Design, synthesis and biological evaluation of novel flavone Mannich base derivatives as potential antibacterial agents

Article abstract of DOI:10.1007/s11030-018-9873-9

Abstract: A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids. After that, four bacteria were used to test antibacterial experiments of these compounds; compound 5g (MIC = 0.5, 0.125?mg/L) showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin (MIC = 2, 0.25?mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MIC = 1, 0.5, 2, 0.05?mg/L) against four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC₅₀ values (0.25–16?mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial antibacterial agents. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11030-018-9873-9

Molecular Diversity
https://doi.org/10.1007/s11030-018-9873-9
ORIGINAL ARTICLE
Design, synthesis and biological evaluation of novel flavone Mannich
base derivatives as potential antibacterial agents
Xian-Hai Lv1,4 · Hao Liu1 · Zi-Li Ren2 · Wei Wang1 · Feng Tang3 · Hai-Qun Cao2
Received: 10 June 2018 / Accepted: 25 August 2018
© Springer Nature Switzerland AG 2018
Abstract
A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich
reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids.
Afterthat, fourbacteriawereusedtotestantibacterialexperimentsofthesecompounds;compound 5g (MICꢀ0.5, 0.125mg/L)
showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin
(MICꢀ2, 0.25 mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MICꢀ1, 0.5, 2, 0.05 mg/L) against
four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC50 values
(0.25–16 mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting
with amino acid residues. It will provide some valuable information for the commercial antibacterial agents.
Graphical Abstract
Keywords Flavonoids · Benzylamine · Mannich · Antibacterial · 3D-QSAR · Molecular docking
2
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11030-018-9873-9) contains supplementary
material, which is available to authorized users.
School of Plant Protection, Anhui Agricultural
University, Hefei 230036, People’s Republic of China
3
4
International Center for Bamboo and Rattan, 8 Fu Tong East
Street, Beijing 100714, People’s Republic of China
Feng Tang
fengtang@icbr.ac.cn
B
Division of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Hai-Qun Cao
haiquncao@163.com
B
1
School of Science, Anhui Agricultural University,
Hefei 230036, People’s Republic of China
123

Molecular Diversity
Introduction
Aseries totaling19compounds were synthesized andused
for testing antifungal activity against Gibberella sanbinetti
and Gaeumannomyces graminis. After the in vitro antifun-
gal activity experiments were completed, we found that the
antifungal activity of these compounds did not achieve the
desired effect. So, we envision bacteria may be a good can-
didate for inhibition experiment of such compounds. Then,
all of the compounds were tested for antibacterial activity
against two gram-positive bacteria, namely Staphylococcus
aureus and Listeria monocytogenes, and two gram-negative
bacteria, namely Escherichia coli and Salmonella galli-
narum. On the other hand, Zhihua Sui et al. [16] and Bernard
et al. [17] have reported that flavonoids can be used as
inhibitors of topoisomerase. Finally, we selected topoiso-
merase II (Topo II) as the target for molecular docking and
3D-QSAR to determine critical structural factors responsible
for their antibacterial efficacy.
Flavonoids are widely found in the plant kingdom and have
a wide variety of biological functions [1–5] and medicinal
values, including antifungal [6], antibacterial [7], antioxi-
dant [8], anti-aging [9] and anti-tumor [10, 11]. Hence, we
tested their antifungal activity and found that orientin and
isoorientin have excellent antifungal activities against Gib-
berella sanbinetti at 20 mg/L (supplementary materials). It
is regrettable that luteolin was almost inactive. The struc-
tural differences between orientin, isoorientin and luteolin
are reflected in the 8th or 6th position of ring A, which a
very interesting phenomenon and worthy of study (Fig. 1).
Although we have found that orientin and isoorientin have
excellent antifungal activity, their costly nature has restricted
their use as antimicrobial agents. In addition, it has been
reported that substitution at the 8th position is superior to
substitution at the 6th position of flavone derivatives [12, 13].
Therefore, compounds that give better antimicrobial activity
by modification of position 8 of the flavone deserve attention
and research.
Results and discussion
Benzylamine is widely used in the field of pesticides
because of its unique imino structure [14, 15], such as pen-
cycuron, which is widely used in the control of rice sheath
blight fungicide. Thus, we introduced the benzylamine struc-
ture at the 8th position of various flavones to try to increase
their activity using the Mannich reaction. After screening the
bioactivities of orientin and isoorientin, we get the inspira-
tion from the orientin and isoorientin, which also introduced
a carbohydrate at the 8th position of the flavone using the
Mannich reaction to examine the effect on antifungal activity,
which method provides a valuable reference for our further
study of flavone carbohydrate.
Chemistry
A series of novel Mannich base derivatives of flavone
were synthesized, and the general pathway is outlined in
Scheme 1. Benzylamine was introduced at the 8th posi-
tion by reaction of benzylamine with flavone in isopropanol
under formaldehyde conditions. The target compounds have
not been reported except for 5a [18] and 5i [19]. In addi-
tion, we have synthesized glucosamine that can react with
flavone by protecting and deprotecting glucosamine groups,
and innovative structures were synthesized that introduced
a glucosamine on the flavone structure using the Mannich
reaction. Since the glucosamine compounds cannot directly
undergo a Mannich reaction, the glucosamine is first pro-
tected by an amino group and then forms an ester with an
acid anhydride [20], and finally the deprotected compound
can undergo a Mannich reaction with kaempferol.
Biological activity
Antibacterial activity
All newly synthesized compounds were evaluated for in vitro
antibacterial activity against two gram-positive bacteria,
namely Staphylococcus aureus and Listeria monocyto-
genes, and two gram-negative bacteria, namely E. coli and
Salmonella gallinarum. Novobiocin and ciprofloxacin were
used as a reference standard. The results of the in vitro
antibacterial activity screening of the test compounds are
summarized in Table 1.
Most of the derivatives exhibited moderate to potent
antibacterial activities, demonstrating the rationality of our
Fig. 1 Skeleton of the flavone scaffold and the structure of orientin,
isoorientin and luteolin
123

Molecular Diversity
Scheme 1 General synthesis of compounds 5a–5s. Reagents and conditions: (a) HCHO (aq), isopropanol, 35 °C; (b) NaOH (aq), 0 °C; (c) pyridine,
40 °C, 6 h; (d) HCl, acetone, rt; (e) H2O, CH3COONa(aq), rt
design strategy. Four compounds (5c, 5g, 5q and 5s) were
found to display improved antibacterial activities against
Staphylococcus aureus compared with novobiocin (MICꢀ
2 mg/L), with MIC values ranging from 0.5 to 2 mg/L.
Particularly, compound 5g was determined to be the most
potent inhibitor against Staphylococcus aureus, with an MIC
value fourfold higher than novobiocin (0.5 mg/L). Three
derivatives (5g, 5k and 5s) exhibited improved antibacte-
rial activity against Listeria monocytogenes in comparison
with ciprofloxacin (MICꢀ1 mg/L), with MIC values ranging
from 0.5 to 2 mg/L. Among these, compound 5s exhibited the
most potent activity against Listeria monocytogenes with an
MIC value of 0.5 mg/L, which was better than ciprofloxacin
(1 mg/L) but worse than novobiocin (0.25 mg/L). Regard-
ing the inhibition of gram-negative bacteria, two derivatives
(5g and 5s) were found to show improved antibacterial
activities against E. coli compared with novobiocin (MICꢀ
4 mg/L), with MIC values ranging from 2 to 4 mg/L. Two
derivatives (5g and 5s) were found to display improved
antibacterial activities against S. gallinarum compared with
ciprofloxacin (MICꢀ0.25 mg/L), with MIC values of 0.125
and 0.05 mg/L, respectively. Noticeably, compound 5s, iden-
tified as the most potent inhibitor against S. gallinarum with
a MIC value at 0.05 mg/L, showed fivefold higher inhibitory
activity than novobiocin (0.5 mg/L), and tenfold higher than
ciprofloxacin (0.25 mg/L).
bacteriostatic effect is increased by about twice until R is
replaced by 4-methoxy and antibacterial effect reached its
peak. In addition, from the data, it can be concluded that
when the flavonoid skeleton of the compound is luteolin
and kaempferol, a very good antibacterial effect is exhibited.
Another eye-catching finding was that compound 5s exhib-
ited a broad spectrum inhibitory effect on all four bacteria,
which we envisioned is due to the introduction of carbo-
hydrate structures. In summary, these findings indicate that
the antibacterial efficacy of the designed compounds may
be attributed to a combination of factors, such as 4-methyl
substitution at the R position, variety of flavonoids and intro-
duction of carbohydrate structure.
Inhibitory effects against Topo II and Topo IV
In order to determine the relationships by which the 4-
methoxybenzylamine and carbohydrate structures induce
their antibacterial activities, the inhibitory activity of selected
compounds (5g and 5s) against topoisomerase II and topoi-
somerase IV isolated from E. coli was examined. As given in
Table 2, compounds 5s showed more potent inhibition than
5g against the two enzymes. On the other hand, there was a
good correlation between the MICs and the IC50s (Tables 1,
2), suggesting that inhibition of the Topo II and Topo IV by
the 4-methyl and carbohydrate structure suppresses bacte-
rial cell growth. These results indicate that the 4-methyl and
carbohydrate structure put a great deal of pressure on the
survival of the bacteria.
As given in Table 1, when the R position is replaced with a
substituent, the antibacterial effect will be improved. When
R is a 3-chloro group, the bacteriostatic effect is slightly
improved, and when the 4-methyl group is substituted, the
123

Molecular Diversity
Table 1 Chemical structure of
target compounds and their MIC
values against S. aureus, L.
monocytogenes, E. coli and S.
gallinarum
aStaphylococcus aureus (ATCC-12600); Listeria monocytogenes (ATCC-15313); Escherichia coli (ATCC-
25922); S. gallinarum (ATCC-9184)
bCiprofloxacin
cNovobiocin
123

Molecular Diversity
Table 2 Inhibitory effects of selected compounds against topoiso-
merase II and topoisomerase IV
zone is located in the luteolin structure, while the electrostat-
ically unfavorable zone covers the space around positions
2 and 3 of the benzylamine structure. In the steric contour
map, the sterically favored region almost covers the entire
structure. We can conclude that the introduction of any other
substituents or carbohydrate structure on the flavonoid skele-
ton can increase its biological activity. The 3D-CoMFA maps
may provide valuable clues for further structural optimiza-
tion.
Compd.
IC50(mg/L)
Topo IIa
Topo IVb
5g
0.5
0.25
0.5
0.5
16
8
5s
NBc
CIPd
4
8
aTopoisomerase II supercoiling activity
bTopoisomerase IV decatenation activity
cCiprofloxacin
dNovobiocin
Molecular docking analysis
In order to further discern the relationship between the struc-
ture of the compounds and the inhibition of bacterial activity,
all synthesized compounds were molecularly docked using
Discover Studio 3.5. The detailed interactions of represen-
tative derivative compounds 5g and 5s with Topo II (PDB
code:2XCS, crystallized from S. aureus) are shown in Fig. 3.
Inthebindingmodelsofcompounds5g and 5s, theirscaffolds
and amino acid residues linked together tightly, suggesting
that the pose of 5g and 5s into the Topo II-binding site
revealed suitable shape complementarity with the binding
pocket. As shown in Fig. 3a, Arg 1122(D) forms a hydrogen
bond with a hydroxyl group located on the kaempferol struc-
ture. Ser 1084(D) and Dc 11(E) form two hydrogen bonds
with hydroxyl groups located on the carbohydrate structure.
Arg 1122(B) not only established a cation–π interaction with
the kaempferol structure, but also formed a hydrogen bond
with the carbohydrate structure. The amino group which
linked the kaempferol structure to the carbohydrate struc-
ture forms cation–π interaction and hydrogen bond with Dg
10(F) and Dc 11(F), respectively. For Fig. 3b, Arg 1122(D)
forms a hydrogen bond with a hydroxyl group located on the
luteolin structure. Asp 1083(D) and Arg 1122(B) form three
hydrogen bonds together with two hydroxyl groups on the
luteolin structure. Dc 11(F) and Dg 10(E) established π–π
interactions with phenyl ring which belongs to the benzy-
3D quantitative structure–activity
relationships
In this study, 3D-QSAR models for the four different bac-
terial species were established (see the support information
for the models not described here). After observation, we
found that the models of the four bacteria are not much dif-
ferent. So, S. gallinarum is used as a target and compound 5g
is taken as the example to show the structure–activity rela-
tionships. The pMIC values were calculated on the basis of
the in vitro activity experiment results, and the linear regres-
sion was determined with a genetic function algorithm (GFA)
resulting in an r2 value of 0.959, demonstrating the accu-
racy and reliability of the model. The 3D-CoMFA maps are
shown in Fig. 2. In the electrostatic map shown in Fig. 2a,
the red region indicates that the stronger the negative charge
of the substituent in this region, the more favorable the activ-
ity of the compound, and the blue region indicates that the
stronger the positive charge of the substituent in this region,
the more favorable the activity of the compound. In the steric
map shown in Fig. 2b, the yellow region indicates that the
increase in substituents in this region is not conducive to the
activity of the compound, while the blue region is the oppo-
site. It can be observed that the electrostatically favorable
Fig. 2 Electrostatic map (a) and steric map (b) for the 3D-CoMFA model (for S. gallinarum)
123

Molecular Diversity
Fig. 3 a Binding model of 5s (3D&2D diagram). b Binding model of 5g (3D&2D diagram). The π interactions are displayed as orange solid line
and H-bond is displayed as green dotted line
lamine structure. From the docking results above, we can see
that the binding effect of 5s and amino acid residues is much
better than 5g, which may be the reason why its antibacterial
effect is better than 5s.
inhibitors and looking for valuable information for further
structural optimization and development of novel Topo II
inhibitors.
Experimental
Conclusion
Chemistry
A series of novel Mannich base derivatives of flavone was
synthesized and evaluated for their antifungal activity against
G. sanbinetti and G. gramini. The result shows that the
antifungal effect is not ideal, but it may provide valuable
information for the synthesis of the fungicide derivatives of
the flavone. Furthermore, the antibacterial activities of the
compound test set were determined against Staphylococcus
aureus, Listeria monocytogenes, E. coli and Salmonella gal-
linarum, and most exhibited moderate to potent activities.
Most surprisingly, 5g and 5s exhibited excellent antibacterial
activity against four bacteria. SAR analysis and molecular
docking simulations show that the promising antibacterial
efficacy of our designed compounds can be attributed to a
combination of factors, such as 4-methyl substitution at the
R position, variety of flavonoids and introduction of car-
bohydrate structure. We are further modifying the flavone
Mannich base derivatives to obtain more effective Topo II
All chemicals were purchased from Energy, Meryer, and
Aladdin Chemicals and were used as received. 1H NMR and
13C NMR spectra were carried out using Agilent DD2 600 Hz
spectrometer with DMSO-d6 as the solvent and tetramethyl-
silane as the internal standard. ESI–MS spectra were carried
out on a Mariner System 5304 mass spectrometer. Elemen-
tal analyses were performed on a CHN-O-Rapid instrument.
Quantitative structure–activity relationship (QSAR) analy-
ses and molecular docking were performed with Discovery
Studio3.5.
General procedure for synthesis of target
compounds
The flavone (1 mmol) was dissolved in isopropanol (20 mL),
37% formaldehyde (75 μL) was added, and the amine
123

Molecular Diversity
(1.5 mmol) was added after stirring for 20 min. The mixture
was reacted at 35 °C until complete, filtered, washed with iso-
propanol and then finally dried to give the target compound.
The experimental process is monitored by TLC.
Acknowledgements This work was supported by The Basic Science
Research Fund Program of ICBR (1632017005), Natural Science Foun-
dation of Education Committee of Anhui Province (KJ2018A0162) and
National Key R&D Program of China (Project No. 2017YFD0600805).
We are grateful to Prof. Hai-Liang Zhu (State Key Laboratory of
Pharmaceutical Biotechnology, Nanjing University, Nanjing) for com-
putational molecular docking assistance.
Biological assay
Minimum inhibitory concentration (MIC) [21]
References
The in vitro antibacterial activity for all synthesized com-
pounds was evaluated using the agar dilution method [22,
23]. Twofold serial dilutions of the compounds and refer-
ence drug (ciprofloxacin) were prepared in LB broth–agar
medium. Compounds (10.0 mg) were dissolved in DMSO
(1 mL), and the solution was diluted with water (9 mL). Fur-
ther progressive double dilution with melted LB broth–agar
medium was performed to obtain the required concentrations
of 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.05 mg/L,
and the MIC values were calculated separately.
1. Tanaka Y, Sasaki N, Ohmiya A (2010) Biosynthesis of plant
pigments: anthocyanins, betalains and carotenoids. Plant
54:733–749. https://doi.org/10.1111/j.1365-313X.2008.03447.x
2. Havsteen BH (2002) The biochemistry and medical significance of
the flavonoids. Pharmacol Therapeut 96:67. https://doi.org/10.101
6/S0163-7258(02)00298-X
3. Shaw LJ, Morris P, Hooker JE (2010) Perception and modification
of plant flavonoid signals by rhizosphere microorganisms. Environ
Microbiol 8:1867–1880. https://doi.org/10.1111/j.1462-2920.200
6.01141.x
4. Sakihama Y, Cohen MF, Grace SC, Yamasaki H (2002) Plant
phenolic antioxidant and prooxidant activities: phenolics-induced
oxidative damage mediated by metals in plants. Toxicology
177:67–80. https://doi.org/10.1016/S0300-483X(02)00196-8
5. Friedman M (2010) Overview of antibacterial, antitoxin, antiviral,
and antifungal activities of tea flavonoids and teas. Mol Nutr Food
Res 51:116–134. https://doi.org/10.1002/mnfr.200600173
6. Cushnie TPT, Lamb AJ (2005) Errata for “Antimicrobial activity
of flavonoids” [Int. J. Antimicrob. Agents 26 (2005) 343–356]. Int
J Antimicrob Ag 27:181
7. Echeverría J, Opazo J, Mendoza L, Urzúa A, Wilkens M
(2017) Structure–activity and lipophilicity relationships of selected
antibacterial natural flavones and flavanones of Chilean Flora.
Molecules 22:608. https://doi.org/10.3390/molecules22040608
8. Tair A, Weiss E-K, Palade LM, Loupassaki S, Makris DP, Ioannou
Eetal(2014)OriganumspeciesnativetotheislandofCrete:invitro
antioxidant characteristics and liquid chromatography–mass spec-
trometry identification of major polyphenolic components. Nat
Prod Res 28:1284–1287. https://doi.org/10.1080/14786419.2014.
896011
J
Enzyme inhibitory effects against Topo II and Topo IV
The in vitro enzymatic inhibition assay of the target com-
pounds was performed based upon methods described by
Sato et al. [24] and Peng and Marians [25]. First, the E.
coli suspension is extracted to obtain a crude enzyme solu-
tion. After the purification steps, the selected compounds are
determined by gel electrophoresis to obtain data of different
gradient concentrations, thereby calculating the IC50 values.
3D-QSAR analysis
The three-dimensional (3D) quantitative structure–activity
relationship was performed with Discovery Studio3.5, using
genetic function algorithm (GFA) [26]. In this study, 19 com-
pounds with definite pMIC values were selected as the model
dataset. Then, Discovery Studio3.5 was used to optimize the
energy of the initial conformation of all compounds. Finally,
we run the “Create 3D-QSAR Model” protocol to get the
model.
9. Jadoon S, Karim S, Bin Asad MHH, Akram MR, Khan AK,
Malik A et al (2015) Anti-aging potential of phytoextract loaded-
pharmaceutical creams for human skin cell longetivity. Oxid Med
Cell Longev. https://doi.org/10.1155/2015/709628
10. Xia JF, Gao JJ, Inagaki Y, Kokudo N, Nakata M, Tang W (2013)
Flavonoids as potential anti-hepatocellular carcinoma agents:
recent approaches using HepG2 cell line. Drug Discov Therapeut
7:1–8. https://doi.org/10.5582/ddt.2013.ddt.v7.1.1
11. Rao YJ, Sowjanya T, Thirupathi G, Kotapalli SS (2018) Synthesis
and biological evaluation of novel flavone/triazole/benzimidazole
hybrids and flavone/isoxazole-annulated heterocycles as antipro-
liferative and antimycobacterial agents. Mol Divers. https://doi.or
g/10.1007/s11030-018-9833-4
12. Kagechika H, Kawachi E, Hashimoto Y, Shudo K (1989)
Retinobenzoic acids. 2. Structure-activity relationships of
chalcone-4-carboxylic acids and flavone-4ꢁ-carboxylic acids. J
Med Chem 32:834. https://doi.org/10.1021/jm00124a016
13. Zwaagstra ME, Timmerman H, Abdoelgafoer RS, Zhang MQ
(1996) Synthesis of carboxylated flavonoids as new leads for LTD4
antagonists. Eur J Med Chem 31:861–874. https://doi.org/10.101
6/S0223-5234(97)89849-2
Molecular docking
The crystal structure of bacterial DNA Topo II (PDB
code:2XCS) was downloaded from the RCSB Protein Data
Bank. In the “Tool Explore,” we run the “Clean Protein” pro-
tocol to get protein that can be used for docking. Then, we
define the active site of the receptor protein. Finally, we draw
all the compounds in “Chemdraw” software and import them
into Discovery Studio for ligand preparation. The molecular
docking procedures were performed by using CDOCKER
protocol for receptor–ligand interactions section of Discov-
ery Studio3.5 [27].
14. Krauss J, Stadler M, Bracher F (2017) Synthesis and struc-
ture–activity relationships of novel benzylamine-type antifungals
123

Molecular Diversity
as butenafine-related antimycotics. Arch Pharm. https://doi.org/1
0.1002/ardp.201600342
22. Jorgensen JH (1993) NCCLS methods for dilution antimicrobial
susceptibility tests for bacteria that grow aerobically, approved
standard. Infect Dis Clin North Am 7:393–409
23. Aragade P, Maddi V, Khode S, Palkar M, Ronad P, Mam-
ledesai S et al (2009) Synthesis and antibacterial activity of a
new series of 3–3-(substituted phenyl)-1-isonicotinoyl-1h-pyrazol-
5-yl-2h-chromen-2-one derivatives. Arch Pharm 342:361–366.
https://doi.org/10.1002/ardp.200800156
24. Sato K, Inoue Y, Fujii T, Aoyama H, Inoue M, Mitsuhashi
S (1986) Purification and properties of DNA gyrase from a
fluoroquinolone-resistant strain of Escherichia coli. Antimicrob
Agents Ch 30:777–780
25. Peng H, Marians KJ (1993) Escherichia coli topoisomerase IV.
Purification, characterization, subunit structure, and subunit inter-
actions. J Biol Chem 268:24481–24490
26. Dai YJ, Wang QA, Zhang XL, Jia SR, Zheng H, Feng DC et al
(2010) Molecular docking and QSAR study on steroidal com-
pounds as aromatase inhibitors. Eur J Med Chem 45:5612–5620.
https://doi.org/10.1016/j.ejmech.2010.09.011
27. Wu G, Robertson DH, Iii CLB, Vieth M (2003) Detailed analysis
of grid-based molecular docking: a case study of CDOCKER—a
CHARMm-based MD docking algorithm. J Co Ch 24:1549–1562.
https://doi.org/10.1002/jcc.10306
15. Kaya B, Saglik BN, Levent S, Ozkay Y, Kaplancikli ZA (2016)
Synthesis of some novel 2-substituted benzothiazole derivatives
containing benzylamine moiety as monoamine oxidase inhibitory
agents. J Enzyme Inhib Med Chem 31:1654–1661. https://doi.org/
10.3109/14756366.2016.1161621
16. Sui Z, Nguyen VN, Altom J, Fernandez J, Hilliard JJ, Bernstein
JI et al (1999) Synthesis and topoisomerase inhibitory activities of
novel aza-analogues of flavones 1. Eur J Med Chem 34:381–387.
https://doi.org/10.1016/S0223-5234(99)80087-7
17. Bernard FX, Sablé S, Cameron B, Provost J, Desnottes JF, Crouzet
J et al (1997) Glycosylated flavones as selective inhibitors of topoi-
somerase IV. Antimicrob Agents Ch 41:992–998
18. Sun X, Hu CQ, Huang XD, Dong JC (2003) Mannich reaction of
baicalein. Chin J Org Chem 23:81–85
19. Helgren TR, Sciotti RJ, Lee P, Duffy S, Avery VM, Igbinoba O et al
(2015) The synthesis, antimalarial activity and CoMFA analysis of
novel aminoalkylated quercetin analogs. Bioorg Med Chem Lett
25:327–332. https://doi.org/10.1016/j.bmcl.2014.11.039
20. Morales JC, Zurita D, Penadés S (1998) Carbohydrate–carbohy-
drate interactions in water with glycophanes as model systems. J
Org Chem 63:9212–9222
21. Lehmann PF (1999) P.R. Murray, E.J. Baron, M.A. Pfaller, F.C.
Tenover and R.H. Yolken, eds. Manual of clinical microbiology,
7th ed. Mycopathologia 146:107–108. https://doi.org/10.1023/a:1
007025717379
123