Antibacterial activity of 2-amino-3-cyanopyridine derivatives

Article abstract of DOI:10.1016/j.mencom.2020.07.031

New 2-amino-4-aryl-3-cyanopyridines were obtained by the three-component condensation of arylidenemalononitriles, malononitrile and (di)amine system or acetoacetanilide. Antibacterial activity of all synthesized compounds against the Gram-negative bacteri

Full text of DOI:10.1016/j.mencom.2020.07.031

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 498–499
Antibacterial activity of 2-amino-3-cyanopyridine derivatives
Ibrahim Mamedov,*a Farid Naghiyev,a Abel Maharramov,a Owens Uwangue,b
Anne Farewell,b Per Sunnerhagenb and Mate Erdelyic
a Department of Chemistry, Baku State University, AZ 1148 Baku, Azerbaijan. E-mail: bsu.nmrlab@mail.ru
b Department of Chemistry and Molecular Biology and the Center for Antibiotic Resistance Research (CARe),
University of Gothenburg, SE-405 30 Gothenburg, Sweden
c Department of Chemistry, BMC, Uppsala University, SE-751 05 Uppsala, Sweden
DOI: 10.1016/j.mencom.2020.07.031
Br
New 2-amino-4-aryl-3-cyanopyridines were obtained by the
three-component condensation of arylidenemalononitriles,
malononitrile and (di)amine system or acetoacetanilide.
Antibacterial activity of all synthesized compounds against
the Gram-negative bacteria E. coli and the Gram-positive
B. subtilis was tested, the only representative showed a
substantial antimicrobial effect.
NC
ꢀN
CN
N
Nꢀ2
Keywords: 3,5-dicyanopyridines, antimicrobial activity, halogen bonding, bacteria, E. coli, B. subtilis.
Pyridine ring, an important structural fragment in heterocyclic
chemistry, is present in many natural products such as nicotinic
acid, nicotinamide, vitamin B6, which play key roles in
metabolism. Functionalized pyridines exhibit a broad range of
biological activities.1–10 Antimicrobial resistance is currently
one of the biggest threats to human health and development.
Besides the optimization of the use of the current antimicrobial
medicines, prevention to reduce the incidences of infections
and improve public awareness, the development of new
pharmaceuticals preferably acting in new ways is crucial. The
seriousness of this is well-reflected by the resistance to penicillin
reaching up to 51% of the infections, and 8–65% of E. coli
associated with urinary tract infections being resistant to
ciprofloxacin.11 Accordingly, the term ‘extreme drug resistance’
has been coined to describe isolates of clinically-important
species such as Enterobacteriaceae that are resistant to virtually
all currently used antibiotics.12 Antibiotic resistance is currently
associated with 700000 deaths yearly, and is projected to cause
extra 10 million deaths a year worldwide by 2050, of which over
4 million cases yearly are expected in Africa and overall 90% in
developing countries.13
According to the concise literature survey above, the three-
component reaction of arylidenemalononitriles, malononitrile
and amines lead the formation of 2-amino-4-aryl-3-cyano-
pyridines 1–6 in good yields, under mild conditions. The
synthesis of compounds 1a–g, 2a,b and 3a–d has been reported
earlier,14 with the structures of 1b,d,e and 2b having been
confirmed by single crystal X-ray diffraction. Compounds 4–6
obtained in this work have not been described previously. Their
synthesis is similar to that of their analogues14 and is given in
Online Supplementary Materials.
Ar
Ar
Ar
N
NC
CN
NC
HN
CN
NC
HN
CN
N
NH2
N
NH2
NH2
N
Ph
3a–d
a Ar = Ph
b Ar = 4-MeOC6H4
c Ar = 4-BrC6H4
d Ar = 4-F3CC6H4
1a–g
2a,b
a Ar = Ph
a Ar = 2,4-Cl2C6H3
b Ar = 2,6-Cl2C6H3
b Ar = 4-MeC6H4
c Ar = 4-BrC6H4
d Ar = 4-FC6H4
e Ar = 4-MeOC6H4
f Ar = 4-Me2NC6H4
g Ar = 3-MeO-4-HOC6H3
Br
OMe
F
O
CN
CN
NC
CN
Me
O
N
NH2
O
N
NH2
H2N
N
NH2
S
4
5
6
phenyl) were used, tetrahydroimidazopyridines 2a,b were
obtained as the major products. Formation of 2-imino-1,2-di-
hydropyridines 3a–d took place when benzylamine was used
instead of ethylenediamine (see ref. 14 and Scheme S1 in Online
Supplementary Materials). The use of (2-thienyl)methylamine in
place of benzylamine resulted in formation of non-oxidized
2-amino-1,4-dihydropyridine system 4.†
When arylidenemalononitriles with electron-donating (Me,
OMe and NMe2) and electron-acceptor (F and Br) substituents
were applied, final oxidation lead to dihydroimidazopyridines
1a–g. Surprisingly, when arylidenmalononitriles bearing aryl
with greater electron-withdrawing effect (2,4- or 2,6-dichloro-
Herein we found that condensation of acetoacetanilide
with 4-bromobenzylidenemalononitrile (Scheme S2, Online
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 498–499
Supplementary Materials) in the presence of the catalytic amount
both Gram-positive and Gram-negative bacteria. The lack of
activity of structurally closely related compounds suggests
halogen bonding to likely play an important role in the bioactivity,
and the importance of the presence of the N-benzyl substituent.
Further studies of 2-amino-3-cyanopyridines are expected to
provide new antibacterial leads along with the understanding of
the mechanism of their action.
of piperidine/piperazine was accompanied by deacetylation
leading to tetrahydropyridine 5. The use of 4-methoxy-
benzylidenemalononitrile with electron-donating substituent in
the same reaction gives product 6 with retained acetyl group.
Previously, 2-amino-3-cyanopyridines have been studied for
a variety of bioactivities, involving anticancer and acetylcholine
esterase inhibitory activity, and as anti-inflammatory agents.15–17
Amongst the synthetic approaches to 2-amino-3-cyanopyridines
those involving multicomponent one-pot reactions forming the
pyridine ring from acyclic precursors are most challenging.15
High yielding synthetic approaches involving malonitrile,
aromatic aldehydes and amines have recently been developed,
facilitating access to a diverse substituent pattern.18,19
The herein considered cyanopyridines 1–6 were tested (at
single concentration of 200 μg ml–1) against Escherichia coli
(Gram-negative) and Bacillus subtilis (Gram-positive) bacteria.
Of these, only compound 3c showed substantial antimicrobial
effect, and it was retested at different concentrations to
determine IC values. Against E. coli, the found MIC value was
577 μg ml–1, and against B. subtilis it was 288 μg ml–1. For
cytotoxicity, we found EC50 of 95 μg ml–1 against the human
MCF-7 cell line.
The authors would like to thank Atash Gurbanov (Baku State
University and Universidade de Lisboa) and Gunay Mamedova
(Baku State University) for their contribution to this work with
X-ray single crystal studies. This work was financially supported
by the Baku State University and Center forAntibiotic Resistance
Research (CARe) at the University of Gothenburg. The NMR
studies were performed using the facilities of Baku State
University and Uppsala University, Department of Chemistry,
BMC and the Disciplinary Domain of Medicine and Pharmacy.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.07.031.
References
The observation that compound 3c encompassing a bromine,
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3b nor 3d showed activity against E. coli or B. subtilis indicates
that hydrogen bonding at this position is unlikely to be of impact
for the antibacterial activity of 3c, whereas the comparable
polarity of the OMe-substituted 3b and the Br-substituted 3c
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It should be noted that compounds 1c and 5, also bearing
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electronic effect of its 4,5-dihydro-1H-imidazole functionality.
In summary, various 2-amino-3-cyanopyridines are readily
accessible via a one-pot multicomponent reaction. The evaluation
of the antimicrobial activity of a series of derivatives resulted in
the identification of a compound with promising activity against
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†
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MeOH (35 ml), and this was stirred for 5–7 min. (2-Thienyl)methylamine
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evaporation of the solvent, the product crystallized and the crystals
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d 39.3 (CH-10), 42.9 (CH2-6), 63.1 (C-9 and C-11), 115.1 (d,
2JC,F 22.5 Hz, C-18 and C-20), 121.6 (CN-14 and CN-15), 126.9 (C-3),
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4
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1JC,F 240.8 Hz, C-19). HRMS, m/z: 352.1036 (calc. for C18H14FN5S,
m/z: 352.0954 [M+H]+).
Received: 28th February 2020; Com. 20/6145
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