Investigating the spectrum of biological activity of substituted quinoline-2-carboxamides and their isosteres

Article abstract of DOI:10.3390/molecules17010613

In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron t

Full text of DOI:10.3390/molecules17010613

Molecules 2012, 17, 613-644; doi:10.3390/molecules17010613
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Investigating the Spectrum of Biological Activity of Substituted
Quinoline-2-Carboxamides and Their Isosteres †
Tomas Gonec 1, Pavel Bobal 1, Josef Sujan 1, Matus Pesko 2, Jiahui Guo 3, Katarina Kralova 4,
Lenka Pavlacka 1, Libor Vesely 1, Eva Kreckova 1, Jiri Kos 1, Aidan Coffey 3, Peter Kollar 5,
Ales Imramovsky 6, Lukas Placek 7 and Josef Jampilek 1,*
1
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical
Sciences, Palackeho 1/3, 61242 Brno, Czech Republic
2
Department of Ecosozology and Physiotactics, Faculty of Natural Sciences, Comenius University,
Mlynska dolina Ch-2, 842 15 Bratislava, Slovakia
3
Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork, Ireland
4
Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina Ch-2,
842 15 Bratislava, Slovakia
5
Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of
Veterinary and Pharmaceutical Sciences, Palackeho 1/3, 61242 Brno, Czech Republic
6
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology,
University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
7
Pragolab s.r.o., Nad Krocinkou 55/285, 19000 Prague 9, Czech Republic
†
Preliminary results were presented at The Fifteenth Electronic Conference on Synthetic Organic
Chemistry (ECSOC-15, http://www.sciforum.net/presentation/588), 1–30 November 2011
(paper B585).
* Author to whom correspondence should be addressed; E-Mail: josef.jampilek@gmail.com;
Tel.: +420-54-156-2925; Fax: +420-54-124-0607.
Received: 28 November 2011; in revised form: 27 December 2011 / Accepted: 4 January 2012 /
Published: 10 January 2012
Abstract: In this study, a series of thirty-five substituted quinoline-2-carboxamides and
thirty-three substituted naphthalene-2-carboxamides were prepared and characterized.
They were tested for their activity related to the inhibition of photosynthetic electron
transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening
of the synthesized compounds was also performed against four mycobacterial species.
N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and

Molecules 2012, 17
N-(2-phenylethyl)quinoline-2-carboxamide showed higher activity against M. tuberculosis
614
than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonyl)quinoline and
1-(2-naphthoyl)pyrrolidine expressed higher activity against M. kansasii and M. avium
paratuberculosis than the standards isoniazid or pyrazinamide. The most effective
antimycobacterial compounds demonstrated insignificant toxicity against the human
monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value
of the most active compound N-benzyl-2-naphthamide was 7.5 μmol/L. For all compounds,
the structure-activity relationships are discussed.
Keywords: quinolines; naphthalene; lipophilicity; photosynthetic electron transport
inhibition; spinach chloroplasts; in vitro antimycobacterial activity; in vitro cytotoxicity
1. Introduction
The presence of an amide or thioamide (-NHCO- or -NHCS-) group is characteristic of a number of
biologically active compounds, e.g., [1–9]. The wide spectrum of biological effects of substituted
quinoline or naphthalene scaffolds includes especially antimicrobial, antineoplastics and antiviral
activity [1,10–25]. In addition, some quinoline derivatives also showed noteworthy herbicidal activity
[13,15–18,26] and they were also found to be uncouplers of photosynthetic phosphorylation [27]. Over
50% of commercially available herbicides act by reversibly binding to photosystem II (PS II), a
membrane-protein complex in the thylakoid membranes, which catalyses the oxidation of water and
the reduction of plastoquinone [28], and thereby inhibit photosynthesis [29–31].
Both pharmaceuticals and pesticides are designed to target particular biological functions, and in
some cases these functions overlap in their molecular target sites, or they target similar processes or
molecules. Modern herbicides express low toxicity against mammals and one of the reasons is that
mammals lack many of the target sites for herbicide action. At present, approximately 20 mechanisms
of action of herbicides are known. It was determined that inhibitors of protoporphyrinogen oxidase,
4-hydroxyphenylpyruvate dioxygenase and glutamine synthetase inhibit these enzymes both in plants
and mammals. However, the consequences of inhibition of the overlapping target site can be
completely different for plants and animals. Therefore a compound that has lethal action on plants may
be beneficial for mammals [32]. Such chemical compounds are characterized by low toxicity on
mammals as a result of quick metabolism and/or elimination of herbicide from the mammal system.
Taking into consideration that mammals may also have molecular sites of action of herbicides, most
pharmaceutical companies until recently had pesticide divisions, sometimes with a different name. All
compounds generated by either division of the company were evaluated for both pesticide and
pharmaceutical uses. In the past, some leading pesticides have become pharmaceuticals and vice versa.
However, little information of this type was published and must usually be deduced from patent
literature. One of the exceptions is fluconazole, a fungicide product discovered by the pharmaceutical
sector that is now used both as a pharmaceutical and patented as a crop production chemical [32–34].
In the context of the previously-described azanaphtalenes [13,15–18,26] or various
amides [3–9], new simple modifications of quinoline and naphtalene as quinoline isosteres that can

Molecules 2012, 17
615
trigger interesting biological activity were investigated. The compounds were tested for their
photosynthesis-inhibiting activity—The inhibition of photosynthetic electron transport in spinach
chloroplasts (Spinacia oleracea L.). The compounds were also assessed for activity against various
mycobacterial species. Relationships between the structure and their in vitro antimycobacterial
activities or/and activity related to inhibition of photosynthetic electron transport (PET) in spinach
chloroplasts are discussed.
2. Results and Discussion
2.1. Chemistry
All the studied compounds were prepared according to Scheme 1. Condensation of the chlorides
of 2-quinaldic and 2-naphthoic acids with commercially available substituted amines yielded a
series of thirty-five substituted quinoline-2-carboxamides 1–19c and thirty-three substituted
naphthalene-2-carboxamides 20–38c. Quinoline-2-carbonyl chloride was prepared using oxalyl
chloride to ensure mild conditions and prevent quinoline nucleus chloration, whereas 2-naphtoyl
chloride was obtained by the classical procedure using thionyl chloride.
Scheme 1. Synthesis of quinoline-2-carboxanilides 1–19c and naphthalene-2-carboxamides 20–38c.
R2
N
R1
R2
a
b
+
+
HN
OH
OH
Cl
Cl
N
R1
N
N
O
O
O
O
O
1-19c
R2
N
R1
R2
c
d
HN
R1
O
20-38c
R1, R2 = H, alkyl, cycloalkyl, aryl
Reagents and conditions: (a) (COCl)2, toluene; (b) TEA, toluene; (c) SOCl2, toluene; (d) TEA, CH2Cl2.
Hydrophobicities (log P) of all compounds 1–38c were calculated using the commercially available
program ACD/LogP (ACD/LogP ver. 1.0, Advanced Chemistry Development Inc., Toronto, Canada).
The results are shown in Tables 1 and 2. Compounds show a wide range of lipophilicities, with log P
(ACD/LogP) values from 1.15 (compound 3, pyrrolidinyl) to 6.98 (compound 2, octyl) within the
series of quinolinecarboxamides and from 2.10 (compound 22, pyrrolidinyl) to 7.94 (compound 21,
octyl) within the series of naphthalenecarboxamides. Individual substituents in the amide part of the
discussed compounds also result in a wide range (from −0.39 to 1.26) of electronic properties
expressed as σ parameters [35–38].

Molecules 2012, 17
Table 1. The calculated lipophilicities (log P/Clog P), electronic σ parameters and
616
IC50 [μmol/L] values related to PET inhibition in spinach chloroplasts of quinoline-2-
carboxamides 1–19c in comparison with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU)
standard. NF = not found in literature, ND = not determined due to precipitation during the
experiment or interaction with 2,6-dichlorophenol-indophenol (DCIPP).
R2
N
N
R1
O
PET inhibition
IC50 [μmol/L]
ND
log P
σ
[35]
Comp.
R1
R2
ACD/Log P
2.02 ± 0.34
6.98 ± 0.32
1.15 ± 0.26
1.72 ± 0.26
2.63 ± 0.33
3.20 ± 0.33
3.76 ± 0.33
4.33 ± 0.33
2.90 ± 0.34
2.91 ± 0.35
3.33 ± 0.33
2.54 ± 0.36
2.55 ± 0.36
2.15 ± 0.35
2.80 ± 0.36
3.06 ± 0.36
2.85 ± 0.36
3.36 ± 0.34
3.36 ± 0.34
3.36 ± 0.34
2.86 ± 0.44
3.38 ± 0.44
3.34 ± 0.44
3.41 ± 0.36
3.93 ± 0.37
3.89 ± 0.36
3.58 ± 0.44
4.10 ± 0.44
4.06 ± 0.44
4.09 ± 0.42
4.25 ± 0.42
3.91 ± 0.41
3.15 ± 0.38
3.28 ± 0.38
3.36 ± 0.38
–
1
2
3
4
5
6
7
8
9
i-Pr
–C12H25
H
H
−0.19 [36]
NF
573
1598
ND
762
1041
ND
415
85.1
59.4
ND
16.3
ND
ND
ND
ND
ND
142.9
100.6
ND
98.1
86.9
75.3
56.3
91.9
147.6
92.2
409.0
307.9
109.4
329.5
ND
–(CH2)4–
–(CH2)5–
c-Pn
c-Hx
c-Hp
c-Oc
Ph
Bn
NF
NF
−0.20 [36]
−0.15 [36]
NF
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–
NF
0.60 [36]/0
0.22 [36]
0.08 [36]
−0.09
0.12
−0.37
−0.39 [37]
0.12
−0.27
NF
−0.07
−0.17
0.24 [38]
0.34
0.06
0.20 [38]
0.37
0.23
0.21 [38]
0.39
10
11
–C2H4Ph
2-OH-Ph
3-OH-Ph
4-OH-Ph
2-OCH3-Ph
3-OCH3-Ph
4-OCH3-Ph
2-CH3-Ph
3-CH3-Ph
4-CH3-Ph
2-F-Ph
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
18c
19a
19b
19c
DCMU
3-F-Ph
4-F-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-Br-Ph
3-Br-Ph
4-Br-Ph
2-CF3-Ph
3-CF3-Ph
4-CF3-Ph
2-NO2-Ph
3-NO2-Ph
4-NO2-Ph
–
0.23
NF
0.43
0.74
ND
ND
ND
1.9
0.80 [38]
0.71
1.26
–

Molecules 2012, 17
Table 2. The calculated lipophilicities (log P/Clog P), electronic σ parameters and
617
IC50 [μmol/L] values related to PET inhibition in spinach chloroplasts of naphthalene-2-
carboxamides 20–38c in comparison with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU)
standard. NF = not found in literature, ND = not determined due to precipitation during the
experiment or interaction with 2,6-dichlorophenol-indophenol (DCIPP).
R2
N
R1
O
PET inhibition
IC50 [μmol/L]
353
log P
σ
[35]
Comp.
R1
R2
ACD/Log P
2.97 ± 0.28
7.94 ± 0.28
2.10 ± 0.23
2.67 ± 0.23
3.59 ± 0.28
4.15 ± 0.28
4.21 ± 0.28
5.28 ± 0.28
3.85 ± 0.29
3.87 ± 0.28
4.28 ± 0.29
3.50 ± 0.31
3.11 ± 0.30
3.75 ± 0.32
4.01 ± 0.32
3.80 ± 0.32
4.31 ± 0.30
4.31 ± 0.30
4.31 ± 0.30
3.82 ± 0.40
4.34 ± 0.41
4.30 ± 0.41
4.36 ± 0.32
4.88 ± 0.33
4.84 ± 0.32
4.54 ± 0.40
5.06 ± 0.41
5.02 ± 0.41
5.20 ± 0.39
4.86 ± 0.37
4.10 ± 0.34
4.24 ± 0.34
4.31 ± 0.34
–
20
21
i-Pr
H
H
−0.19 [36]
NF
–C12H25
845
22
–(CH2)4–
–(CH2)5–
c-Pn
ND
NF
23
ND
NF
24
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–
ND
−0.20 [36]
−0.15 [36]
NF
25
c-Hx
c-Hp
ND
26
216
27
c-Oc
688
NF
28
Ph
20.7
7.5
0.60 [36]/0
0.22 [36]
0.08 [36]
0.12
29
Bn
30
–C2H4Ph
3-OH-Ph
4-OH-Ph
2-OCH3-Ph
3-OCH3-Ph
4-OCH3-Ph
2-CH3-Ph
3-CH3-Ph
4-CH3-Ph
2-F-Ph
ND
31b
31c
32a
32b
32c
33a
33b
33c
34a
34b
34c
35a
35b
35c
36a
36b
36c
37b
37c
38a
38b
38c
DCMU
ND
ND
−0.37
−0.39 [37]
0.12
763.0
306.2
ND
−0.27
NF
ND
ND
−0.07
−0.17
0.24 [38]
0.34
ND
ND
3-F-Ph
ND
4-F-Ph
ND
0.06
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-Br-Ph
3-Br-Ph
4-Br-Ph
3-CF3-Ph
4-CF3-Ph
2-NO2-Ph
3-NO2-Ph
4-NO2-Ph
–
ND
0.20 [38]
0.37
81.0
ND
0.23
ND
0.21 [38]
0.39
102.8
ND
0.23
309.4
ND
0.43
0.74
ND
0.80 [38]
0.71
633.3
260.0
1.9
1.26
–

Molecules 2012, 17
618
2.3. Biological Activities
The compounds under investigation could be divided into two groups based on their chemical structure:
Group 1 included quinoline-2-carboxamides 1–19c; Group 2 contained naphthalene-2-carboxamides
20–38c. Compounds within both series can be also divided according to whether they contain an
aromatic or a non-aromatic amine. The compounds showed a wide range of biological activities and
some interesting structure-activity relationships were observed. All the results are summarized in
Tables 1–3. Generally, all the discussed compounds exhibited problematic solubility, but quinoline
derivatives generally possess better aqueous solubility in comparison to the naphthamides.
Table 3. In vitro antimycobacterial activity (IC90) of compounds 1–3, 5–7, 11, 14b, 22 and
32a in comparison with standards isoniazid (INH) and pyrazinamide (PZA), in vitro
cytotoxicity assay (LD50) of compounds 3, 7, 11 and 22 and calculated selectivity index
(SI). ND = not determined; used IC90 for calculation of SI is marked by *.
MIC/IC90 [µmol/L]
LD50
SI
Comp.
M. avium
complex
583
M. avium
M. tuberculosis #
M. kansasii
[µmol/L] [LD50/IC90]
paratuberculosis
1167
734
1
2
280
367
1167
734
ND
ND
–
367
–
3
552
552
111 *
491
111 *
491
>100
ND
>0.90
5
491
491
–
6
125
520
520
520
ND
–
0.56
>0.92
–
7
111 *
109 *
469
466
223
466
62 ± 4.5
>100
ND
11
14b
22
32a
INH
452
905
452
469
939
469
554
554
111 *
216
111 *
451
>100
ND
>0.90
–
901
451
>729
>812
<72.9
>812
>729
>812
<72.9
>812
ND
–
PZA
ND
–
#
Clinical isolate of M. tuberculosis CUH071 (Cork University Hospital TB lab), with partial INH
and PZA resistance.
2.3.1. Inhibition of Photosynthetic Electron Transport (PET) in Spinach Chloroplasts
The activity of all the evaluated derivatives related to inhibition of photosynthetic electron transport
(PET) in spinach (Spinacia oleracea L.) chloroplasts was moderate or rather low relative to the
standard, see Tables 1 and 2. N-(2-Hydroxyphenyl)quinoline-2-carboxamide (12a) expressed the
highest PET-inhibiting activity (IC50 = 16.3 µmol/L) within the series of quinolinecarboxamides
whereas N-benzyl-2-naphthamide (29) from the second set investigated was two-fold more effective
with a PET inhibition IC50 value of 7.5 µmol/L. The PET-inhibiting activity was expressed by the
negative logarithm of the IC50 value (compound concentration in mol/L causing 50% inhibition of
PET). Despite the relatively low inhibitory activity of the rest studied compounds, correlations
between log (1/IC50) and the lipophilicity expressed as log P (ACD/LogP) or electronic properties
expressed as Hammett’s σ parameters of the individual substituents in compounds 1–38c were

Molecules 2012, 17
619
performed, see Figures 1, 2 and 3. Generally, non-aromatic N-substituents showed lower PET-inhibiting
activity than anilides.
The PET-inhibiting activity of the evaluated quinoline derivatives (Group 1) is summarized
in Table 1. According to both Figure 1, where all compounds except substituted phenyl rings are
illustrated, it can be stated that the dependence of PET-inhibiting activity on the lipophilicity showed
a parabolic course. Cyclic non-aromatic N-substituents are illustrated in Figure 1a, where the most
active compound N-cyclooctyl 8 has a lipophilicity optimum at log P = 4.33. The dependence of
PET-inhibiting activity on electronic constants σ of non-aromatic as well as phenyl 9 and benzyl 10
substituents obtained from literature [36] seems to also follow a parabolic course, see Figure 1b.
Benzyl derivative 10 showed an optimum of weak electron-withdrawing effect influencing the
electronic density of the amido moiety. It is evident that bulkiness of the N-substituents did not
influence PET-inhibiting activity.
Figure 1. Relationships between PET inhibition log (1/IC50) [mol/L] in spinach
chloroplasts and lipophilicity (a) or N-substituent electronic σ parameters (b) of studied
compounds 1–10.
3.5
8
3.4
3.3
2
3.2
5
3.1
3.0
6
2.9
2.8
3
2.7
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
log P [ACD/LogP]
(a)
4.4
10
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
9
5
6
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7

(b)

Molecules 2012, 17
620
Figure 2 shows the correlations between log (1/IC50) and the lipophilicity or Hammett’s σ
parameters of the individual anilide substituents in compounds 9, 12a–19c. Based on the results
obtained it is not possible to decide whether some of the ortho-, meta- or para-positions are preferred
from the PET-inhibiting activity point of view. Nevertheless, according to Figure 2a it can be stated
that the PET inhibition showed linear decrease with increasing lipophilicity and the lipophilicity of the
compounds was decisive for PET inhibition:
log (1/IC50) = 5.952(±0.406) − 0.559(±0.113) log P
(1)
r = 0.819, s = 0.211, F = 24.50, n = 14
On the other hand, the biological activity was also affected by electronic σ properties of these
anilide substituents, see Figure 2b.
Figure 2. Relationships between PET inhibition log (1/IC50) [mol/L] in spinach
chloroplasts and lipophilicity (a) or N-substituent electronic Hammett’s σ parameters (b) of
studied compounds 9, 12a–19c.
5.0
12a
4.5
16a
15c
16b
17a
15b
9
18a
4.0
3.5
3.0
2.5
14b
16c
15a
14a
17c
18b
17b
2.4
2.6
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
4.4
log P [ACD/LogP]
(a)
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
3.0
12a
16a
17a
15b
16b
9
15c
15a
14b
16c
17c
18b
17b
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5

(b)

Molecules 2012, 17
Figure 3. Relationships between PET-inhibition log (1/IC50) [mol/L] in spinach
621
chloroplasts and lipophilicity (a, b) or N-substituent electronic σ parameters (c) of studied
naphthalene-2-carboxamides 20–38c.
5.5
29
5.0
28
4.5
4.0
26
3.5
3.0
2.5
20
21
27
2.7
3.2
3.7
4.2
4.7
5.2
5.7
6.2
6.7
7.2
7.7
8.2
log P [ACD/LogP]
(a)
5.5
5.0
4.5
4.0
3.5
3.0
2.5
28
35b
36b
38c
32b
37b
38b
32a
3.5
4.0
4.5
5.0
5.5
log P [ACD/LogP]
(b)
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
3.0
28
35b
36b
38c
37b
32b
38b
32a
-0.5
-0.3
-0.1
0.1
0.3
0.5
0.7
0.9
1.1
1.3
1.5

(c)

Molecules 2012, 17
622
In general, the dependence of log (1/IC50) on σ reflects two trends. The first, i.e., compounds with
extreme electron σ effects, show a similar trend as in case of lipophilicity and thus, the activity
decreases with increasing σ value. The second trend is a parabolic course with an optimum activity for
compound 16a (2-Cl-Ph; σ = 0.20). In this case the σ values of the corresponding compounds ranged
from −0.07 to 0.37, but the differences between activities of the compounds expressed as IC50 values
were relatively low and they ranged from 100.6 (14b) to 56.3 μmol/L (16a). However, the importance
of the lipophilicity of the anilide substituent was unambiguously much more significant for the inhibitory
activity (IC50 [mol/L]) of the studied compounds than the electronic properties of the substituent.
The most active compound from the series Group 1 was 12a (R = 2-OH, IC50 = 16.3 μmol/L). The
result indicates that PET inhibition could be associated with additional interaction of the phenol
moiety with photosynthetic proteins. This compound can be understood as a bioisoster of
2-[(2-hydroxyphenylimino)methyl]quinolin-8-ol that expresses high herbicide effect [18].
Generally, the activity of the evaluated naphthalene derivatives (Group 2) related to PET inhibition
in spinach (Spinacia oleracea L.) chloroplasts seems to be higher than that of the corresponding
quinoline isosters (Table 2). The PET inhibition of 34 of the 68 compounds could not be determined
due to their precipitation during the experiments. With respect to these small but closed specifically
substituted groups of compounds some structure-activity relationships (SAR) can be proposed.
Figure 3a illustrates the exponential decay of PET-inhibiting activity on the lipophilicity increase of
all naphthalene derivatives (compounds 20, 21, 26–29) except substituted phenyl moieties. Dependence
of the activity on the electronic properties could not be performed due to small amount of data. As
mentioned above, PET-inhibiting activity is not influenced by bulkiness of the N-substituents. Benzyl
derivative 29 showed higher activity (IC50 = 7.5 μmol/L) than unsubstituted phenyl derivative 28
(IC50 = 20.7 μmol/L), similarly to quinolinecarboxamides [IC50 = 59.4 μmol/L (10) and 85.1 μmol/L (9),
respectively].
Dependence of PET inhibition on the lipophilicity of all compounds with the aromatic
N-substituents is shown on Figure 3b. It is evident that unsubstituted phenyl 28 derivative expressed
the highest PET inhibition; and this decreases as lipophilicity increases. This is observed for lipophilic
meta-substituted derivatives 35b (3-Cl), 36b (3-Br) and 37b (3-CF3), contrary to the quinaldinanilides,
and it is not valid for methoxy and nitro moieties (32a/b, 38b/c). This lower inhibitory activity of
compounds 32a (2-OCH3-Ph), 32b (2-OCH3-Ph) and 38c (4-NO2-Ph) could be a result of the limited
solubility of the compounds, which is typical for -OCH3 and -NO2 substituents. Figure 3c shows PET
inhibition of naphtanilides on Hammett’s σ parameters of the individual substituents. Based on the
results from Figure 3c it can be concluded that PET-inhibiting activity is strongly decreased by the
electron-withdrawing effect of substituents in the anilide part of the molecule: 29 (Ph) >> 35b (3-Cl) >
36b (3-Br) > 37b (3-CF3) > 38b (3-NO3), especially in meta-position, contrary to the SAR of
quinaldinanilides discussed above.
2.3.3. In Vitro Antimycobacterial Evaluation
Although all the compounds were evaluated for their in vitro antimycobacterial activity against
M. tuberculosis (clinical isolate with partial INH and PZA resistance) and other atypical mycobacterial
strains, most compounds did not show any activity due to their low solubility and precipitation during

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the experiments. Only the 10 compounds presented in Table 3 showed actimycobacterial activities.
N-Cycloheptylquinoline-2-carboxamide (7) and N-(2-phenylethyl)quinoline-2-carboxamide (11) showed
high activity against M. tuberculosis, whereas 2-(pyrrolidin-1-ylcarbonyl)quinoline (3) and
1-(2-naphthoyl)pyrrolidine (22) expressed high activity against M. avium paratuberculosis and
M. kansasii. Compounds 6, 1 and 32a also showed noteworthy activity. Nevertheless, no thorough
structure-activity relationships could be established.
According to the results, it can be generally concluded that quinaldinamides (Group 1) possessed
higher activity than corresponding naphtamides (Group 2), and anilides seem to be less effective than
amides, e.g., highly effective compound 11 and non-active phenyl derivative 9 (not-discussed). Figure
4 shows dependence of the average of antituberculosis/antimycobacterial activities expressed as
log 1/MIC [mol/L] on lipophilicity expressed as log P. Based on these results, it can be concluded that
activity increases as lipophilicity increases. Also, it seems that the increase in antituberculosis activity
is connected with the increase in the bulkiness of individual N-substituents within the series of
cycloalkane, (i.e., cycloheptyl 7 > cyclohexyl 6 > cyclopentyl 5). As cyclooctyl derivative 8
demonstrated no activity, it can be concluded that cycloheptyl compound 7 showed the maximum
antituberculosis efficacy within this type of compound and under these testing conditions. This
decrease might have also actually been caused by decreased solubility of compound 8 in the test media
(precipitation occurred). It can be speculated that substituents which are bulkier than cyclooctyl could
further potentiate the antimycobacterial activity. But the testing conditions for these more lipophilic
compounds would have to be changed to prevent the precipitation during the dilution of samples.
Figure 4. Dependence of in vitro average antimycobacterial activity against Mycobacterium
sp. (log 1/MIC [mol/L]) on lipophilicity expressed as log P of the studied quinaldinamides.
(red rhomb = branched alkyl quinaldinamides, green triangle = unbranched long-chain alkyl
quinaldinamide, blue square = aromatic quinaldinamides, black point = naphtamides).
3.6
7
3
22
3.5
3.4
3.3
3.2
3.1
6
11
5
32a
2
14b
1
0.5
1.5
2.5
3.5
4.5
5.5
6.5
7.5
log P [ACD/LogP]
Branching within the N-substituents seems also very important, especially from the point of view of
antitubercular versus antimycobacterial activity. Unbranched long-chain alkyl dodecyl compound 2 or
ethylphenyl one 11 as well as isopropyl compound 1 and other cycloalkyl moietis branched in the
α position of individual N-substituents, seem to be the most advantageous for antituberculosis activity,

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while N,N-disubstitution, e.g., compounds 3 and 22, is fundamental for high efficacy against the
atypical mycobacterial strains M. avium paratuberculosis and M. kansasii.
2.3.4. In Vitro Cytotoxicity Assay
The most effective antimycobacterial compounds 11, 7, 3 and 22 were tested for their in vitro
cytotoxicity LD50 (µmol/L), and subsequently the Selectivity Index, i.e., the ratio of cell toxicity
(LD50) to activity (MIC), was obtained; the results are presented in Table 3. The LD50 exact values of
compounds 3, 11 and 22 could not be determined due to their limited solubility and their precipitation
from solution during the tests in concentration higher than 100 µmol/L, but the highest dose achieved
in the medium (100 µmol/L) did not lead to the 100% lethal effect on THP-1 cells. All the evaluated
compounds demonstrated low toxicity against the human monocytic leukemia THP-1 cell line
(e.g., LD50 of oxaliplatin 1.7 ± 6.4 and camptothecin 0.16 ± 0.07 assessed in this line formerly showed
much lower values). It can be drawn from Table 3 that compounds 3, 7 and 11 from Group 1 and
compound 22 from Group 2 showed the highest inhibition activity and also moderate cytotoxicity
against THP-1 cells; compound 7 expressed the highest toxicity within the series of compounds, but it
can not be considered toxic as its LD50 value (62 ± 4.5) is fairly high. Based on these observations it
can be concluded that the discussed amides 11, 3 and 22 can be considered as promising agents for
subsequent design of novel antitubercular/antimycobacterial agents.
3. Experimental
3.1. General
All reagents were purchased from Aldrich. Kieselgel 60, 0.040–0.063 mm (Merck, Darmstadt,
Germany) was used for column chromatography. TLC experiments were performed on alumina-backed
silica gel 40 F254 plates (Merck, Darmstadt, Germany). The plates were illuminated under UV (254 nm)
and evaluated in iodine vapour. The melting points were determined on Kofler hot-plate apparatus
HMK (Franz Kustner Nacht KG, Dresden, Germany) and are uncorrected. Infrared (IR) spectra were
recorded on a Smart MIRacle™ ATR ZnSe for Nicolet™ Impact 410 FT-IR spectrometer (Thermo
Scientific, USA). The spectra were obtained by accumulation of 256 scans with 2 cm−1 resolution in
1
13
the region of 4,000–600 cm−1. All H and C NMR spectra were recorded on a Bruker Avance III
1
13
400 MHz FT-NMR spectrometer (400 MHz for H and 100 MHz for C, Bruker Co., Karlsruhe,
Germany). Chemicals shifts are reported in ppm () using internal Si(CH3)4 as the reference with
diffuse, easily exchangeable signals being omitted. Mass spectra were measured using a LTQ Orbitrap
Hybrid Mass Spectrometer (Thermo Electron Corporation, USA) with direct injection into an APCI
source (400 °C) in the positive mode.
3.2. Synthesis
3.2.1. General Procedure for Synthesis of Carboxamide Derivatives 1–19c
2-Quinaldic acid (1 g, 5.8 mmol) was suspended in dry toluene (15 mL) at room temperature and
oxalyl chloride (1 mL, 1.61 g, 12.7 mmol, 2.2 eq.) was added dropwise. The reaction mixture was

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stirred for 30 min at the same temperature and then DMF (2 drops) was added. The mixture was stirred
for 24 h and then evaporated to dryness. The residue was washed with petroleum ether and used
directly in the next step. Into the solution of 2-quinaldic acid chloride in dry toluene (15 mL),
triethylamine (4.5 mL, 2.92 g, 32.5 mmol) and corresponding substituted aniline (5.8 mmol) were
added dropwise. The mixture was stirred at room temperature for 24 h after which the solvent was
removed under reduced pressure. The residue was extracted with CHCl3. Combined organic layers
were washed with water and saturated aqueous solution of NaHCO3 and dried over anhydrous MgSO4.
The solvent was evaporated to dryness under reduced pressure. The crude product was recrystallized
from isopropanol or EtOAc. The studied compounds 1–19c are presented in Table 1.
N-Isopropylquinoline-2-carboxamide (1). Yield 40%; Mp. 75–76 °C; IR (Zn/Se ATR, cm−1): 3,339m,
3,052w, 2,925w, 2,852w, 1,676s, 1,589m, 1,556m, 1,525s, 1,501m, 1,434w, 1,418w, 1,205w, 1,119m,
1
903w, 841w, 770m, 747m, 686w, 666w; H-NMR (DMSO-d6), δ: 8.60 (d, J = 8.0 Hz, 1H), 8.54 (d,
J = 8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.80–7.89 (m, 1H), 7.64–7.74 (m,
13
1H), 4.03–4.28 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H); C-NMR (DMSO-d6), δ: 163.02, 150.32, 145.96,
137.83, 130.45, 129.18, 128.76, 128.07, 127.98, 118.65, 40.94, 22.27; HR-MS: for C13H15N2O [M+H]+
calculated 215.1179 m/z, found 215.1139 m/z.
N-Dodecylquinoline-2-carboxamide (2). Yield 24%; Mp. 45–46 °C; IR (Zn/Se ATR, cm−1): 3,411s,
3,052w, 2,983w, 2,901w, 1,671s, 1,589w, 1,561m, 1,521m, 1,492m, 1,450w, 1,423s, 1,201w, 1,131w,
1
1,107w, 1,074w, 1,054w, 907w, 841m, 768w, 735m, 696m; H-NMR (DMSO-d6), δ: 8.88 (t,
J = 6.0 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.05 (d,
J = 8.0 Hz, 1H), 7.81–7.86 (m, 1H), 7.65–7.71 (m, 1H), 3.31–3.38 (m, 2H), 1.54 (quin, J = 6.9 Hz,
13
2H), 1.10–1.31 (m, 18H), 0.78 (t, J = 6.9 Hz, 3H); C-NMR (DMSO-d6), δ: 163.78, 150.29, 145.99,
137.72, 130.37, 129.13, 128.76, 128.04, 127.89, 118.60, 38.96, 31.30, 29.24, 29.06, 29.03, 29.02,
29.00, 28.81, 28.73, 26.49, 22.09, 13.89; HR-MS: for C22H33N2O [M+H]+ calculated 341.2587 m/z,
found 341.2599 m/z.
2-(Pyrrolidin-1-ylcarbonyl)quinoline (3) [39]. Yield 41%; Mp. 71–72 °C; IR (Zn/Se ATR, cm−1):
3,291m, 3,064w, 2,919s, 2,844w, 1,644s, 1,561w, 1,532s, 1,498m, 1,467m, 1,438w, 1,422m, 1,344w,
1
1,324w, 1,201w, 1,168m, 1,070m, 1,009w, 903m, 842m, 774s, 735m, 678m; H-NMR (DMSO-d6),
δ: 8.46 (d, J = 8.5 Hz, 1H), 8.03 (t, J = 9.2 Hz, 2H), 7.77–7.83 (m, 2H), 7.66 (ddd, J = 8.0 Hz,
J = 6.9 Hz, J = 1.1 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 6.5 Hz, 2H), 1.78–1.89 (m, 4H);
13C-NMR (DMSO-d6), δ: 165.56, 154.22, 145.87, 137.07, 130.14, 129.15, 127.90, 127.75, 127.64,
120.41, 48.46, 46.39, 26.05, 23.59; HR-MS: for C14H15N2O [M+H]+ calculated 227.1179 m/z, found
227.1203 m/z.
2-(Piperidin-1-ylcarbonyl)quinoline (4) [40]. Yield 59%; Mp. 83–84 °C; IR (Zn/Se ATR, cm−1):
3,327s, 3,023w, 2,934w, 1,655s, 1,561w, 1,522m, 1,495m, 1,454m, 1,426s, 1,360m, 1,331w, 1,230w,
1
1,209w, 1,156m, 1,074w, 837m, 772w, 735m, 701m; H-NMR (DMSO-d6), δ: 8.48 (d, J = 8.3 Hz, 1H),
7.96–8.07 (m, 2H), 7.81 (ddd, J = 8.5 Hz, J = 6.8 Hz, J = 1.5 Hz, 1H), 7.57–7.71 (m, 2H), 3.61–3.69
13
(m, 2H), 3.22–3.35 (m, 2H), 1.38–1.73 (m, 6H); C-NMR (DMSO-d6), δ: 166.63, 154.67, 146.14,

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137.34, 130.26, 128.99, 128.00, 127.46, 127.38, 120.04, 47.45, 42.22, 25.97, 25.31, 23.97; HR-MS:
for C15H17N2O [M+H]+ calculated 241.1335 m/z, found 241.1384 m/z.
N-Cyclopentylquinoline-2-carboxamide (5). Yield 36%; Mp. 63–64 °C; IR (Zn/Se ATR, cm−1):
3,387m, 3,305m, 2,933m, 2,848m, 1,655s, 1,614w, 1,561w, 1,524s, 1,497s, 1,446m, 1,373w, 1,205w,
1
1,160m, 1,136m, 1,074w, 849m, 796w, 779s, 735w; H-NMR (DMSO-d6), δ: 8.68 (d, J = 8.0 Hz, 1H),
8.54 (d, J = 8.5 Hz, 1H), 8.15 (dd, J = 8.4 Hz, J = 2.6 Hz, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.85 (dd,
J = 8.3 Hz, J = 7.0 Hz, 1H), 7.65–7.74 (m, 1H), 4.30 (sxt, J = 7.3 Hz, 1H), 1.85–2.01 (m, 2H),
1.48–1.74 (m, 6H); 13C-NMR (DMSO-d6), δ: 163.59, 150.30, 145.97, 137.85, 130.46, 129.22, 128.77,
128.09, 128.00, 118.66, 50.72, 32.17, 23.60; HR-MS: for C15H17N2O [M+H]+ calculated 241.1335 m/z,
found 241.1375 m/z.
N-Cyclohexylquinoline-2-carboxamide (6) [40]. Yield 40%; Mp. 98–99 °C; IR (Zn/Se ATR, cm−1):
3,329m, 3,313m, 2,969s, 2,933m, 2,875m, 1,648s, 1,556w, 1,522s, 1,498s, 1,470m, 1,423s, 1,382w,
1,361m, 1,341w, 1,324w, 1,201w, 1,178m, 1,130m, 1,105w, 903w, 844m, 776w, 735w, 674w; 1H-NMR
(DMSO-d6), δ: 8.57 (d, J = 8.5 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.06 (d,
J = 8.0 Hz, 1H), 7.81–7.88 (m, 1H), 7.66–7.72 (m, 1H), 3.78–3.89 (m, 1H), 1.06–1.88 (m, 10H);
13C-NMR (DMSO-d6), δ: 162.92, 150.27, 145.94, 137.84, 130.44, 129.20, 128.77, 128.06, 127.98,
118.64, 48.12, 32.26, 25.12, 24.83; HR-MS: for C16H19N2O [M+H]+ calculated 255.1492 m/z, found
255.1525 m/z.
N-Cycloheptylquinoline-2-carboxamide (7). Yield 39%; Mp. 72–73 °C; IR (Zn/Se ATR, cm−1):
3,056w, 2,958m, 2,864m, 1,615s, 1,552m, 1,469m, 1,436m, 1,417s, 1,373w, 1,332w, 1,205w, 1,181w,
1
1,156w, 842m, 764m, 731w, 657w; H-NMR (DMSO-d6), δ: 8.61 (d, J = 8.5 Hz, 1H), 8.54 (d,
J = 8.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 7.5 Hz, 1H), 7.85 (ddd, J = 8.4 Hz, J = 6.9 Hz,
J = 1.3 Hz, 1H), 7.69 (ddd, J = 8.0 Hz, J = 6.9 Hz, J = 1.1 Hz, 1H), 4.01 (qt, J = 9.0 Hz, J = 4.5 Hz,
1H), 1.81–1.93 (m, 2H), 1.37–1.72 (m, 10H); 13C-NMR (DMSO-d6), δ: 162.64, 150.30, 145.94,
137.85, 130.45, 129.21, 128.78, 128.06, 127.98, 118.63, 50.32, 34.30, 27.57, 23.88; HR-MS: for
C17H21N2O [M+H]+ calculated 269.1648 m/z, found 269.1619 m/z.
N-Cyclooctylquinoline-2-carboxamide (8) [41]. Yield 44%; Mp. 72–73 °C; IR (Zn/Se ATR, cm−1):
3,301w, 2,954m, 2,916s, 2,848s, 1,667s, 1,649s, 1,593w, 1,532s, 1,498s, 1,462m, 1,418m, 1,373w,
1,340w, 1,315w, 1,295m, 1,209w, 1,168m, 1136w, 1,111w, 903w, 850s, 796w, 772s, 735m, 715w,
666w; 1H-NMR (DMSO-d6), δ: 8.59 (d, J = 7.8 Hz, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.3 Hz,
2H), 8.06 (d, J = 8.0 Hz, 1H), 7.81–7.88 (m, 1H), 7.66–7.73 (m, 1H), 4.00–4.12 (m, 1H), 1.45–1.81
13
(m, 14H); C-NMR (DMSO-d6), δ: 162.60, 150.32, 145.94, 137.85, 130.45, 129.21, 128.78, 128.06,
127.98, 118.61, 49.11, 31.80, 26.71, 25.00, 23.50; HR-MS: for C18H23N2O [M+H]+ calculated
283.1805 m/z, found 283.1777 m/z.
N-Phenylquinoline-2-carboxamide (9). Yield 59%; Mp. 139–140 °C (Mp. 139.5–140 °C [42]); IR
(Zn/Se ATR, cm−1): 3,293m, 2,927s, 2,855m, 1,643s, 1,562m, 1,530s, 1,500s, 1,426m, 1,315w, 1,205w,
1,185w, 1,160w, 1,070w, 1,042w, 910m, 870w, 841m, 776m, 731w; 1H-NMR (DMSO-d6), δ: 10.75 (bs,
1H), 8.62 (d, J = 8.5 Hz, 1H), 8.22–8.30 (m, 2H), 8.11 (d, J = 7.5 Hz, 1H), 7.94–7.99 (m, 2H), 7.91

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(ddd, J = 8.5 Hz, J = 7.0 Hz, J = 1.4 Hz, 1H), 7.75 (ddd, J = 8.1 Hz, J = 7.0 Hz, J = 1.3 Hz, 1H),
13
7.38–7.45 (m, 2H), 7.12–7.19 (m, 1H); C-NMR (DMSO-d6), δ: 162.71, 150.08, 145.88, 138.31,
138.22, 130.68, 129.35, 128.94, 128.78, 128.37, 128.15, 124.05, 120.29, 118.77; HR-MS: for
C16H13N2O [M+H]+ calculated 249.1022 m/z, found 249.1015 m/z.
N-Benzylquinoline-2-carboxamide (10). Yield 60%; Mp. 123–124 °C (Mp. 124–125 °C [43]); IR
(Zn/Se ATR, cm−1): 3,273m, 2,952m, 2,856m, 1,657s, 1,643s, 1,589w, 1,562m, 1,527s, 1,498s, 1,446w,
1,424m, 1,315w, 1,299w, 1,205m, 1,181 w, 1,152w, 1,143w, 956w, 899m, 846s, 792m, 770m, 776m,
1
739m, 686m; H-NMR (DMSO-d6), δ: 9.50 (t, J = 6.4 Hz, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.19 (d,
J = 8.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.07 (dd, J = 8.3 Hz, J = 0.8 Hz, 1H), 7.86 (ddd, J = 8.4 Hz,
J = 6.9 Hz, J = 1.5 Hz, 1H), 7.70 (ddd, J = 8.2 Hz, J = 6.9 Hz, J = 1.0 Hz, 1H), 7.36–7.41 (m, 2 H),
13
7.29–7.35 (m, 2H), 7.20–7.26 (m, 1H), 4.59 (d, J = 6.5 Hz, 2H); C-NMR (DMSO-d6), δ: 164.13,
150.15, 146.04, 139.52, 137.88, 130.52, 129.19, 128.84, 128.30, 128.11, 128.07, 127.46, 126.82,
118.74, 42.56; HR-MS: for C17H15N2O [M+H]+ calculated 263.1179 m/z, found 263.1202 m/z.
N-(2-Phenylethyl)quinoline-2-carboxamide (11) [44]. Yield 38%; Mp. 80–81 °C; IR (Zn/Se ATR, cm−1):
3,236w, 2,935s, 2,852m, 1,633s, 1,552w, 1,467m, 1,450m, 1,422m, 1,344w, 1,279m, 1,103w, 1,025w,
1
1,005w, 952w, 890w, 841m, 760m, 731w, 682w; H-NMR (DMSO-d6), δ: 9.00 (t, J = 5.90 Hz, 1H),
8.54 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H),
7.85 (td, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.66–7.73 (m, 1H), 7.25–7.33 (m, 4H), 7.16–7.22 (m, 1H),
3.58–3.65 (m, 2H), 2.92 (t, J = 7.5 Hz, 2H); 13C-NMR (DMSO-d6), δ: 163.88, 150.14, 145.96, 139.36,
137.83, 130.48, 129.13, 128.78, 128.64, 128.38, 128.08, 128.00, 126.14, 118.59, 40.58, 35.23;
HR-MS: for C18H17N2O [M+H]+ calculated 277.1335 m/z, found 277.1384 m/z.
1
N-(2-Hydroxyphenyl)quinoline-2-carboxamide (12a) [45]. Yield 27%; Mp. 219–220 °C; H-NMR
(DMSO-d6), δ: 10.67 (bs, 1H), 10.44 (bs, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.29
(d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 7.3 Hz, 1H), 7.73 (t,
J = 7.2 Hz, 1H), 7.00 (m, 2H), 6.89 (m, 1H); 13C-NMR (DMSO-d6), δ: 161.26, 149.65, 146.77, 145.74,
138.59, 130.91, 129.29, 129.08, 128.46, 128.22, 126.20, 124.29, 119.37, 119.26, 118.42, 114.84;
HR-MS: for C16H13N2O2 [M+H]+ calculated 265.0977 m/z, found 265.0983 m/z.
N-(3-Hydroxyphenyl)quinoline-2-carboxamide (12b). Yield 52%; Mp. 154–155 °C; IR (Zn/Se ATR,
cm−1): 3,338w, 2,973w, 1,760m, 1,680m, 1,605w, 1,530s, 1,504s, 1,462w, 1,425m, 1,263m, 1,235m,
1,216m, 1,171w, 1,145s, 1,096m, 1,054w, 1,002w, 964w, 908m, 879w, 841m, 773s, 754s, 685m, 665m;
1H-NMR (DMSO-d6), δ: 10.98 (bs, 1H), 8.62 (d, J = 8.7 Hz, 1H), 8.20–8.36 (m, 3H), 8.06–8.18 (m,
1H), 7.87–7.97 (m, 2H), 7.71–7.83 (m, 2H), 7.54 (t, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.0 Hz, J = 1.8 Hz,
1H); 13C-NMR (DMSO-d6), δ: 163.05, 150.91, 149.86, 147.01, 145.90, 139.63, 138.29, 130.94,
129.99, 129.19, 128.49, 128.16, 121.35, 118.83, 117.99, 113.65; HR-MS: for C16H13N2O2 [M+H]+
calculated 265.0977 m/z, found 265.0985 m/z.
1
N-(4-Hydroxyphenyl)quinoline-2-carboxamide (12c) [46]. Yield 48%; Mp. 230–231 °C; H-NMR
(DMSO-d6), δ: 10.34 (bs, 1H), 8.28–8.48 (m, 3H), 8.21 (d, J = 8.5 Hz, 1H), 7.88–8.04 (m, 3H),
13
7.77–7.87 (m, 1H), 7.69 (m, 1H), 7.39 (d, J = 9.0 Hz, 2H); C-NMR (DMSO-d6), δ: 162.11, 149.40,

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147.23, 146.23, 137.94, 135.82, 130.84, 129.62, 129.45, 128.95, 127.60, 122.38, 120.66, 118.73;
HR-MS: for C16H13N2O2 [M+H]+ calculated 265.0977 m/z, found 265.0971 m/z.
N-(2-Methoxyphenyl)quinoline-2-carboxamide (13a) [47]. Yield 37%; Mp. 111–112 °C; IR (Zn/Se
ATR, cm−1): 3,382w, 1,676s, 1,596m, 1,532s, 1,485w, 1,454m, 1,426m, 1,334w, 1,288w, 1,253m,
1
1,138m, 1,129m, 1,093w, 1,020s, 951w, 908m, 873w, 840m, 820w, 770s, 732s; H-NMR (DMSO-d6),
δ: 10.68 (bs, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.15 (d,
J = 8.5 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.3 Hz, 1H), 7.67–7.75 (m, 1H), 7.11 (d,
J = 4.0 Hz, 2H), 7.01 (dt, J = 8.2 Hz, J = 4.2 Hz, 1H), 3.98 (s, 3H); 13C-NMR (DMSO-d6), δ: 161.25,
149.34, 148.51, 145.62, 138.55, 130.82, 129.30, 129.06, 128.44, 128.14, 126.87, 124.25, 120.68,
118.84, 118.27, 110.91, 56.05; HR-MS: for C17H15N2O2 [M+H]+ calculated 279.1134 m/z, found
279.1148 m/z.
N-(3-Methoxyphenyl)quinoline-2-carboxamide (13b). Yield 47%; Mp. 117–118 °C; IR (Zn/Se ATR,
cm−1): 3,352w, 1,687m, 1,589m, 1,524m, 1,503m, 1,456m, 1,425 m, 1,334w, 1,284m, 1,203 m, 1,157m,
1
1,128m, 1,049s, 906w, 876m, 854 m, 823 w, 798w, 762s, 740s, 685m; H-NMR (DMSO-d6), δ: 10.73
(bs, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.19–8.32 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H), 7.82–7.96 (m, 1H),
7.65–7.79 (m, 2H), 7.59 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H), 7.29 (t, J = 8.2 Hz, 1H), 6.72 (dd, J = 8.3 Hz,
13
J = 2.01 Hz, 1H), 3.78 (s, 3H); C-NMR (DMSO-d6), δ: 162.70, 159.61, 149.99, 145.88, 139.53,
138.23, 130.67, 129.61, 129.37, 128.97, 128.37, 128.16, 118.75, 112.47, 109.68, 105.91, 55.09;
HR-MS: for C17H15N2O2 [M+H]+ calculated 279.1134 m/z, found 279.1129 m/z.
1
N-(4-Methoxyphenyl)quinoline-2-carboxamide (13c) [48]. Yield 53%; Mp. 130–131 °C; H-NMR
(DMSO-d6), δ: 10.65 (bs, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 7.8 Hz,
1H), 7.82–7.95 (m, 3H), 7.63–7.78 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 3.75 (s, 3H); 13C-NMR
(DMSO-d6), δ: 162.28, 155.80, 150.25, 145.90, 138.09, 131.47, 130.59, 129.32, 128.87, 128.22,
128.11, 121.85, 118.73, 113.87, 55.17; HR-MS: for C17H15N2O2 [M+H]+ calculated 279.1134 m/z,
found 279.1145 m/z.
N-(2-Methylphenyl)quinoline-2-carboxamide (14a). Yield 40%; Mp. 100–101 °C; IR (Zn/Se ATR,
cm−1): 3,334w, 1,686s, 1,587s, 1,528s, 1,498m, 1,454s, 1,427s, 1,422 m, 1,373w, 1,305m, 1,249w,
1,201w, 1,132m, 1,091w, 1,040w, 1,013w, 981w, 954m, 932w, 907m, 872m, 842s, 793w, 765s, 750s,
731s, 681s; 1H-NMR (DMSO-d6), δ: 10.45 (bs, 1H), 8.60 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H),
8.17 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.83–7.91 (m, 1H),
7.69–7.77 (m, 1H), 7.22–7.31 (m, 2H), 7.08–7.16 (m, 1H), 2.37 (s, 3H); 13C-NMR (DMSO-d6),
δ: 161.92, 149.67, 145.74, 138.35, 135.97, 130.72, 130.42, 130.01, 129.38, 129.01, 128.38, 128.11,
126.40, 124.96, 122.65, 118.49, 17.49; HR-MS: for C17H15N2O [M+H]+ calculated 263.1184 m/z,
found 263.1182 m/z.
N-(3-Methylphenyl)quinoline-2-carboxamide (14b). Yield 43%; Mp. 82–83 °C; IR (Zn/Se ATR,
cm−1): 3,355w, 1,685m, 1,592 m, 1,527s, 1,503s 1,457w, 1,424 m, 1,300w, 1,171w, 1,125m, 908w,
1
852m, 773s, 740w, 690s; H-NMR (DMSO-d6), δ: 10.66 (bs, 1H), 8.61 (d, J = 8.5 Hz, 1H), 8.25 (dd,
J = 7.9 Hz, J = 5.40 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.5 Hz, 1H), 7.67–7.84 (m, 3H),

Molecules 2012, 17
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13
7.27 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 2.32 (s, 3H); C-NMR (DMSO-d6), δ: 162.54,
150.03, 145.88, 138.22, 138.20, 138.03, 130.68, 129.35, 128.94, 128.65, 128.35, 128.15,
124.75, 120.72, 118.70, 117.35, 21.23; HR-MS: for C17H15N2O [M+H]+ calculated 263.1184 m/z,
found 263.1191 m/z.
N-(4-Methylphenyl)quinoline-2-carboxamide (14c). Yield 44%; Mp. 107–108 °C (Mp. 109.5–110 °C
1
[39]); H-NMR (DMSO-d6), δ: 10.67 (bs, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.18–8.30 (m, 2H), 8.08 (d,
J = 8.0 Hz, 1H), 7.79–7.94 (m, 3H), 7.72 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 2.27 (s, 3H);
13C-NMR (DMSO-d6), δ: 162.51, 150.17, 145.93, 138.21, 135.86, 133.09, 130.69, 129.39, 129.24, 128.94,
128.35, 128.18, 120.27, 118.77, 20.59; HR-MS: for C17H15N2O [M+H]+ calculated 263.1184 m/z,
found 263.1193 m/z.
N-(2-Fluorophenyl)quinoline-2-carboxamide (15a). Yield 30%; Mp. 116–117 °C; IR (Zn/Se ATR,
cm−1): 3,328w, 1,691m, 1,615m, 1,591w, 1,530s, 1,504m, 1,477w, 1,454m, 1,428m, 1,317w, 1,247w,
1
1,185w, 1,126m, 1,088w, 910w, 837m, 772s, 746s, 683m; H-NMR (DMSO-d6), δ: 10.48 (bs, 1H),
8.57 (d, J = 8.5 Hz, 1H), 8.17–8.25 (m, 2H), 8.13 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.85 (t,
13
J = 7.3 Hz, 1H), 7.65–7.76 (m, 1H), 7.28–7.40 (m, 1H), 7.13–7.27 (m, 2H); C-NMR (DMSO-d6),
1
δ: 162.00, 153.58 (d, JFC = 244 Hz), 148.95, 145.67, 138.39, 130.76, 129.24, 129.15 (d,
3
3
2JFC = 19.1 Hz), 128.45, 128.08, 125.70 (d, JFC = 11.0 Hz), 125.53 (d, JFC = 7.3 Hz), 124.63 (d,
4JFC = 3.7 Hz), 122.91, 118.37, 115.43 (d, JFC = 19.1 Hz); HR-MS: for C16H12FN2O [M+H]+
2
calculated 267.0934 m/z, found 267.0950 m/z.
N-(3-Fluorophenyl)quinoline-2-carboxamide (15b). Yield 38%; Mp. 126–127 °C; IR (Zn/Se ATR,
cm−1): 3,343w, 1,690s, 1,588m, 1,531s, 1,504m, 1,481s, 1,409s, 1,170m, 1,137m, 899m, 841s, 791m,
1
768s, 738m, 682s; H-NMR (DMSO-d6), δ: 10.91 (bs, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.16–8.31 (m,
2H), 8.08 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 11.8 Hz, 1H), 7.86–7.92 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H),
13
7.68–7.75 (m, 1H), 7.35–7.49 (m, 1H), 6.96 (td, J = 8.4 Hz, J = 2.0 Hz, 1H); C-NMR (DMSO-d6),
1
3
δ: 163.01, 162.15 (d, JFC = 241 Hz), 149.73, 145.86, 140.11 (d, JFC = 11.0 Hz), 138.18, 130.65,
130.31 (d, 3JFC = 9.5 Hz), 129.33, 128.97, 128.39, 128.12, 118.77, 116.15 (d, 4JFC = 2.9 Hz), 110.47 (d,
2JFC = 21.3 Hz), 107.09 (d, 2JFC = 26.4 Hz); HR-MS: for C16H12FN2O [M+H]+ calculated 267.0934 m/z,
found 267.0953 m/z.
1
N-(4-Fluorophenyl)quinoline-2-carboxamide (15c) [46,48]. Yield 33%; Mp. 115–116 °C; H-NMR
(DMSO-d6), δ: 10.83 (bs, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.17–8.29 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H),
7.94–8.02 (m, 2H), 7.87 (td, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.66–7.76 (m, 1H), 7.17–7.28 (m, 2H);
1
13C-NMR (DMSO-d6), δ: 162.76, 158.58 (d, JFC = 237 Hz), 150.03, 145.95, 138.18, 134.81 (d,
3
4JFC = 2.2 Hz), 130.67, 129.39, 128.98, 128.37, 128.17, 122.31 (d, JFC = 7.3 Hz), 118.83, 115.26 (d,
2JFC = 22.7 Hz); HR-MS: for C16H12FN2O [M+H]+ calculated 267.0934 m/z, found 267.0954 m/z.
1
N-(2-Chlorophenyl)quinoline-2-carboxamide (16a) [48]. Yield 39%; Mp. 130–131 °C; H-NMR
(DMSO-d6), δ: 10.77 (bs, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.5 Hz,
1H), 8.10 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.64–7.75 (m, 1H),
7.54 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.10–7.24 (m, 1H); 13C-NMR (DMSO-d6), δ: 161.54,

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148.70, 145.47, 138.50, 134.21, 130.75, 129.29, 129.20, 129.07, 128.46, 128.00, 127.88, 125.23, 123.38,
121.27, 118.15; HR-MS: for C16H12ClN2O [M+H]+ calculated 283.0638 m/z, found 283.0652 m/z.
1
N-(3-Chlorophenyl)quinoline-2-carboxamide (16b) [48]. Yield 46%; Mp. 127–128 °C; H-NMR
(DMSO-d6), δ: 10.90 (bs, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.18–8.31 (m, 2H), 8.15 (s, 1H), 8.07 (d,
J = 8.0 Hz, 1H), 7.82–7.97 (m, 2H), 7.66–7.78 (m, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.11–7.23 (m, 1H);
13C-NMR (DMSO-d6), δ: 163.02, 149.67, 145.87, 139.85, 138.20, 133.12, 130.68, 130.36, 129.34,
128.98, 128.43, 128.14, 123.70, 119.82, 118.77; HR-MS: for C16H12ClN2O [M+H]+ calculated
283.0638 m/z, found 283.0648 m/z.
N-(4-Chlorophenyl)quinoline-2-carboxamide (16c). Yield 34%; Mp. 134–135 °C (Mp. 135–135.5 °C [39]);
1H-NMR (DMSO-d6), δ: 10.88 (bs, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.17–8.30 (m, 2H), 8.08 (d,
J = 8.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.84–7.93 (m, 1H), 7.68–7.77 (m, 1H), 7.43 (d, J = 8.8 Hz,
2H); 13C-NMR (DMSO-d6), δ: 162.87, 149.85, 145.88, 138.16, 137.34, 130.65, 129.34, 128.95,
128.62, 128.37, 128.14, 127.69, 121.92, 118.78; HR-MS: for C16H12ClN2O [M+H]+ calculated
283.0638 m/z, found 283.0631 m/z.
N-(2-Bromophenyl)quinoline-2-carboxamide (17a). Yield 26%; Mp. 134–135 °C; IR (Zn/Se ATR,
cm−1): 3,277w, 1,689s, 1,588m, 1,579m, 1,543m, 1,530s, 1,496m, 1,440m, 1,427m, 1,302w, 1,132w,
1,204m, 908w, 842m, 768s, 736m, 698m; 1H-NMR (DMSO-d6), δ: 10.82 (bs, 1H), 8.60 (d, J = 8.5 Hz,
1H), 8.44 (d, J = 8.3 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.3 Hz,
1H), 7.87 (t, J = 7.5 Hz, 1H), 7.64–7.77 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H);
13C-NMR (DMSO-d6), δ: 161.61, 148.71, 145.50, 138.60, 135.46, 132.58, 130.83, 129.26, 129.13,
128.55, 128.53, 128.08, 125.74, 121.39, 118.19, 114.08; HR-MS: for C16H12BrN2O [M+H]+ calculated
327.0133 m/z, found 327.0138 m/z.
N-(3-Bromophenyl)quinoline-2-carboxamide (17b). Yield 35%; Mp. 139–140 °C; IR (Zn/Se ATR,
cm−1): 3,318w, 1,687m, 1,581m, 1,519m, 1,478w, 1,408m, 1,296w, 1,124m, 1,067w, 912w, 847m, 764s,
1
685m; H-NMR (DMSO-d6), δ: 10.89 (bs, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.19–8.32 (m, 3H), 8.09 (d,
J = 8.0 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.87–7.93 (m, 1H), 7.68–7.78 (m, 1H), 7.27–7.40 (m, 2H);
13C-NMR (DMSO-d6), δ: 163.02, 149.67, 145.86, 139.98, 138.21, 130.69, 130.67, 129.32, 128.97,
128.44, 128.14, 126.59, 122.66, 121.55, 119.14, 118.77; HR-MS: for C16H12BrN2O [M+H]+ calculated
327.0133 m/z, found 327.0143 m/z.
N-(4-Bromophenyl)quinoline-2-carboxamide (17c). Yield 57%; Mp. 157–158 °C; IR (Zn/Se ATR,
cm−1): 3,355w, 1,693s, 1,581m, 1,522s, 1,496s, 1,423w, 1,389m, 1,305w, 1,120m, 1,095w, 1,068m,
1
998w, 907w, 839s, 807s, 769s, 693w; H-NMR (DMSO-d6), δ: 10.84 (bs, 1H), 8.58 (d, J = 8.5 Hz,
1H), 8.18–8.30 (m, 2H), 8.07 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.86–7.92 (m, 1H),
7.67–7.78 (m, 1H), 7.56 (d, J = 8.8 Hz, 2H); 13C-NMR (DMSO-d6), δ: 162.86, 149.82, 145.87, 138.16,
137.74, 131.53, 130.64, 129.33, 128.94, 128.37, 128.12, 122.28, 118.77, 115.80; HR-MS: for
C16H12BrN2O [M+H]+ calculated 327.0133 m/z, found 327.0129 m/z.

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N-(2-Trifluoromethylphenyl)quinoline-2-carboxamide (18a). Yield 32%; Mp. 120–121 °C; IR (Zn/Se
ATR, cm−1): 3,316w, 1,698s, 1,590s, 1,537s, 1,498w, 1,452m, 1,423m, 1,320m, 1,288m, 1,244w,
1,202w, 1,165m, 1,124m, 1,094m, 1,054m, 1,026m, 953w, 906w, 871w, 836m, 792w, 763s, 676m;
1H-NMR (DMSO-d6), δ: 10.78 (bs, 1H), 8.61 (d, J = 8.3 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.23 (d,
J = 8.3 Hz, 1H), 8.07 (t, J = 8.3 Hz, 2H), 7.87 (t, J = 7.5 Hz, 1H), 7.64–7.81 (m, 3H), 7.38 (t,
13
J = 7.7 Hz, 1H); C-NMR (DMSO-d6), δ: 162.05, 148.48, 145.53, 138.74, 135.14, 133.57, 131.01,
129.48 (q, 2JFC = 37 Hz), 129.21, 129.17, 128.68, 128.16, 126.41 (q, 3JFC = 5.1 Hz), 125.05, 124.10 (q,
3
1JFC = 274 Hz), 123.89 (q, JFC = 5.9 Hz), 118.31; HR-MS: for C17H12F3N2O [M+H]+ calculated
317.0896 m/z, found 317.0891 m/z.
N-(3-Trifluoromethylphenyl)quinoline-2-carboxamide (18b). Yield 31%; Mp. 121–122 °C; IR (Zn/Se
ATR, cm−1): 3,339w, 1,692s, 1,614w, 1,536m, 1,490m, 1,424w, 1,330s, 1,223w, 1,166m, 1,109s,
1,091s, 1,065m, 952w, 933w, 874s, 844m, 808s, 771s, 744w, 698s; 1H-NMR (DMSO-d6), δ: 11.08 (bs,
1H), 8.59 (d, J = 8.5 Hz, 1H), 8.46 (s, 1H), 8.17–8.31 (m, 3H), 8.08 (d, J = 8.0 Hz, 1H), 7.89 (t,
13
J = 7.4 Hz, 1H), 7.68–7.78 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H); C-NMR
(DMSO-d6), δ: 163.26, 149.64, 145.90, 139.23, 138.21, 130.69, 129.86, 129.35 (q, 2JFC = 32 Hz), 129.34,
1
3
129.03, 128.45, 128.16, 124.20 (q, JFC = 273 Hz), 123.91, 120.24 (q, JFC = 3.7 Hz), 118.78, 116.61
(q, 3JFC = 3.7 Hz); HR-MS: for C17H12F3N2O [M+H]+ calculated 317.0896 m/z, found 317.0892 m/z.
N-(4-Trifluoromethylphenyl)quinoline-2-carboxamide (18c) [41,44]. Yield 43%; Mp. 147–148 °C;
1H-NMR (DMSO-d6), δ: 11.02 (bs, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.23 (d,
J = 8.3 Hz, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.86–7.93 (m, 1H), 7.69–7.77 (m,
3H); 13C-NMR (DMSO-d6), δ: 163.27, 149.63, 145.88, 141.95, 138.23, 130.69, 129.38, 129.03,
128.48, 128.14, 125.96 (q, 3JFC = 3.7 Hz), 124.39 (q, 1JFC = 271 Hz), 124.00 (q, 2JFC = 32 Hz), 120.29,
118.81; HR-MS: for C17H12F3N2O [M+H]+ calculated 317.0896 m/z, found 317.0890 m/z.
N-(2-Nitrophenyl)quinoline-2-carboxamide (19a). Yield 29%; Mp. 181–182 °C (Mp. 179.5–180 °C [39]);
1H-NMR (DMSO-d6), δ: 12.55 (bs, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.17–8.28
(m, 2H), 8.09 (dd, J = 13.9, 8.4 Hz, 2H), 7.86–7.95 (m, 1H), 7.78–7.85 (m, 1H), 7.70–7.77 (m, 1H),
13
7.34 (t, J = 7.8 Hz, 1H); C-NMR (DMSO-d6), δ: 162.61, 148.50, 145.57, 138.55, 137.44, 135.73,
133.47, 130.94, 129.20, 129.16, 128.70, 128.09, 125.80, 123.97, 121.77, 118.38; HR-MS: for
C16H12N3O3 [M+H]+ calculated 294.0879 m/z, found 294.0888 m/z.
N-(3-Nitrophenyl)quinoline-2-carboxamide (19b). Yield 30%; Mp. 189–190 °C; IR (Zn/Se ATR,
cm−1): 3,305w, 1,687m, 1,620w, 1,591w, 1,529m, 1,496w, 1,427m, 1,344m, 1,202w, 1,128m, 1,068w,
1
939w, 291m, 837m, 798m, 773s, 733s, 675s; H-NMR (DMSO-d6), δ: 11.14 (bs, 1H), 8.95 (t,
J = 1.9 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.34 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H), 8.16–8.28 (m, 2H),
13
8.06 (d, J = 8.0 Hz, 1H), 7.83–7.99 (m, 2H), 7.69–7.77 (m, 1H), 7.64 (t, J = 8.2 Hz, 1H); C-NMR
(DMSO-d6), δ: 163.35, 149.40, 147.88, 145.85, 139.56, 138.16, 130.64, 129.94, 129.30, 128.99, 128.44,
128.10, 126.34, 118.74, 118.34, 114.54; HR-MS: for C16H12N3O3 [M+H]+ calculated 294.0879 m/z,
found 294.0871 m/z.

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1
N-(4-Nitrophenyl)quinoline-2-carboxamide (19c) [48,49]. Yield 29%; Mp. 227–228 °C; H-NMR
(DMSO-d6), δ: 11.29 (bs, 1H), 8.64 (d, J = 8.5 Hz, 1H), 8.18–8.35 (m, 6H), 8.12 (d, J = 8.0 Hz, 1H),
7.88–7.99 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H); 13C-NMR (DMSO-d6), δ: 163.61, 149.43, 145.88, 144.58,
142.77, 138.38, 130.83, 129.40, 129.11, 128.68, 128.21, 124.81, 120.17, 118.92; HR-MS: for
C16H12N3O3 [M+H]+ calculated 294.0879 m/z, found 294.0870 m/z.
3.2.2. General Procedure for Synthesis of Carboxamide Derivatives 20–38c
2-Naphthoic acid (1 g, 5.8 mmol) was suspended in dry toluene (40 mL) and SOCl2 (0.6 mL,
8 mmol, 1.4 eq.) was added dropwise. The mixture was refluxed for 2 h and then evaporated to
dryness. The crystalline residue was washed with dry toluene and used directly in the next step. Yield:
99%; Mp. 46–47 °C (Mp. 43 °C [50]). Into the solution of 2-naphtoyl chloride (1.1 g, 5.8 mmol) in dry
CH2Cl2 (30 mL), triethylamine (1.2 mL, 0.88 g, 8.66 mmol, 1.5 eq.) and corresponding substituted amine
(5.8 mmol) were added dropwise. The mixture was stirred at room temperature for 20 h after which the
solvent was removed under reduced pressure. The solid residue was washed with 10% HCl and the
crude product was recrystallized from EtOH, cyclohexan, CHCl3 or acetone. The studied compounds
20–38c are presented in Table 2.
N-Isopropyl-2-naphthamide (20). Yield 18%; Mp. 174–176 °C (Mp. 170 °C [51]); IR (Zn/Se ATR,
cm−1): 3,246m, 3,054w, 2,969w, 2,935w, 1,632m, 1,618s, 1,543s 1,499w, 1,352w, 1,327w, 1,294m,
1,201w, 1,168m, 1,136w, 1,106w, 953w, 911m, 835m, 781m 766w, 736m, 690w; 1H-NMR (DMSO-d6),
δ: 8.37–8.51 (m, 2H), 7.88–8.09 (m, 4H), 7.47–7.67 (m, 2H), 4.18 (dsxt, J = 13.8 Hz, J = 6.7 Hz, 1H),
13
1.21 (d, J = 6.5 Hz, 6H); C-NMR (DMSO-d6), δ: 165.42, 134.05, 132.23, 132.16, 128.79, 127.72,
127.60, 127.44, 127.33, 126.66, 124.38, 41.14, 22.41; HR-MS: for C14H16NO [M+H]+ calculated
214.1226 m/z, found 214.1187 m/z.
N-Dodecyl-2-naphthamide (21). Yield 15%; Mp. 102–103 °C; IR (Zn/Se ATR, cm−1): 3,259m, 2,915s,
2,848s, 1,643m, 1,619s, 1,552s, 1,501w, 1,467w, 1,432w, 1,317m, 1,204w, 1,146w, 954w, 912w, 871w,
1
839w, 779w, 734w; H-NMR (DMSO-d6), δ: 8.61 (t, J = 5.8 Hz, 1H), 8.37–8.52 (m, 1H), 7.88–8.10
(m, 4H), 7.46–7.69 (m, 2H), 3.26–3.34 (m, 2H), 1.55 (quin, J = 7.2 Hz, 2H), 1.13–1.37 (m, 18H),
0.78–0.87 (m, 3H); 13C-NMR (DMSO-d6), δ: 166.06, 134.06, 132.17, 132.08, 128.78, 127.76, 127.59,
127.43, 127.28, 126.63, 124.20, 39.34, 31.32, 29.17, 29.16, 29.09, 29.06, 29.05, 28.84, 28.75, 26.55,
22.11, 13.95; HR-MS: for C23H34NO [M+H]+ calculated 340.2635 m/z, found 340.2655 m/z.
1-(2-Naphthoyl)pyrrolidine (22). Yield 12%; Mp. 76–77 °C (Mp. 75.5–76.5 °C [52]); IR (Zn/Se ATR,
1
cm−1): 3,050m, 2,963s, 2,863s, 1,629m, 1,608s, 1,469m, 1,434w, 1,417m, 1,353w, 1,337w; H-NMR
(DMSO-d6), δ: 8.10 (s, 1H), 7.97–8.03 (m, 1H), 7.91–7.97 (m, 2H), 7.51–7.64 (m, 3H), 3.51 (t,
13
J = 6.9 Hz, 2H), 3.37–3.45 (m, 2H), 1.82–1.92 (m, 2H), 1.69–1.82 (m, 2H); C-NMR (DMSO-d6),
δ: 168.18, 134.50, 133.23, 132.15, 128.47, 127.77, 127.60, 127.10, 126.62, 126.59, 124.61, 48.97,
46.01, 25.99, 23.97; HR-MS: for C15H16NO [M+H]+ calculated 226.1226 m/z, found 226.1200 m/z.
1-(2-Naphthoyl)piperidine (23) [53]. Yield 40%; Mp. 97–98 °C; IR (Zn/Se ATR, cm−1): 3,050w,
2,933m, 2,852m, 1,633w, 1,612s, 1,476m, 1,432m, 1,347w, 1,278m, 1,269m, 1,229w, 1,199w, 1,126w,

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1
1,100w, 1,007w, 954w, 906w, 833w, 807w, 758m; H-NMR (DMSO-d6), δ: 7.86–8.08 (m, 4H),
13
7.39–7.67 (m, 4H), 3.09–3.85 (m, 4H), 1.26–1.77 (m, 6H); C-NMR (DMSO-d6), δ: 168.84, 133.91,
132.96, 132.31, 128.27, 127.98, 127.65, 126.93, 126.66, 125.96, 124.29, 48.95, 43.22, 26.51, 26.01,
24.05; HR-MS: for C16H18NO [M+H]+ calculated 240.1383 m/z, found 240.1349 m/z.
N-Cyclopentyl-2-naphthamide (24). Yield 21%; Mp. 190–191 °C; IR (Zn/Se ATR, cm−1): 3,245s,
1
2,954m, 2,867w, 1,618m, 1,545m; H-NMR (DMSO-d6), δ: 8.37–8.56 (m, 2H), 7.89–8.11 (m, 4H),
13
7.48–7.67 (m, 2H), 4.31 (sxt, J = 7.0 Hz, 1H), 1.42–2.05 (m, 8H); C-NMR (DMSO-d6), δ: 166.00,
134.04, 132.20, 132.15, 128.78, 127.68, 127.60, 127.41, 127.38, 126.62, 124.45, 51.08, 32.20, 23.70;
HR-MS: for C16H18NO [M+H]+ calculated 240.1383 m/z, found 240.1372 m/z.
N-Cyclohexyl-2-naphthamide (25). Yield 45%; Mp. 184–185 °C (Mp. 183–184 °C [52]); IR (Zn/Se
ATR, cm−1): 3,316m, 3,051w, 2,933s, 2,917m, 2,850m, 1,635m, 1,622s, 1,601m, 1,531s, 1,446w,
1,318m, 1,288m, 1,231m, 1,202w, 1,151w, 1,081m, 890m, 859w, 819m, 779m, 758m, 728w, 667w;
1H-NMR (DMSO-d6), δ: 8.30–8.54 (m, 2H), 7.85–8.12 (m, 4H), 7.46–7.71 (m, 2H), 3.70–3.97 (m,
1H), 1.87 (d, J = 9.8 Hz, 2H), 1.74 (dd, J = 9.8 Hz, J = 2.5 Hz, 2H), 1.61 (d, J = 12.6 Hz, 1H),
13
1.23–1.43 (m, 4H), 1.04–1.21 (m, 1H); C-NMR (DMSO-d6), δ: 165.42, 134.04, 132.26, 132.15,
128.78, 127.68, 127.59, 127.41, 127.34, 126.63, 124.42, 48.49, 32.50, 25.31, 25.00; HR-MS: for
C17H20NO [M+H]+ calculated 254.1539 m/z, found 254.1493 m/z.
N-Cycloheptyl-2-naphthamide (26). Yield 18%; Mp. 157–158 °C; IR (Zn/Se ATR, cm−1): 3,318m,
2,918m, 2,655m, 1,635m, 1,623s, 1,600w, 1,529s, 1,504m, 1,446w, 1,314m, 1,234w, 1,201w, 1,186w,
1
1,053w, 907w, 819w, 777w, 758w, 729w, 679w; H-NMR (DMSO-d6), δ: 8.34–8.56 (m, 2H),
7.87–8.12 (m, 4H), 7.45–7.71 (m, 2H), 4.04 (qt, J = 8.8 Hz, J = 4.6 Hz, 1H), 1.81–2.03 (m, 2H),
1.29–1.77 (m, 10H); 13C-NMR (DMSO-d6), δ: 165.20, 134.05, 132.35, 132.17, 128.78, 127.69, 127.61,
127.41, 127.35, 126.63, 124.47, 50.59, 34.42, 27.89, 24.00; HR-MS: for C18H22NO [M+H]+ calculated
268.1696 m/z, found 268.1621 m/z.
N-Cyclooctyl-2-naphthamide (27). Yield 17%; Mp. 145–146 °C; IR (Zn/Se ATR, cm−1): 3,252s,
2,921s, 2,849m, 1,634s, 1,623s, 1,548s, 1,446w, 1,348w, 1,326m, 1,279w, 1,243w, 1,199w, 1,066m,
897w, 864w, 825w, 774m, 762w, 737m, 712m; 1H-NMR (DMSO-d6), δ: 8.30–8.55 (m, 2H), 7.87–8.10
13
(m, 4H), 7.46–7.69 (m, 2H), 4.09 (qt, J = 8.3 Hz, J = 4.2 Hz, 1H), 1.37–1.92 (m, 14H); C-NMR
(DMSO-d6), δ: 165.18, 134.03, 132.37, 132.15, 128.76, 127.66, 127.59, 127.38, 127.32, 126.60,
124.47, 49.39, 31.72, 26.86, 25.14, 23.60; HR-MS: for C19H24NO [M+H]+ calculated 282.1852 m/z,
found 282.1873 m/z.
N-Phenyl-2-naphthamide (28). Yield 96%; Mp. 175–176 °C (170 °C [50], Mp. 160 °C [54]); IR (Zn/Se
ATR, cm−1): 3,360m, 3,256w, 3,053w, 2,989w, 1,640s, 1,595s, 1,519s, 1,489s, 1,431s, 1,313m, 1,245w,
1
1,131w, 1,076w, 956w, 912m, 870w, 824w, 777w, 749s, 731m, 689m; H-NMR (DMSO-d6) [55,56],
δ: 10.48 (bs, 1H), 8.61 (s, 1H), 7.96–8.17 (m, 4H), 7.88 (d, J = 8.0 Hz, 2H), 7.56–7.71 (m, 2H), 7.39 (t,
J = 7.5 Hz, 2H), 7.05–7.19 (m, 1H); 13C-NMR (DMSO-d6), δ: 165.66, 139.31, 134.30, 132.35, 132.12,
128.98, 128.69, 128.04, 128.03, 127.83, 127.71, 126.87, 124.53, 123.72, 120.42; HR-MS: for
C17H14NO [M+H]+ calculated 248.1070 m/z, found 248.1095 m/z.

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N-Benzyl-2-naphthamide (29). Yield 42%; Mp. 138–139 °C (Mp. 140–143 °C [57]); IR (Zn/Se ATR,
cm−1): 3,287s, 3,054w, 3,027w, 2,920w, 1,635s, 1,622s, 1,600w, 1,543s, 1,504m, 1,495m, 1,449w,
1,414m, 1,359w, 1,316m, 1,300m, 1,263m, 1,206w, 1,146w, 1,119w, 1,047w, 996w, 910m, 869m,
1
835m, 777m, 737w, 719m, 693m; H-NMR (DMSO-d6), δ: 9.25 (t, J = 6.02 Hz, 1H), 8.53 (s, 1H),
7.91–8.11 (m, 4H), 7.53–7.70 (m, 2H), 7.29–7.46 (m, 4H), 7.21–7.28 (m, 1H), 4.56 (d, J = 6.02 Hz,
2H); 13C-NMR (DMSO-d6), δ: 166.29, 139.70, 134.17, 132.18, 131.72, 128.87, 128.32, 127.92,
127.63, 127.61, 127.55, 127.30, 126.77, 126.74, 124.22, 42.77; HR-MS: for C18H16NO [M+H]+ calculated
262.1226 m/z, found 262.1257 m/z.
N-(2-Phenylethyl)-2-naphthamide (30). Yield 26%; Mp. 133–134 °C (Mp. 133–134 °C [52]); IR
(Zn/Se ATR, cm−1): 3,325s, 3,054w, 3,027w, 2,933w, 2,900w, 1,639s, 1,626m, 1,600m, 1,541s,
1
1,452m, 1,302w, 1,211w, 1,074w, 829w, 779w, 756w, 692w; H-NMR (DMSO-d6), δ: 8.78 (t,
J = 5.5 Hz, 1H), 8.45 (s, 1H), 7.86–8.11 (m, 4H), 7.48–7.71 (m, 2H), 7.12–7.41 (m, 5H), 3.49–3.66 (m,
2H), 2.91 (t, J = 7.5 Hz, 2H); 13C-NMR (DMSO-d6), δ: 166.23, 139.58, 134.11, 132.17, 131.99,
128.84, 128.71, 128.38, 127.87, 127.63, 127.54, 127.37, 126.73, 126.13, 124.17, 41.06, 35.19;
HR-MS: for C19H18NO [M+H]+ calculated 276.1383 m/z, found 276.1353 m/z.
N-(3-Hydroxyphenyl)-2-naphthamide (31b). Yield 69%; Mp. 194 °C; IR (Zn/Se ATR, cm−1): 3,349s,
1,712s, 1,663s, 1,603s, 1,530s, 1,432s, 1,277s, 1,220s, 1,192s, 1,144s, 1,081s, 970s, 913s, 861s, 820s,
1
772s, 760s, 679s; H-NMR (DMSO-d6), δ: 10.32 (s, 1H), 8.57 (s, 1H), 8.11–7.99 (m, 5H), 7.69–7.60
(m, 2H), 7.43 (t, J = 1.8 Hz, 1H), 7.25–7.10 (m, 2H), 6.54 (dt, J = 7.7 Hz, J = 2.2 Hz, 1H); 13C-NMR
(DMSO-d6), δ: 165.36, 157.44, 140.13, 134.10, 132.34, 131.97, 129.04, 128.76, 127.75, 127.73,
127.58, 127.50, 126.62, 124.35, 111.09, 110.74, 107.51; HR-MS: for C17H14NO2 [M+H]+ calculated
264.1019 m/z, found 264.1012 m/z.
N-(4-Hydroxyphenyl)-2-naphthamide (31c). Yield 66%; Mp. 250–255 °C; IR (Zn/Se ATR, cm−1):
3,376s, 3,055w, 1,731s, 1,660s, 1,520s, 1,311s, 1,267s, 1,221s, 1,202s, 1,081s, 953s, 802s, 775s, 760s,
1
754s; H-NMR (DMSO-d6), δ: 10.58 (s, 1H), 8.61 (s, 1H), 8.14–7.99 (m, 5H), 7.70–7.61 (m, 2H),
13
7.40–7.34 (m, 2H), 6.79–6.74 (m, 2H); C-NMR (DMSO-d6), δ: 165.53, 153.65, 146.38, 134.21,
132.04, 131.36, 128.84, 127.93, 127.90, 127.66, 127.57, 124.32, 121.91, 121.31, 114.91; HR-MS: for
C17H14NO2 [M+H]+ calculated 264.1019 m/z, found 264.1010 m/z.
N-(2-Methoxyphenyl)-2-naphthamide (32a). Yield 46%; Mp. 82 °C; IR (Zn/Se ATR, cm−1): 3,274s,
3,060w, 2,997w, 2,973w, 1,647s, 1,598m, 1,535s, 1,493s, 1,460s, 1,433s, 1,336s, 1,259s, 1,026m, 749s;
1H-NMR (DMSO-d6), δ: 9.62 (s, 1H), 8.62 (s, 1H), 8.10–8.08 (m, 1H), 8.04 (d, J = 1.0 Hz, 2H), 8.01
(dd, J = 8.2 Hz, J = 1.1 Hz, 1H), 7.85 (dd, J = 7.9 Hz, J = 1.3 Hz, 1H), 7.66–7.60 (m, 2H), 7.22–7.18
(m, 1H), 7.12–7.10 (m, 1H), 7.00 (td, J = 7.7 Hz, J = 1.2 Hz, 1H), 3.86 (s, 3H); 13C-NMR (DMSO-d6),
δ: 165.08, 151.52, 134.30, 132.16, 131.84, 129.02, 128.12, 127.92, 127.84, 127.66, 126.89, 126.83,
125.76, 124.36, 124.24, 120.24, 111.41, 55.73; HR-MS: for C18H16NO2 [M+H]+ calculated 278.1176 m/z,
found 278.1179 m/z.
N-(3-Methoxyphenyl)-2-naphthamide (32b). Yield 47%; Mp. 142 °C; IR (Zn/Se ATR, cm−1): 3,243s,
1
3,005w, 1,640s, 1,591s, 1,530s, 1,451s, 1,429s, 1,301s, 1,282s, 1,158s, 1,049s, 771s; H-NMR

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(DMSO-d6), δ: 10.43 (s, 1H), 8.59 (s, 1H), 8.11–8.07 (m, 1H), 8.05 (s, 1H), 8.04 (d, J = 1.5 Hz, 1H),
8.02–8.00 (m, 1H), 7.66–7.60 (m, 2H), 7.55 (t, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H),
13
7.28 (t, J = 8.2 Hz, 1H), 6.71 (dd, J = 8.2 Hz, J = 1.8 Hz, 1H); 3.78 (s, 3H); C-NMR (DMSO-d6),
δ: 165.44, 159.38, 140.30, 134.13, 132.16, 131.95, 129.20, 128.75, 127.81, 127.75, 127.61, 127.49,
126.64, 124.26, 112.51, 109.10, 106.06, 54.90; HR-MS: for C18H16NO2 [M+H]+ calculated 278.1176 m/z,
found 278.1175 m/z.
N-(4-Methoxyphenyl)-2-naphthamide (32c). Yield 65%; Mp. 182 °C; IR (Zn/Se ATR, cm−1): 3,371s,
3,049w, 2,949w, 2,835w, 1,656s, 1,598s, 1,527s, 1,511s, 1,463s, 1,414s, 1,314s, 1,303s, 1,220s,
1
1,182s, 1,033s, 820s, 761s; H-NMR (DMSO-d6), δ: 10.34 (s, 1H), 8.58 (s, 1H), 8.08 (d, J = 8.8 Hz,
1H), 8.04 (s, 2H), 8.00 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.66–7.59 (m, 2H), 6.69 (d,
J = 8.3 Hz, 2H), 3.76 (s, 3H); 13C-NMR (DMSO-d6), δ: 165.15, 155.57, 134.21, 132.39, 132.33,
132.12, 128.92, 127.97, 127.81, 127.72, 127.67, 126.81, 124.46, 121.99, 113.78, 55.18; HR-MS: for
C18H16NO2 [M+H]+ calculated 278.1176 m/z, found 278.1173 m/z.
N-(2-Methylphenyl)-2-naphthamide (33a). Yield 33%; Mp. 146 °C; IR (Zn/Se ATR, cm−1): 3,239s,
1
3,057w, 1,639s, 1,584s, 1,531s, 1,454s, 1,315s, 1,134s, 916s, 777s, 749s, 731s, 692m; H-NMR
(DMSO-d6), δ: 10.09 (s, 1H), 8.63 (s, 1H), 8.10–8.08 (m, 1H), 8.08–8.06 (m, 2H), 8.04–8.01 (m, 1H),
7.67–7.60 (m, 2H), 7.41 (d, J = 6.7 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.28 (td, J = 7.5 Hz, J = 1.5 Hz,
1H), 7.19 (td, J = 7.3 Hz, J = 1.3 Hz, 1H); 2.29 (s, 3H); 13C-NMR (DMSO-d6), δ: 166.05,
137.16, 134.95, 134.41, 132.82, 132.55, 131.02, 129.62, 128.69, 128.68, 128.42, 128.33, 127.49,
127.27, 126.70, 126.67, 125.12, 18.66; HR-MS: for C18H16NO [M+H]+ calculated 262.1226 m/z,
found 262.1225 m/z.
N-(3-Methylphenyl)-2-naphthamide (33b). Yield 59%; Mp. 160 °C; IR (Zn/Se ATR, cm−1): 3,246s,
1
3,055w, 1,641s, 1,590s, 1,550s, 1,432s, 1,309s, 1,130s, 777s, 749s, 731s, 690s; H-NMR (DMSO-d6),
δ: 10.37 (s, 1H), 8.59 (s, 1H), 8.10–8.07 (m, 1H), 8.04–8.02 (m, 2H), 8.02–8.00 (m, 1H), 7.69 (s, 1H),
7.66–7.60 (m, 3H), 7.26 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 2.33 (s, 3H); 13C-NMR (DMSO-d6),
δ: 165.35, 139.02, 137.61, 134.12, 132.22, 131.97, 128.75, 128.28, 127.81, 127.72, 127.60, 127.49,
126.64, 124.29, 124.23, 120.84, 117.47, 21.03; HR-MS: for C18H16NO [M+H]+ calculated 262.1226 m/z,
found 262.1224 m/z.
N-(4-Methylphenyl)-2-naphthamide (33c). Yield 67%; Mp. 195 °C (Mp. 191 °C [50); IR (Zn/Se ATR,
cm−1): 3,254s, 3,056w, 2,917w, 1,640s, 1,602s, 1,538s, 1,513s, 1,404s, 1,329s, 1,132s, 914s, 811s,
1
754s, 733s, 707m; H-NMR (DMSO-d6) [56], δ: 10.38 (s, 1H), 8.59 (s, 1H), 8.10–8.06 (m, 1H), 8.04
(s, 2H), 8.02–8.00 (m, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.66–7.60 (m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 2.29
13
(s, 3H); C-NMR (DMSO-d6), δ: 165.22, 136.59, 134.10, 132.51, 132.27, 132.00, 128.85, 128.75,
127.79, 127.69, 127.57, 127.50, 126.64, 124.30, 120.34, 20.34; HR-MS: for C18H16NO [M+H]+
calculated 262.1226 m/z, found 262.1225 m/z.
N-(2-Fluorophenyl)-2-naphthamide (34a). Yield 59%; Mp. 122 °C; IR (Zn/Se ATR, cm−1): 3,316s,
1
3,054w, 3,023w, 1,648s, 1,541s, 1,489s, 1,456s, 1,321s, 1,257s, 1,192m, 829m, 750s; H-NMR
(DMSO-d6), δ: 10.33 (s, 1H), 8.64 (s, 1H), 8.11–8.08 (m, 1H), 8.06 (d, J = 1.0 Hz, 2H), 8.03–8.01 (m,

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1H), 7.70–7.60 (m, 3H), 7.36–7.23 (m, 3H); 13C-NMR (DMSO-d6), δ: 165.38, 155.64 (d,
J = 245.8 Hz), 134.27, 131.98, 131.21, 128.82, 128.13, 127.88, 127.73, 127.50, 126.72 (d, J = 8.8 Hz),
126.68, 126.68 (d, J = 7.6 Hz), 125.75 (d, J = 11.4 Hz), 124.24, 124.13 (d, J = 3.8 Hz), 115.65 (d,
J = 20.5 Hz); HR-MS: for C17H13NOF [M+H]+ calculated 266.0976 m/z, found 266.0974 m/z.
N-(3-Fluorophenyl)-2-naphthamide (34b). Yield 21%; Mp. 167 °C; IR (Zn/Se ATR, cm−1): 3,267s,
3,140w, 3,058w, 1,642s, 1,604s, 1,541s, 1,444s, 1,322s, 1,301s, 1,142m, 775m, 765m, 682m; 1H-NMR
(DMSO-d6), δ: 10.64 (s, 1H), 8.59 (s, 1H), 8.11-8.09 (m, 1H), 8.08–8.01 (m, 3H), 7.83 (dt, J = 11.8 Hz,
J = 2.5 Hz, 1H), 7.68–7.61 (m, 3H), 7.42 (dt, J = 8.2 Hz, J = 7.0 Hz, 1H), 6.95 (tdd, J = 8.5 Hz,
13
J = 2.5 Hz, J = 0.75 Hz, 1H); C-NMR (DMSO-d6), δ: 165.71, 161.98 (d, J = 239.7 Hz), 140.89 (d,
J = 11.4 Hz), 134.23, 131.93, 131.83, 130.06 (d, J = 9.9 Hz), 128.79, 127.93, 127.90, 127.75, 127.53,
126.73, 124.21, 115.90 (d, J = 3.1 Hz), 109.94 (d, J = 20.5 Hz), 106.90 (d, J = 25.8 Hz); HR-MS: for
C17H13NOF [M+H]+ calculated 266.0976 m/z, found 266.0972 m/z.
N-(4-Fluorophenyl)-2-naphthamide (34c). Yield 70%; Mp. 191 °C; IR (Zn/Se ATR, cm−1): 3,380s,
1
3,063w, 1,654s, 1,527s, 1,506s, 1,405s, 1,313m, 1,212s, 1,197s, 826s, 814s, 764s; H-NMR
(DMSO-d6) [56], δ: 10.51 (s, 1H), 8.58 (s, 1H), 8.10–8.08 (m, 1H), 8.07–8.00 (m, 3H), 7.88–7.84 (m,
2H), 7.66–7.60 (m, 2H), 7.25–7.20 (m, 2H); 13C-NMR (DMSO-d6), δ: 165.36, 158.22 (d,
J = 238.9 Hz), 135.46 (d, J = 2.3 Hz), 134.17, 132.03, 131.98, 128.75, 127.84, 127.78, 127.64, 127.50,
126.67, 124.24, 122.13 (d, J = 8.0 Hz), 115.01 (d, J = 22.0 Hz); HR-MS: for C17H13NOF [M+H]+
calculated 266.0976 m/z, found 266.0975 m/z.
N-(2-Chlorophenyl)-2-naphthamide (35a) [58]. Yield 45%; Mp. 116 °C; IR (Zn/Se ATR, cm−1):
1
3,281s, 3,061w, 1,653s, 1,583s, 1,523s, 1,439s, 1,305s, 1,053m, 777s, 759s, 746s; H-NMR
(DMSO-d6), δ: 10.26 (s, 1H), 8.65 (s, 1H), 8.11–8.09 (m, 1H), 8.09–8.05 (m, 2H), 8.04–8.00 (m, 1H),
7.68–7.61 (m, 3H), 7.59 (dd, J = 7.9 Hz, J = 1.3 Hz, 1H), 7.42 (td, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.32
13
(td, J = 7.8 Hz, J = 1.5 Hz, 1H); C-NMR (DMSO-d6), δ: 165.48, 135.16, 134.42, 132.11, 131.30,
129.61, 129.55, 129.02, 128.50, 128.25, 128.15, 127.96, 127.70, 127.52, 127.51, 126.92, 124.34;
HR-MS: for C17H13NOCl [M+H]+ calculated 282.0680 m/z, found 282.0679 m/z.
N-(3-Chlorophenyl)-2-naphthamide (35b). Yield 67%; Mp. 180 °C; IR (Zn/Se ATR, cm−1): 3,262s,
3,236s, 3,110w, 3,055w, 1,644s, 1,591s, 1,531s, 1,420s, 1,316s, 1,301s, 1,133m, 778s, 765s, 695m;
1H-NMR (DMSO-d6), δ: 10.61 (s, 1H), 8.59 (s, 1H), 8.11–8.09 (m, 1H), 8.08–8.01 (m, 4H), 7.78 (ddd,
J = 8.3 Hz, J = 1.8 Hz, J = 0.8 Hz, 1H), 7.68–7.61 (m, 2H), 7.41 (t, J = 8.2 Hz, 1H), 7.18 (ddd,
13
J = 8.0 Hz, J = 1.9 Hz, J = 0.8 Hz, 1H); C-NMR (DMSO-d6), δ: 165.69, 140.61, 134.24, 132.86,
131.93, 131.77, 130.14, 128.81, 127.95, 127.92, 127.78, 127.53, 126.75, 124.21, 123.21, 119.68,
118.55; HR-MS: for C17H13NOCl [M+H]+ calculated 282.0680 m/z, found 282.0681 m/z.
N-(4-Chlorophenyl)-2-naphthamide (35c). Yield 81%; Mp. 218 °C; IR (Zn/Se ATR, cm−1): 3,377s,
1
3,058w, 1,657s, 1,628s, 1,593s, 1,514s, 1,492s, 1,398s, 1,310s, 1,097m, 823s, 760s; H-NMR
(DMSO-d6) [56], δ: 10.58 (s, 1H), 8.59 (s, 1H), 8.10–8.08 (m, 1H), 8.08–8.01 (m, 3H), 7.91–7.87 (m,
2H), 7.67–7.60 (m, 2H), 7.46–7.42 (m, 2H); 13C-NMR (DMSO-d6), δ: 165.54, 138.10, 134.21, 131.95,

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131.92, 128.78, 128.38, 127.89, 127.88, 127.72, 127.52, 127.20, 126.72, 124.24, 121.78; HR-MS: for
C17H13NOCl [M+H]+ calculated 282.0680 m/z, found 282.0679 m/z.
N-(2-Bromophenyl)-2-naphthamide (36a) [58]. Yield 70%; Mp. 123 °C; IR (Zn/Se ATR, cm−1):
3,277s, 3,060w, 1,652s, 1,629m, 1,578m, 1,523s, 1,433s, 1,304s, 1,028m, 777m, 759m, 745s; 1H-NMR
(DMSO-d6), δ: 10.25 (s, 1H), 8.65 (s, 1H), 8.10-8.08 (m, 1H), 8.07 (s, 2H), 8.03-8.01 (m, 1H), 7.75 (dd,
J = 7.8 Hz, J = 0.8 Hz, 1H), 7.68–7.61 (m, 3H), 7.46 (td, J = 7.5 Hz, J = 1.0 Hz, 1H), 7.25 (td,
J = 7.7 Hz, J = 1.4 Hz, 1H); 13C-NMR (DMSO-d6), δ: 165.43, 136.70, 134.41, 132.73, 132.13, 131.41,
129.01, 128.93, 128.22, 128.15, 128.15, 127.95, 127.72, 126.94, 124.37, 124.34, 120.68; HR-MS: for
C17H13NOBr [M+H]+ calculated 326.0175 m/z, found 326.0175 m/z.
N-(3-Bromophenyl)-2-naphthamide (36b). Yield 69%; Mp. 193 °C; IR (Zn/Se ATR, cm−1): 3,261s,
3,233s, 3,106w, 3,056w, 1,644s, 1,590s, 1,526s, 1,415s, 1,313s, 1,300s, 1,133m, 778s, 765s, 686m;
1H-NMR (DMSO-d6) [56], δ: 10.59 (s, 1H), 8.59 (s, 1H), 8.18 (t, J = 1.9 Hz, 1H), 8.11–8.08 (m, 1H),
8.08–8.00 (m, 3H), 7.83 (dt, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.68–7.61 (m, 2H), 7.37–7.30 (m, 2H);
13C-NMR (DMSO-d6), δ: 165.63, 140.74, 134.23, 131.92, 131.72, 130.43, 128.78, 127.93, 127.90,
127.75, 127.52, 126.73, 126.08, 124.20, 122.51, 121.25, 118.92; HR-MS: for C17H13NOBr [M+H]+
calculated 326.0175 m/z, found 326.0174 m/z.
N-(4-Bromophenyl)-2-naphthamide (36c). Yield 55%; Mp. 231 °C; IR (Zn/Se ATR, cm−1): 3,375s,
3,283w, 3,056w, 1,658s, 1,591s, 1,516s, 1,489s, 1,395s, 1,310s, 1,073m, 1,009m, 820s, 760s; 1H-NMR
(DMSO-d6) [56], δ: 10.57 (s, 1H), 8.58 (s, 1H), 8.10–8.08 (m, 1H), 8.08–7.99 (m, 3H), 7.83 (d,
J = 8.5 Hz, 2H), 7.67–7.61 (m, 2H) 7.57 (d, J = 8.5 Hz, 2H); 13C-NMR (DMSO-d6), δ: 165.54, 138.52,
134.21, 131.93, 131.90, 131.30, 128.79, 127.90, 127.72, 127.52, 126.72, 124.24, 122.16, 122.15,
115.21; HR-MS: for C17H13NOBr [M+H]+ calculated 326.0175 m/z, found 326.0173 m/z.
N-(3-Trifluoromethylphenyl)-2-naphthamide (37b). Yield 82%; Mp. 150 °C; IR (Zn/Se ATR, cm−1):
3,261s, 3,100w, 3,062w, 1,648s, 1,602s, 1,552s, 1,445s, 1,434s, 1,324s, 1,309s, 1,165s, 1,107s, 1,069s,
1
778m, 697m; H-NMR (DMSO-d6), δ: 10.75 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 8.15–8.01 (m, 5H),
7.69–7.60 (m, 3H), 7.47 (d, J = 7.8 Hz, 1H); 13C-NMR (DMSO-d6), δ: 165.85, 139.95, 134.29, 131.93,
131.66, 129.72, 129.31 (q, J = 32.1 Hz), 128.83, 128.02, 127.97, 127.82, 127.55, 126.78, 124.21,
124.06 (q, J = 273.1 Hz), 123.68, 119.79 (q, J = 3.8 Hz), 116.31 (q, J = 3.8 Hz); HR-MS: for
C18H13NOF3 [M+H]+ calculated 316.0944 m/z, found 316.0942 m/z.
N-(4-Trifluoromethylphenyl)-2-naphthamide (37c). Yield 80%; Mp. 224 °C; IR (Zn/Se ATR, cm−1):
3,372s, 3,073w, 1,662s, 1,600s, 1,556s, 1,514s, 1,408s, 1,316s, 1,159s, 1,112s, 1,067s, 1,018m, 836s,
1
826s, 764m; H-NMR (DMSO-d6), δ: 10.78 (s, 1H), 8.62 (s, 1H), 8.12–8.01 (m, 6H), 7.76 (d,
13
J = 8.8 Hz, 2H), 7.69–7.61 (m, 2H); C-NMR (DMSO-d6), δ: 165.97, 142.80, 134.32, 131.93, 131.71,
128.87, 128.13, 127.97, 127.87, 127.58, 126.81, 125.80 (q, J = 3.8 Hz), 124.29, 124.29 (q, J = 270.9 Hz),
123.57 (q, J = 32.1 Hz), 120.07; HR-MS: for C18H13NOF3 [M+H]+ calculated 316.0944 m/z,
found 316.0942 m/z.

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N-(2-Nitrophenyl)-2-naphthamide (38a). Yield 66%; Mp. 136 °C (Mp. 138–139 °C [59]); IR (Zn/Se
ATR, cm−1): 3,383s, 3,124w, 3,054w, 1,678s, 1,582s, 1,493s, 1,448s, 1,427s, 1,335s, 1,284s, 1,273s,
1,195s, 759s, 738s; 1H-NMR (DMSO-d6), δ: 10.97 (s, 1H), 8.62 (s, 1H), 8.15–8.00 (m, 5H), 7.86–7.82
13
(m, 1H), 7.81–7.76 (m, 1H), 7.70–7.62 (m, 2H), 7.44 (t, J = 7.7 Hz, 1H); C-NMR (DMSO-d6),
δ: 165.32, 142.68, 134.45, 133.94, 131.98, 131.63, 130.83, 128.92, 128.28, 128.20, 128.04, 127.60,
126.91, 125.80, 125.43, 124.88, 123.92; HR-MS: for C17H13N2O3 [M+H]+ calculated 293.0921 m/z,
found 293.0919 m/z.
N-(3-Nitrophenyl)-2-naphthamide (38b). Yield 68%; Mp. 177 °C; IR (Zn/Se ATR, cm−1): 3,269s,
1
3,093w, 1,648s, 1,626s, 1,522s, 1,429s, 1,341s, 1,321s, 1,288s, 1,272s, 761s, 736s, 669s; H-NMR
(DMSO-d6) [56], δ: 10.88 (s, 1H), 8.85 (t, J = 2.1 Hz, 1H), 8.63 (s, 1H), 8.26 (ddd, J = 8.2 Hz, J = 2.0 Hz,
J = 0.9 Hz, 1H), 8.11–7.99 (m, 4H), 7.97 (ddd, J = 8.2 Hz, J = 2.0 Hz, J = 0.9 Hz, 1H), 7.69–7.61 (m,
3H); 13C-NMR (DMSO-d6), δ: 165.94, 147.88, 140.34, 134.35, 131.92, 131.42, 129.92, 128.85,
128.14, 128.02, 127.91, 127.58, 126.82, 126.06, 124.20, 117.96, 114.30; HR-MS: for C17H13N2O3
[M+H]+ calculated 293.0921 m/z, found 293.0917 m/z.
N-(4-Nitrophenyl)-2-naphthamide (38c). Yield 46%; Mp. 200 °C; IR (Zn/Se ATR, cm−1): 3,410s,
3,054w, 1,679s, 1,611s, 1,595s, 1,538s, 1,499s, 1,481s, 1,324s, 1,302s, 1,284s, 1,243s, 1,109s, 849s,
771s, 750s; 1H-NMR (DMSO-d6) [56], δ: 10.99 (s, 1H), 8.62 (s, 1H), 8.29 (dd, J = 9.3 Hz, J = 2.3 Hz,
2H), 8.13–8.01 (m, 6H), 7.69–7.61 (m, 2H); 13C-NMR (DMSO-d6), δ: 166.20, 145.45, 142.43, 134.41,
131.90, 131.43, 128.92, 128.37, 128.07, 128.02, 127.61, 126.88, 124.67, 124.27, 119.80; HR-MS: for
C17H13N2O3 [M+H]+ calculated 293.0921 m/z, found 293.0918 m/z.
3.3. Study of Inhibition Photosynthetic Electron Transport (PET) in Spinach Chloroplasts
Chloroplasts were prepared from spinach (Spinacia oleracea L.) according to Masarovicova and
Kralova [60]. The inhibition of photosynthetic electron transport (PET) in spinach chloroplasts was
determined spectrophotometrically (Genesys 6, Thermo Scientific, USA), using an artificial electron
acceptor 2,6-dichlorophenol-indophenol (DCIPP) according to Kralova et al. [61], and the rate of
photosynthetic electron transport was monitored as a photoreduction of DCPIP. The measurements
were carried out in phosphate buffer (0.02 mol/L, pH 7.2) containing sucrose (0.4 mol/L),
MgCl2 (0.005 mol/L) and NaCl (0.015 mol/L). The chlorophyll content was 30 mg/L in these
experiments and the samples were irradiated (~100 W/m2 with 10 cm distance) with a halogen lamp
(250 W) using a 4 cm water filter to prevent warming of the samples (suspension temperature 22 °C).
The studied compounds were dissolved in DMSO due to their limited water solubility. The applied
DMSO concentration (up to 4%) did not affect the photochemical activity in spinach chloroplasts. The
inhibitory efficiency of the studied compounds was expressed by IC50 values, i.e., by molar concentration
of the compounds causing 50% decrease in the oxygen evolution rate relative to the untreated control.
The comparable IC50 value for a selective herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea, DCMU
(Diurone®) was about 1.9 μmol/L. The results are summarized in Tables 1 and 2.

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3.4. In Vitro Antimycobacterial Evaluation
Clinical isolates of Mycobacterium tuberculosis CUH071 (Cork University Hospital TB lab, with
partial INH and PZA resistance), M. avium complex CIT19/06, M. avium paratuberculosis
ATCC19698, and M. kansasii CIT11/06 were grown in Middlebrook broth (MB), supplemented with
Oleic-Albumin-Dextrose-Catalase supplement (OADC, Becton Dickinson, UK). Identification of these
isolates was performed using biochemical and molecular protocols. At log phase growth, culture
(10 mL) was centrifuged at 15,000 rpm/20 min using a bench top centrifuge (Model CR 4-12, Jouan
Inc., UK). Following removal of the supernatant, the pellet was washed in fresh Middlebrook 7H9GC
broth and re-suspended in fresh supplemented MB (10 mL). The turbidity was adjusted to match
McFarland standard No. 1 (3 × 108 cfu) with MB broth. A further 1:20 dilution of the culture was then
performed in MB broth.
The antimicrobial susceptibility of all four mycobacterial species was investigated in a 96-well
plate format. In these experiments, sterile deionised water (300 µL) was added to all outer-perimeter
wells of the plates to minimize evaporation of the medium in the test wells during incubation. Each
evaluated compound (100 µL) was incubated with each of the mycobacterial species (100 µL).
Dilutions of each compound were prepared in duplicate. For all synthesized compounds, final
concentrations ranged from 1,000 µg/mL to 8 µg/mL. All compounds were prepared in DMSO and
subsequent dilutions were made in supplemented MB. The plates were sealed with parafilm and
incubated at 37 °C, for 5 days in the case of M. kansasii and M. avium complex, 7 days in the case of
M. tuberculosis and 11 days in the case of M. avium paratuberculosis. Following incubation, a 10%
addition of alamarBlue (AbD Serotec) was mixed into each well and readings at 570 nm and 600 nm
were taken, initially for background subtraction and subsequently after 24 h re-incubation. The
background subtraction is necessary for strongly coloured compounds, where the colour may interfere
with the interpretation of any colour change. For non-interfering compounds, a blue colour in the well
was interpreted as an absence of growth and a pink colour was scored as growth. The MIC was
initially defined as the lowest concentration which prevented a visual colour change from blue to pink.
Isoniazid (INH) and pyrazinamide (PZA) were used as the standards as it is a clinically used
antimycobacterial drug. The MIC for mycobacteria was defined as a 90% or greater (IC90) reduction of
growth in comparison with the control. The MIC/IC90 value is routinely and widely used in bacterial
assays and is a standard detection limit according to the Clinical and Laboratory Standards Institute
(CLSI, www.clsi.org). The results are summarized in Table 3.
3.5. In Vitro Cytotoxicity Assay
Human monocytic leukemia THP-1 cells were obtained from the European Collection of Cell
Cultures (ECACC). These cells were routinely cultured in RPMI medium supplemented with 10%
fetal bovine serum, 2% L-glutamine, 1% penicillin and streptomycin at 37 °C with 5% CO2. The tested
compounds were dissolved in DMSO and added in four increasing concentrations to the cell
suspension in the culture medium. Subsequently, the cells were incubated for 24 h at 37 °C with 5%
CO2. Cell toxicity was determined using a WST-1 assay kit (Roche Diagnostics, Mannheim, Germany)
according to the manufacturer’s instructions. For WST-1 assays, cells were seeded into 96-well plates
(5 × 104 cells·well−1 in 100 μL culture medium) in triplicate in serum-free RPMI 1640 medium, and

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measurements were taken 24 h after the treatment with tested compounds. The median lethal
dose values, LD50, were deduced through the production of a dose-response curve. All data were
evaluated using GraphPad Prism 5.00 software (GraphPad Software, San Diego, CA, USA,
http://www.graphpad.com). The results are summarized in Table 3.
4. Conclusions
A series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted
naphthalene-2-carboxamides were prepared and characterized. The prepared compounds were tested
for their ability to inhibit photosynthetic electron transport (PET) in spinach chloroplasts (Spinacia
oleracea L.) and for their antituberculosis/antimycobacterial activity. Two compounds, N-benzyl-2-
naphthamide (29) and N-(2-hydroxyphenyl)quinoline-2-carboxamide (12a) showed relatively high PET
inhibition. N-(2-Phenylethyl)quinoline-2-carboxamide (11), N-cycloheptylquinoline-2-carboxamide (7)
and N-cyclohexylquinoline-2-carboxamide (6) expressed high activity against Mycobacterium
tuberculosis. 1-(2-Naphthoyl)pyrrolidine (22) and 2-(pyrrolidin-1-ylcarbonyl)quinoline (3) showed
high activity against M. kansasii and M. avium paratuberculosis. All five compounds exhibited
activity comparable with or higher than the standards isoniazid or pyrazinamide. Lipophilicity was
fundamental for the biological activities of all compounds in both biological assays. It can be stated
that the dependence of PET-inhibiting activity on the lipophilicity decreases with increasing lipophilicity,
while antimycobacterial activity increases with lipophilicity increase. Highly effective compounds
against M. tuberculosis were detected, namely quinaldinamides, while naphtamides were more active
against the other mycobacterial species. Substituted N-quinaldinanilides and/or N-naphtanilides seem
to be less effective than other discussed N-nonaromatic amide derivatives. The most effective
antimycobacterial compounds 11, 7, 3 and 22 were tested for their in vitro cytotoxicity against THP-1
cells. According to the calculated selectivity index of compounds 11, 3 and 22 it can be concluded that
the discussed amides can be considered as promising agents for subsequent design of novel
antitubercular/ antimycobacterial agents.
Acknowledgements
This study was supported by the IGA VFU Brno 49/2011/FaF, the Slovak Grant Agency VEGA,
Grant No. 1/0612/11, by Sanofi-Aventis Pharma Slovakia and by the Irish Department of Agriculture
Fisheries and Food 08RDCIT601.
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