product 8 (Scheme 2).
The reaction of compound 1 with malononitrile in the presence of drops of piperi-
dine in boiling butanol produced 2, 4-diamino-5-(4-methoxyphenyl)-7-phenyl-1,
1
8-naphthyridine-3-carbonitrile (9). Its H-NMR spectrum figures out one singlet signal
at 4. 32, and broad singlet one at 6.05 due to 4H of two NH2 groups (D2O
exchangeable).
The reaction of compound 1 with phenacyl bromide in butanol yielded 4-(4-methox-
yphenyl)-2-((2-oxo-2-phenylethyl) amino)-6-phenylnicotinonitrile (10), whereas its reac-
tion with ethyl bromoacetate in refluxing butanol and/or under microwave irradiation
yielded 2-(methyl amino)-nicotinonitrile derivative 11, the latter procedure offered
higher yield with short reaction time. The reaction proceeded through the following

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Scheme 2. Formation of compounds 2–8.
sequence; elimination of HBr, hydrolysis, and decarboxylation. Chemical evidence for
the proposed structure of derivative 11 was received throughout the production of the
authentic sample from the reaction of compound 1 with chloroacetic acid in refluxing
pyridine by the elimination of HCl and decarboxylation. It was a matching pair in,
mmp, mp as well as TLC.
In addition, 2-amino-6-phenylnicotinonitrile 1 was reacted with p-toluene sulfonyl
chloride/butanol, chloroacetyl chloride/butanol plus drops of triethylamine, and benzoyl
chloride/dioxane to give N-4-methylbenzene-sulfonamide derivative 12, 2-chloro-N-
acetamide derivative 13, and N-benzamide derivative 14, respectively. Three absorption
bands were detected in their infrared spectra at 3339, 3378, and 3374 cm–1, respectively,
1
for NH group. Also, the H-NMR characterize NH proton as singlet signals at 7.25,
9.88, and 8.23 ppm (D2O exchangeable), respectively (Scheme 3).
When the starting material 1 was interacted with diethyl malonate, ethyl
cyanoacetate, as well as cyanoacetic acid, it produced the ethyl3-((3-cyano-4-(4-methoxy-
phenyl)-6-phenylpyridin-2-yl)amino)-3-oxopropanoate
(15),4-amino-5-(4-methoxy
phenyl)-2-oxo-7-phenyl-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (18) along with 2-
cyano-N-(3-cyano-4-(4-methoxyphenyl)-6-phenylpyridin-2-yl)acetamide (19).The infra-
red spectra of derivatives 15 and 19 lost the characteristic bands of the amino group.
The 1H-NMR spectrum of derivative 18 presents singlet signal at d 6.92 ppm

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S. Y. MANSOUR ET AL.
Scheme 3. Formation of compounds 9–14.
(s,2H, NH2, D2O exchangeable plus 2 singlet signals, exchangeable at d 10.67,
11.27 ppm for OH and NH protons which were adequate affirmation for its existence as
lactam lactim forms 18a, 18 b.
Afterward, propanoate derivative 15 was reacted with hydrazine hydrate and/or 4-nitro
aniline, to produce pyrazolonicotinonitrile derivative 16, in addition to malonamide deriva-
tive 17, respectively.
In parallel acetamide derivative 19 underwent a similar reaction with hydrazine
hydrate/ethanol to yield 2-((5-amino-4H-pyrazol-3-yl) amino)-4-(4-methoxyphenyl)-6-
phenyl nicotinonitrile (20). The NH2 and NH absorption bands with the 2 singlets at d
6.91 and 10.19 ppm for 2H, NH and 1H, NH (D2O exchangeable) was taken as evi-
2,
dence for the recommended structure of derivative 20 (Scheme 4).
Condensation of compound 1 with carbon electrophilic agents like anisaldehyde fol-
lowed by reduction of the double bond gave nicotinonitrile derivative 21. Although its
reaction with phenyl isocyanate gave derivative 22, the proposed structure of compound
22 got its approval from the existence of two exchangeable singlet signals at d 6.92,
8.62 ppm due to 2H, 2NH protons.
Although compound 1 was reacted with triethyl orthoformate by different proce-
dures, reflux, and by irradiating in the microwave for 3 min., gave the formamide
derivative 23, the latter procedure gave the higher yield. It was proved through its
1H-NMR spectrum which defines exchangeable signals at d 9.27 ppm (s, 1H, CHO),

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Scheme 4. Formation of compounds 15–18.
10.94, and 10.96 (s, 1H, NH, D2O exchangeable, the rate of NH exchange is slow and
the proton couples with the nitrogen atom) (Scheme 5).
In addition to the above, since the starting compound, 1 possesses the primary NH2
group, so it can interact with nitrous acid at 0-5 ꢁC similar to ordinary aromatic amine
and couple with aniline to offer 4-(4-methoxyphenyl)-6-phenyl-2-(3-phenyltriaz-1-en-1-
yl) nicotinonitrile (24).
Further, the reaction of compound 1 with isatine gave the 2-oxoindolin-3-ylidene 25.
Also, compound 1 was allowed to undergo dimerization by reacting with 1,3- di bro-
mopropane in 2:1 ratio to give the dimer 26 (Scheme 6).
Biological activity
Cytotoxic activity
Cytotoxic activity utilizing an in vitro Ehrlich Ascites Assay, 21 derivatives out of all the
newly synthesized compounds were elected to be evaluated for their in vitro cytotoxic
effect against a panel of two cell lines (human tumor) namely: hepatocellular carcinoma
(liver) HepG2 and mammary gland breast MCF-7 cancer cell lines (Table 1).
Generally, the activity detected by all the selected compounds ranged from very
strong to a noncytotoxic effect. In general, compounds 1, 5, 6, 12, 15, 16, and 25 were
found to be the most potent derivatives against the two cell lines. Compound 1 showed
moderate activity against the cell line HePG-2 (IC50 ¼ 26.46 2.0) and strong activity
against the cell line MCF-7 (IC50 ¼ 18.02 1.5). Compounds 5 and 6 showed very

1166
S. Y. MANSOUR ET AL.
Scheme 5. Formation of compounds 19–23.
Scheme 6. Formation of compounds 24–26.
strong cytotoxic activities against HePG-2 (IC50 ¼ 7.48 0.6), (IC50 ¼ 9.63 0.8) and
MCF-7 (IC50 ¼ 5.69 0.4), and (IC50 ¼ 10.66 0.9), respectively. Compound 25 showed
strong and very strong activity against the two cell lines HePG-2 (IC50 ¼ 12.77 1.0)
and MCF-7 (IC50 ¼ 8.31 0.6), respectively. On the contrary, compound 15 displayed
strong activity (IC50 ¼ 16.12 1.3) and (IC50 ¼ 13.57 1.1) against the two cell lines,
respectively. While compound 12 showed strong activity against the cell line HePG-2
(IC50 ¼ 17.03 1.4) and moderate activity against the cell line MCF-7
(IC50 ¼ 24.28 1.9), respectively. Compound 16 offered strong activity against the two
cell lines HePG-2 (IC50 ¼ 19.37 1.6) and MCF-7 (IC50 ¼ 15.49 1.3), respectively.

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Table 1. Cytotoxicity (IC50) of the evaluated compounds on various cell lines.
IC50 (lg/mL)a,b
Comp. no.
HePG2
MCF-7
DOX
1
2
4
5
6
7
8
4.50 0.3
26.46 2.0
71.08 3.8
36.85 2.4
9.63 0.8
7.48 0.6
83.17 4.3
>100
4.17 0.2
18.02 1.5
77.37 4.3
41.83 3.1
10.66 0.9
5.69 0.4
80.68 4.5
>100
9
59.26 3.4
17.03 1.4
48.82 2.9
76.51 4.1
16.12 1.3
19.37 1.6
39.12 2.6
52.60 3.0
45.23 2.9
88.42 4.6
31.29 2.2
23.89 1.9
12.77 1.0
54.71 3.2
73.09 4.0
24.28 1.9
85.20 4.7
37.01 2.8
13.57 1.1
15.49 1.3
46.67 3.3
58.64 3.7
52.35 3.6
91.30 5.1
32.21 2.5
27.33 2.2
8.31 0.6
67.26 3.9
12
13
14
15
16
17
18
19
22
23
24
25
26
aIC50 (mM): 1–10 (very strong). 11–20 (strong). 21–50 (moderate). 51–100 (weak) and above 100 (non-cytotoxic).
bDOX: doxorubicin
However, the rest of the compounds presented activity ranged from moderate to noncy-
totoxic effect toward the two cell lines HePG-2 and MCF-7.
Structure–activity relationship (SAR)
Inserting different groups and rings to the nicotinonitrile derivative 1 which has strong
and moderate reactivity change its reactivity toward the two cell lines:
ꢂ
ꢂ
Presence of the acetamide group increases the cytotoxic effect of compound 5
due to the formation of a hydrogen bond with the C ¼ O group.
Compound 6 displayed very strong activity, this may be attributed to the pres-
ence of three NH groups which may be added to any unsaturated moiety in
DNA (aza Michael addition) or hydrogen bond formation with either one of the
nucleobases of the DNA and causes its damage.
ꢂ
Compound 12 showed strong activity against the cell line HePG-2 because the
presence of the NH group available to form a hydrogen bond with the nucleo-
bases of the DNA and lead to its damage. Also, introducing the SO2Ph group as
a strong electron attracting group creates a positively charged molecule, generates
electrostatic attraction with the DNA nucleobases. Moreover, the SO2 group acts
on the mitoticspindle.[21]
ꢂ
ꢂ
ꢂ
Presence of the ester group increases the cytotoxic effect of compound 15.
Presence of pyrazolyl ring in compound 16 showed strong activity.
Presence of oxoindolinylidene ring increases the cytotoxic effect of compound 25.

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S. Y. MANSOUR ET AL.
Antimicrobial activity
The antimicrobial activity of 19 compounds was checked against Gram-positive bacteria
(B. subtilis) and Gram-negative bacteria (E. coli). The antifungal activities of the com-
pounds were tested against two fungi (C. albicans, A. flavus). Largely, the activity
noticed by all these compounds ranged from very strong to no activity. Most of all
compounds displayed good inhibition against Gram-positive strains and Gram-negative
strains with respect to the reference drugs. In general, it is clear that all the compounds
were more toxic with respect to Gram-positive strains than Gram-negative strains. This
could be attributed to their cell wall structural differences,[22] whereas the walls of
Gram-negative cells are more complex than those of Gram-positive species, therefore it
might be a little complicated for these compounds to diffuse inside the Gram-negative
cell. The data outlined in Table 2 clarified that most of the compounds have marked
antifungal potency. The most active compounds against the Gram-positive strain,
Gram-negative strain, and fungi were compounds 5, 6, 15, and 25.
Experimental
All melting points were decided on Gallenkamp electronic melting point equipment.
The infrared (IR) spectra were recorded on a Mattson 5000 Fourier transform-IR (FT-
1
IR) spectrophotometer (k, cmꢃ1). The H-NMR (DMSO-d6), and 13C-NMR (DMSO-
d6), spectra were determined on a Bruker AV 400 MHz, using TMS as an internal
standard. Mass spectra were obtained on GCMS/QP1000 Ex mass spectrometer at
70 eV. Elemental analyses (C, H, and N) had been done at the Microanalytical Center of
Table 2. Results of antimicrobial activity of the synthesized compounds against different types of
microorganisms.
E. coli
Bacillus subtilis
Diameter of
C. Albicans
Diameter of
A. flavus
Diameter of
Diameter of
inhibition % Activity inhibition % Activity inhibition % Activity inhibition % Activity
Compound
zone (mm)
index
zone (mm)
index
zone (mm)
index
zone (mm)
index
1
2
4
5
6
7
8
12
13
14
15
16
17
18
22
23
9
NA
8
15
17
NA
NA
11
3
NA
12
10
7
2
NA
9
9
12
2
25
NA
36
–
32
60
68
–
15
4
12
19
22
3
NA
16
5
NA
19
17
10
9
65.2
17.4
52.2
82.6
95.6
13
17
4
10
20
21
4
NA
17
3
10
19
18
9
63
14.8
37
74.1
77.8
14.8
–
63
11.1
37
70.4
66.7
33.3
25.9
7.4
51.8
55.5
77.8
22.2
–
18
6
14
20
23
3
NA
17
2
15
18
19
14
10
NA
16
17
22
10
NA
25
72
24
56
80
92
12
–
–
–
44
12
–
48
40
28
8
69.6
21.7
–
82.6
73.9
43.5
39.1
8.7
56.5
69.6
86.9
34.8
100
–
68
8
60
72
76
56
40
–
64
68
88
40
–
7
2
–
2
36
36
48
8
100
–
13
16
20
8
23
NA
14
15
21
6
NA
27
24
25
26
Ampicillin
Colitrimazole
100
100

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Cairo University, Giza, Egypt. The biological evaluation of the products was carried out
at the Department of Pharmacology, Faculty of Pharmacy, Mansoura University,
Mansoura, Egypt.
Synthesis of 2-amino-4-(4-methoxyphenyl)-6-phenylnicotinonitrile (1)
A mixture of acetophenone (1.2 mL, 0.01 mol), anisaldehyde (1.4 mL, 0.01 mol), malono-
nitrile (0.66 g, 0.01 mol), and ammonium acetate (2.3 g, 0.03 mol) was heated under
microwave irradiation for 7 min at power 270 W. After cooling, the separated solid
material was filtered off, washed with ethanol, dried and recrystallized from ethanol to
17
afford 1 as yellow crystals, Yield: 90%, m.p.178-180 ꢁC. Lit;
IR (KBr, ꢀ/cm–1) : 3307,
3182, 2205,1639 (NH2, CꢀN, C ¼ N); 1H- NMR (DMSO-d6), d, ppm: 3.84 (s, 3H,
OCH3) , 7.08–8.23 (m, 10H,Ar-H), 10.07 (s, 2H, NH2, D2O exchangeable). 13C-NMR
(DMSO-d6): 55.81, 86.83, 100.59, 109.49, 114.61(2), 117.76, 127.66(2), 129.06(2), 129.53,
130.30, 130.46, 138.11, 154.91, 158.91, 160.88, 161.40. .MS m/z (%):301 [M].þ (100), 286
(80), 270 (33), 257 (88),198 (62),77 (54). Found, %: C, 75.78; H, 4.98 N, 13.85%.
For C19H15N3O (301). Calculated, %: C, 75.73; H, 5.02; N, 13.94%.
5-(4-Methoxyphenyl)-7-phenylpyrido [2, 3-d] pyrimidin-4(3H)-one (2)
Method 1: A mixture of nicotinonitrile derivative 1 (3.01 g, 0.01 mol) and formamide
(15 mL) was refluxed for 12 h. The reaction mixture was concentrated, left to cool and
the separated solid was filtered off, washed with ethanol, dried, and crystallized from
methanol to afford 2 as green crystals. Yield: 49.5%.
Supporting information
1
Full experimental detail, H-NMR and 13C-NMR spectra. This material can be found
via the “Supplementary Content” section of this article’s webpage.
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