Synthesis of some novel 3,4,5-trisubstituted triazole derivatives bearing quinoline ring and evaluation of their antimicrobial activity

Article abstract of DOI:10.1080/10426507.2020.1756808

Some new 3,4,5-trisubstituted 1,2,4-triazole derivatives were synthesized and studied for their antimicrobial activity. The lead compounds were obtained starting from 8-hydroxyquinoline and ethyl 2-chloroacetate. The obtained ester compound (1) first reac

Full text of DOI:10.1080/10426507.2020.1756808

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis of some novel 3,4,5-trisubstituted
triazole derivatives bearing quinoline ring and
evaluation of their antimicrobial activity
Leyla Yurttaş, Aslıhan Kubilay, Asaf Evrim Evren, İpek Kısacık & Hülya Karaca
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1756808
Synthesis of some novel 3,4,5-trisubstituted triazole derivatives bearing
quinoline ring and evaluation of their antimicrobial activity
c
c
Leyla Yurttas¸a, Aslıhan Kubilaya, Asaf Evrim Evrena,b, Ipek Kısacık , and Hulya Karaca Genc¸er
_
€
b
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskis¸ehir, Turkey; Department of Pharmacy Services,
c
Vocational School of Health Services, Bilecik Seyh Edebali University, Eskis¸ehir, Turkey; Department of Pharmaceutical Microbiology, Faculty
of Pharmacy, Anadolu University, Eskis¸ehir, Turkey
ABSTRACT
ARTICLE HISTORY
Received 5 November 2019
Accepted 14 April 2020
Some new 3,4,5-trisubstituted 1,2,4-triazole derivatives were synthesized and studied for their anti-
microbial activity. The lead compounds were obtained starting from 8-hydroxyquinoline and ethyl
2-chloroacetate. The obtained ester compound (1) first reacted with hydrazine hydrate (2) then
with phenyl isothiocyanate (3). Ring closure by KOH led to 3-mercapto-1,2,4-triazole derivative (4).
Lastly, it reacted with 2-chloro-N-(substituted (benzo)/thiazole)acetamide derivatives to obtain the
KEYWORDS
Quinoline; triazole;
antimicrobial activity
1
final compounds (5a–j). The structural elucidation of the compounds was performed by H NMR
and 13C NMR spectroscopy and high resolution mass spectrometry techniques and elemental ana-
lysis. The synthesized compounds were investigated for their antimicrobial activities against seven
bacteria and four fungi. As a result of the activity studies, it was observed that compounds N-(6-
nitrobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide
(5a) and N-(6-fluorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-
yl]thio]acetamide (5d) were the most active molecules. Also, the antifungal activity of the com-
pounds was found to be higher than their antibacterial activity although lower than the standard
drug’s potential. Additionally, the physicochemical properties of the compounds were calculated
which were evaluated to be at a suitable range for oral administration.
GRAPHICAL ABSTRACT
CONTACT Leyla Yurttas¸
lyurttas@anadolu.edu.tr
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskis¸ehir,
26470, Turkey.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1756808.
ß 2020 Taylor & Francis Group, LLC

2
L. YURTTAŞ ET AL.
based on our previous work.[20] Initially, 8-hydroxyquinoline
and ethyl chloroacetate were refluxed with potassium carbon-
ate. After the reaction was complete, the solvent was evapo-
rated and the material was washed with water to acquire
intermediate ether compound. The obtained product, ethyl 2-
(quinolin-8-yloxy)acetate (1) was reacted with hydrazine
hydrate in ethanol. At the end of the reaction, the hydrazi-
nated compound was isolated by filtration. All intermediate
compounds were recrystallised from ethanol to gain pure
products. The acquired molecule, (quinolin-8-yloxy)acetohy-
drazide (2) was dissolved in ethanol and refluxed with phenyli-
sothiocyanate to synthesize N-phenyl-2-(2-(quinolin-8-
yloxy)acetyl)hydrazine-1-carbothioamide (3) and then in the
next step this compound was refluxed with 2 N potassium
hydroxide prepared in ethanol. The reaction was terminated
by controlling with TLC. The pH was set to 7 to allow the
material to settle in a cold environment. The resulting triazole
molecule (4) was treated with the appropriate 2-chloro-N-sub-
stituted acetamide derivatives to form ten different final com-
pounds (5a–j). The target compounds (5a–j) were obtained
purely and the structures of the compounds were elucidated
with spectroscopic methods (Scheme 1).
Introduction
Microbial infections are among the most common diseases
that cause millions of people to die each year due to insuffi-
cient treatment options and/or development of resistance to
existing antibiotics. Increased use of antibiotics leads to a
rapid increase in resistant bacteria which becomes a serious
public health problem.[1,2] If the resistance continues to
increase, it is stated that deaths due to antimicrobial infec-
tions will exceed the number of cancer-related deaths by
2050.[3] New antimicrobial agents that are more selective,
more potent and less toxic than those available in the clinics
are needed to prevent microbial resistance and thus to
improve the effectiveness of treatment.[4]
Nitrogen-containing heterocyclic compounds have a sig-
nificant place in medicinal chemistry in terms of both being
involved in biological materials and forming the pharmaco-
phoric skeleton for the efficacy of many drugs. Among
them, quinoline is a distinguished heterocyclic ring which
has C9H7N molecular formula and a benzene ring fused
with two adjacent carbon atoms of the pyridine ring. The
quinoline nucleus exists in many biologically effective nat-
ural substances such as quinine, quinidine, berberine, camp-
tothecin. Synthetic derivatives of the ring are also evaluated
for a broad spectrum of pharmacological activity profile
including their anti-inflammatory,[5] antimalarial,[6] anti-
microbial,[7] anticonvulsant,[8] antineoplastic,[9] vasorelax-
ing,[10] antiproliferative[11] properties. Quinolines which are
a separate chemical group involved in many drugs structures
used in the clinic. Fluoroquinolones (ciprofloxazine) as anti-
bacterial, 4-aminoquinolines (chlorokine) as antimalarial,
isoquinolines (praziquantel) as anthelmintic are prominent
groups possessing the ring. Additionally, many molecules
derived from 8-hydroxyquinoline are involved in the treat-
ment of amebiasis, malaria and fungal infections.[12,13]
Another five-membered nitrogen heterocycle is triazole
which is a useful skeleton for new drug discovery studies
due to its applications in many biological fields such as anti-
microbial,[14] analgesic,[15] anti-inflammatory,[16] anti-
cancer,[17] antioxidant.[18] Although there are many
antimicrobial agents being developed against antimicrobial
resistance, triazoles are still the most used molecules in this
class.[19] Triazole-containing antifungal drugs (posaconazole,
fluconazole, itraconazole and terconazole) are currently
being used clinically. Triazole derivatives have been widely
studied due to their synthetic convenience and antimicro-
bial potency.
The structures of the synthesized substances were eluci-
1
dated by using H NMR and 13C NMR spectroscopy, high
resolution mass spectrometry and elemental analysis. The
chemical shifts belonging to NH, O-CH2 and S-CH2 protons
in all materials were seen at about 12.50–13.16 ppm and
5.27 ppm and 3.81–4.36 ppm, respectively. The methoxy pro-
ton of compound 5b, was observed as singlet at 3.81 ppm.
For compound 5c, the signal belonged to substituent CH3
was determined as singlet at 1.34 ppm, and the signal
for O-CH2-CH3 protons at 4.06 ppm as quartet. The signal
at 2.40 ppm assigned to CH3 substituent was an expected
value for compound 5f. The signals attributed to the
substituents CH3, O-CH2-CH3 and O-CH2-CH3 peaks in the
compound 5h were determined at 1.26 ppm, 2.55 ppm and
4.20–4.25 ppm, respectively. Two singlet signals were
detected for compound 5i indicating CH3 at 2.48 ppm and
CH3 bound to the carbonyl group was observed at 2.58 ppm.
The expected CH3 peaks for 5j molecule was seen as a sing-
let at 2.47 ppm. In addition, multiple peaks were observed in
the aromatic region due to the phenyl ring in the substitu-
ent. In 13C-NMR spectra of the compounds, signals belong
to S-CH2 and O-CH2 were detected at 35.84–37.97 ppm and
61.01–61.23 ppm, respectively. The signal of carbonyl carbon
was detected at 166.31–170.64 ppm in common with all final
compounds. In HRMS analysis, compounds were processed
in negative ion mode and peaks were detected in accordance
with molecular weights of the compounds. Elemental ana-
lysis results also confirmed molecular formula which were
found in the range of 0.4% with molecular weights.
In this work, some new 3,4,5-trisubstituted triazole deriv-
atives were synthesized and their structures were elucidated.
Also, an evaluation of their antimicrobial activities and
physicochemical properties is reported.
Result and discussion
Antimicrobial study
Chemistry
The antimicrobial activity of 5a-j compounds was screened
In this study, novel N-substituted-2-[(4-phenyl-5-((quinolin- on seven bacteria and four fungi according to standard pro-
8-yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio]acetamide deriva- cedure of CLSI (Table S1, Supplemental Materials). Their
tives (5a–j) were synthesized in a five-step synthetic procedure antimicrobial activities were tested against Escherichia coli

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 1. Synthesis of compounds (5a–j) Reactions and conditions: (a) acetone, potassium carbonate, reflux; (b) ethanol, hydrazinium hydroxide, rt; (c) ethanol,
phenylisothiocyanate, reflux; (d) ethanol, 2 N potassium hydroxide, reflux; (e) 2-chloro(benzo)/thiazolyl acetamide derivatives, acetone, potassium carbonate, rt.
(ATCC 25922), Enterococcus faecalis (ATCC 51299), compound derivatized with 6-fluorobenzathiazole had min-
Escherichia coli (ATCC 35218), Yersinia enterocolitica (Y53), imum inhibitory concentration (MIC) value of 125 mg/mL
Enterococcus faecalis (ATCC 29212), Pseudomonas aerugi- against two bacteria spp. Compounds 5a and 5d had a MIC
nosa (ATCC 27853), Salmonella typhimirium (NRRL B- value of 15.625 mg/mL and were reported as the most active
4420), Candida glabrata (ATCC 90030), Candida parapsilosis compounds against E. faecalis (ATCC 29212). 5d and 5i
(ATCC 22019), Candida albicans (ATCC 90028), Candida showed a low activity against P. aeruginosa (ATCC 27853)
krusei (ATCC 6258). Fluconazole and chloramphenicol were and the MIC values was 500 mg/mL. The compounds 5a and
used as standard reference drugs. The synthesized chemicals 5i were the derivatives that showed the best activity against
showed no activity against E. coli (ATCC 25922) and E. fae- S. typhimirium (NRRL B-4420) and their MIC values of
calis (ATCC 51299). The most active compound against E. were 7.8 mg/ml. Compound 5d showed lower activity than
coli (ATCC 35218) and Y. enterocolitica (Y53) were 5d. The them. The compounds showed low activity against fungi

4
L. YURTTAŞ ET AL.
where MIC values ranged between 31.25 and 1000 mg/mL, 2-(Quinolin-8-yloxy)acetohydrazide (2)
while standard drug had a MIC range of 1.95–62.5 mg/mL
m. p. 143–145 ꢀC, m. p. 140 ꢀC.[25] Ethyl 2-(quinolin-8-ylox-
against four Candida species. In general, the antifungal
activities were found to be higher than their antibacterial
activities. When evaluating the highest potency, antibacterial
activity of compounds 5a and 5d against E. faecalis and
antibacterial activity of compounds 5a and 5i against S.
typhimurium show half the efficiency of the standard drug.
To evaluate druglikeness of molecules, several physico-
chemical and pharmacokinetic properties were predicted for
three most active compounds as shown in Table S2.
Number of hydrogen bond acceptors, donors and volume,
polar surface area, partition coefficient (log P), water solubil-
ity (log S), gastrointestinal absorption and log Kp (skin
penetration) were identified using SwissADME soft-
ware.[21–23] All findings were showed in the Table S2 with
the violations of Lipinski’s rule of five.[24] There is no dis-
crepancy pursuant to the Lipinski’s rule for the compounds
(5b–5j), except compound 5a. Also, their skin penetration
values were found to be in favorable ranges. The final com-
pounds (5a–5j) were evaluated as easy regarding synthetic
accessibility as the reference drugs (Chloramphenicol and
Fluconazole). However, all compounds showed antimicrobial
activity, and they could be used orally or topically in the
treatment after future tests.
y)acetate (1) (0.025 mol, 5.7 g) and hydrazine hydrate
(0.1 mol of 85% 7.3 mL) were stirred in ethanol (250 mL) at
room temperature overnight. After control using TLC, stir-
ring was stopped and the mixture was awaited till two
phases solvent and precipitate were formed. The precipitated
material was filtered. It was recrystallized from ethanol
after drying.
N-phenyl-2-[2-(quinolin-8-yloxy)acetyl)hydrazine-1-
carbothioamide (3)
m. p. 187–191 ꢀC, m. p. 195–197 ꢀC.[26] 2-(Quinolin-8-ylox-
y)acetohydrazide (2) (0.017 mol, 3.8 g) and phenylisothiocya-
nate (0.02 mol, 2.4 mL) were refluxed in ethanol (150 mL)
for 3 h. The reaction was monitored by TLC. The solvent
was evaporated and the material scraped off. The raw prod-
uct was recrystallised from ethanol.
4-Phenyl-5-[(quinolin-8-yloxy)methyl)-4H-1,2,4-triazole-3-
thiol (4)
m.p. 221–223 ꢀC, m. p. 224–226 ꢀC.[27] N-phenyl-2-(2-(qui-
nolin-8-yloxy)acetyl)hydrazine-1-carbothioamide
(3)
(0.014 mol, 4.8 g) was refluxed with 2 N potassium hydrox-
ide prepared in ethanol (100 mL). After TLC, the pH was
adjusted to
the material.
7 in a cold environment to precipitate
Experimental
All chemicals were purchased from Sigma-Aldrich Chemical
Co (Sigma-Aldrich Corp., St. Louis, MO, USA) and Merck
Chemicals (Merck KGaA, Darmstadt, Germany). All melting
points (m.p.) were determined by MP90 digital melting
point apparatus (Mettler Toledo, Ohio, USA) and were
uncorrected. All reactions were monitored by thin-layer
chromatography (TLC) using Silica Gel 60 F254 TLC plates
(Merck KGaA, Darmstadt, Germany). Spectroscopic data
General procedure for the synthesis of N-substituted-2-
((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-
3-yl)thio)acetamide derivatives (5a–j)
4-Phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazole-3-
thiol (0.001 mol, 3.33 g) and equivalent (0.001 mol) 2-chloro-
N-substituted acetamide derivatives were reacted in the pres-
ence of potassium carbonate (0.001 mol, 0.14 g) in 50 mL
acetone. From the reaction mixture, the solvent was evapo-
rated and treated with water to yield the final product. All
final compounds were recrystallised from ethanol.
1
were recorded with the following instruments: H NMR and
13C NMR spectra were recorded by a Bruker 300 MHz and
75 MHz digital FT-NMR spectrometer (Bruker Bioscience,
Billerica, MA, USA) in DMSO-d6, respectively; M-1 peaks
were determined by Shimadzu 8040 LC/MS/MS system
(Shimadzu, Tokyo, Japan). Elemental analyses were per-
formed on a Leco 932 CHNS analyzer (Leco, Michigan,
N-(6-nitrobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-
yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5a)
m. p. 206 ꢀC, yield 78%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 4.29 (s, 2H, S-CH2), 5.27 (s, 2H, O-CH2), 7.21 (d,
J ¼ 7.69 Hz, 1H, Ar-H), 7.41–7.46 (m, 4H, Ar-H), 7.54 (d,
J ¼ 8.22 Hz, 2H, Ar-H), 7.64–7.66 (m, 2H, Ar-H), 7.73 (d,
J ¼ 8.94 Hz, 1H, Ar-H), 8.20 (d, J ¼ 8.91 Hz, 1H, Ar-H), 8.31
(d, J ¼ 8.35 Hz, 1H, Ar-H), 8.88 (s, 2H, Ar-H), 13.16 (brs,
1H, NH). 13C-NMR (75 MHz, DMSO-d6, ppm) d 37.97 (S-
CH2), 61.20 (O-CH2), 111.86, 118.84, 119.92, 121.52, 121.83,
122.42, 127.02, 127.64, 129.50, 130.09, 130.49, 132.94,
133.05, 136.34, 140.22, 142.28, 149.83, 152.11, 152.51,
153.56, 155.29, 170.64 (C ¼ O). For C27H19N7O4S2 calcu-
lated: 56.93% C, 3.36% H, 17.21% N, 11.23% O, 11.26% S;
found: 56.79% C, 3.35% H, 17.18% N, 11.20% O, 11.29% S.
1
USA). The Supplemental Materials contains sample H and
13C NMR and HRMS of the products 5 (Figures S1–S30).
Material and methods
Ethyl 2-(quinolin-8-yloxy)acetate (1)
m. p. 58–61 ꢀC, m. p. 60 ꢀC.[25] 8-Hydroxyquinoline
(0.034 mol, 5 g), ethyl chloroacetate (0.04 mol, 4.3 mL) and
potassium carbonate were mixed and boiled in acetone
(200 mL) for 6 h. After TLC analysis, the solvent was evapo-
rated and the material was filtered and washed with water,
then recrystallised from ethanol.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
HRMS (m/z): [M-H]ꢁ calcd for C27H19N7O4S2: 568.0867; 5.90% O, 11.82% S; found: 59.65% C, 3.54% H, 15.51% N,
5.88% O, 11.79% S. HRMS (m/z): [M-H]ꢁ calcd for
found: 568.0871.
C27H19FN6O2S2: 541.0922; found: 541.0919.
N-(6-methoxybenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-
8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5b)
m. p. 248 ꢀC, yield 81%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 3.81 (s, 3H, O-CH3), 4.34 (s, 2H, S-CH2), 5.27 (s,
2H, O-CH2), 7.02–7.06 (dd, J ¼ 8.36 and 2.59 Hz, 1H, Ar-
H), 7.19–7.21 (m, 1H, Ar-H), 7.44–7.46 (m, 4H, Ar-H),
7.52–7.54 (m, 1H, Ar-H), 7.55–7.57 (m, 1H, Ar-H),
7.58–7.59 (m, 1H, Ar-H), 7.63–7.64 (m, 1H, Ar-H),
7.65–7.68 (m, 2H, Ar-H), 8.29–8.33 (m, 1H, Ar-H),
8.86–8.88 (m, 1H, Ar-H), 12.60 (brs, 1H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 36.02 (S-CH2), 56.08 (O-CH3),
61.22 (O-CH2), 105.16, 111.89, 115.49, 121.55, 121.74,
122.41, 127.00, 127.61, 129.50, 130.10, 130.56, 132.81,
133.24, 136.33, 140.23, 149.83, 151.86, 152.37, 153.56,
156.15, 156.65, 167.11 (C ¼ O). For C28H22N6O3S2 calcu-
lated: 60.64% C, 4.00% H, 15.15% N, 8.65% O, 11.56% S;
found: 60.51% C, 3.99% H, 15.13% N, 8.63% O, 11.59% S.
HRMS (m/z): [M-H]ꢁ calcd for C28H22N6O3S2: 553.1122;
found: 553.1138.
N-(benzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)-
methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5e)
m. p. 283 ꢀC, yield 79%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 4.36 (s, 2H, S-CH2), 5.27 (s, 2H, O-CH2), 7.20 (d,
J ¼ 7.53 Hz, 1H, Ar-H), 7.30–7.34 (m, 1H, Ar-H), 7.39–7.45
(m, 5H, Ar-H), 7.54 (d, J ¼ 8.21 Hz, 2H, Ar-H), 7.64 (d,
J ¼ 7.43 Hz, 2H, Ar-H), 7.77 (d, J ¼ 8.02 Hz, 1H, Ar-H), 7.99
(d, J ¼ 7.82 Hz, 1H, Ar-H), 8.30 (d, J ¼ 8.29 Hz, 1H, Ar-H),
8.85–8.87 (m, 1H, Ar-H), 12.74 (brs, 1H, NH).13C-NMR
(75 MHz, DMSO-d6, ppm) d 36.07 (S-CH2), 61.22 (O-CH2),
111.88, 121.15, 121.55, 122.26, 122.41, 124.15, 126.67,
127.00, 127.61, 129.50, 130.10, 130.56, 131.92, 132.81,
136.33, 140.23, 148.99, 149.82, 151.84, 152.38, 153.56,
158.19, 167.42 (C ¼ O). For C27H20N6O2S2 calculated:
61.82% C, 3.84% H, 16.02% N, 6.10% O, 12.22% S; found:
61.74% C, 3.83% H, 16.10% N, 6.11% O, 12.27% S. HRMS
(m/z): [M-H]ꢁ calcd for C27H20N6O2S2: 523.1016;
found: 523.1033.
N-(6-ethoxybenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-
yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5c)
m. p. 240 ꢀC, yield 80%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 1.34 (t, J ¼ 6.92 Hz, 3H, CH3), 4.06 (q, J ¼ 6.88 Hz,
J2¼6.91 Hz, 2H, O-CH2-CH3), 4.34, (s, 2H, S-CH2), 5.27 (s,
2H, O-CH2), 7.00–7.04 (m, 1H, Ar-H), 7.20 (d, J ¼ 7.44, 1H,
Ar-H), 7.44 (m, 4H, Ar-H), 7.52–7.56, (m, 3H, Ar-H), 7.64
(d, J ¼ 8.88 Hz, 3H, Ar-H), 8.29–8.32 (m, 1H, Ar-H),
8.86–8.87 (m, 1H, Ar-H), 12.61 (brs, 1H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 15.17 (CH3), 36.13 (O-CH2-
CH3), 61.22 (S-CH2), 64.02 (O-CH2), 105.77, 111.88, 115.76,
121.55, 121.69, 122.41, 127.00, 127.61, 129.50, 130.10,
130.55, 132.82, 133.26, 136.33, 140.23, 142.99, 149.82,
151.91, 152.35, 153.56, 155.85, 156.34, 167.18 (C ¼ O). For
C29H24N6O3S2 calculated: 61.25% C, 4.25% H, 14.78% N,
8.44% O, 11.28% S; found: 61.14% C, 4.26% H, 14.73% N,
8.42% O, 11.25% S. HRMS (m/z): [M-H]ꢁ calcd for
C29H24N6O3S2: 567.1279; found: 567.1264.
N-(6-methylbenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-
yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5f)
m. p. 289 ꢀC, yield 79%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 2.40 (s, 3H, CH3), 4.34 (s, 2H, S-CH2), 5.27 (s, 2H,
O-CH2), 7.20 (d, J ¼ 7.58 Hz, 1H, Ar-H), 7.24–7.27 (m, 1H,
Ar-H), 7.41–7.45 (m, 4H, Ar-H), 7.52–7.56 (m, 2H, Ar-H),
7.63–7.67 (m, 3H, Ar-H), 7.77 (s, 1H, Ar-H), 8.29–8.32 (m,
1H, Ar-H), 8.85–8.87 (m, 1H, Ar-H), 12.66 (brs, 1H, NH).
13C-NMR (75 MHz, DMSO-d6, ppm) d 21.46 (CH3), 36.05
(S-CH2), 61.23 (O-CH2), 111.89, 120.79, 121.55, 121.83,
122.41, 127.00, 127.61, 127.99, 129.50, 130.10, 130.55,
132.06, 132.81, 133.61, 136.33, 140.23, 149.82, 151.84,
152.37, 153.56, 157.31, 167.25 (C ¼ O). For C28H22N6O2S2
calculated: 62.44% C, 4.12% H, 15.60% N, 5.94% O, 11.90%
S; found: 62.31% C, 4.13% H, 15.57% N, 5.92% O, 11.93% S.
HRMS (m/z): [M-H]ꢁ calcd for C28H22N6O2S2: 537.1173;
found: 537.1179.
N-(6-chlorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-
yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5g)
m. p. 290 ꢀC, yield 80%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 4.36 (s, 2H, S-CH2), 5.27 (S, 2H, O-CH2), 7.20 (d,
J ¼ 7.57 Hz, 1H, Ar-H), 7.43–7.47 (m, 5H, Ar-H), 7.52–7.56
(m, 2H, Ar-H), 7.63–7.66 (m, 2H, Ar-H), 7.76 (d, J ¼ 8.65,
1H, Ar-H), 8.13 (s, 1H, Ar-H), 8.28–8.32 (m, 1H, Ar-H),
8.85–8.87 (m, 1H, Ar-H), 12.84 (brs, 1H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 36.10 (S-CH2), 61.22 (O-CH2),
111.88, 121.55, 121.96, 122.32, 122.40, 126.99, 127.60,
128.15, 129.50, 130.10, 130.56, 132.80, 133.64, 136.33,
140.23, 147.88, 149.81, 151.84, 152.38, 153.56, 159.19, 167.73
(C ¼ O). For C27H19ClN6O2S2 calculated: 58.01% C, 3.43%
N-(6-fluorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-
yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5d)
m. p. 231 ꢀC, yield 81%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 4.35 (s, 2H, S-CH2), 5.27 (s, 2H, O-CH2), 7.18–7.21
(m, 1H, Ar-H), 7.26–7.33 (m, 1H, Ar-H), 7.41–7.45 (m, 4H,
Ar-H), 7.52–7.56 (m, 2H, Ar-H), 7.63–7.66 (m, 2H, Ar-H),
7.75–7.80 (m, 1H, Ar-H), 7.88–7.92 (m, 1H, Ar-H),
8.29–8.32 (m, 1H, Ar-H), 8.85–8.87 (m, 1H, Ar-H), 12.77
(brs, 1H, NH). 13C-NMR (75 MHz, DMSO-d6, ppm) d 36.13
(S-CH2), 61.22 (O-CH2), 108.50, 108.87, 111.89, 114.57,
114.90, 121.55, 122.14, 122.26, 122.41, 127.00, 129.50,
130.10, 132.81, 133.12, 133.27, 136.33, 140.23, 145.73,
149.82, 151.87, 152.37, 153.56, 157.53, 167.66 (C ¼ O). For
C27H19FN6O2S2 calculated: 59.77% C, 3.53% H, 15.49% N, H, 15.03% N, 5.72% O, 11.47% S; found: 58.17% C, 3.44%

6
L. YURTTAŞ ET AL.
H, 15.08% N, 5.71% O, 11.44% S. HRMS (m/z): [M-H]ꢁ 5.67% O, 11.36% S; found: 63.72% C, 4.27% H, 14.78% N,
calcd for C27H19ClN6O2S2: 557.0627; found: 557.0621.
5.69% O, 11.33% S. HRMS (m/z): [M-H]ꢁ calcd for
C30H24N6O2S2: 563.1329; found: 563.1318.
Ethyl 4-methyl-2-[2-[(4-phenyl-5-((quinolin-8-yloxy)methyl)-
4H-1,2,4-triazol-3-yl)thio]acetamido]thiazole-5-carboxyl-
ate (5h)
Conclusion
Spectroscopic data showed that the compounds with the
intended 3,4,5-trisubstituted triazole derivatives were synthe-
sized and screened to determine their antimicrobial activity
potential against seven bacteria and four fungi species. In
general, efficiency exhibited against fungi was better than
that against bacteria which means that the synthesized sub-
stances have higher antifungal activity than antibacterial
activity. However, when evaluating in terms of their poten-
tial, compounds 5a and 5d exhibited half the potency of
chloramphenicol against E. feacalis. Likewise, 5a and 5i
showed half the potency of chloramphenicol against S. typhi-
murium. Additionally, compounds 5a with 6-nitrobenzothia-
zole, 5d with 6-fluorobenzothiazole and 5i with 4-methyl-5-
acetyl-thiazole moieties were found as the most active com-
pounds with antibacterial potential.
m. p. 246 ꢀC, yield 81%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 1.26 (t, J ¼ 7.06 Hz, 3H, CH3), 2.55 (s, 3H, O-CH2-
CH3), 4.20–4.25 (q, J1¼7.05 Hz, J2¼14.18 Hz, O-CH2-CH3),
4.29 (s, 2H, S-CH2), 5.27 (S, 2H, O-CH2), 7.20 (d,
J ¼ 7.59 Hz, 1H, Ar-H), 7.41–7.46 (m, 4H, Ar-H), 7.53–7.56
(m, 2H, Ar-H), 7.61–7.65 (m, 2H, Ar-H), 8.29–8.32 (m, 1H,
Ar-H), 8.86–8.87 (m, 1H, Ar-H), 12.85 (brs, 1H, NH). 13C-
NMR (75 MHz, DMSO-d6, ppm) d 14.65 (CH3), 17.50 (O-
CH2-CH3), 35.92 (S-CH2), 61.01 (O-CH2-CH3), 61.22 (O-
CH2), 111.89, 114.60, 121.55, 122.40, 126.99, 127.60, 129.60,
130.09, 130.55, 132.80, 136.32, 140.23, 149.82, 151.75,
152.35, 153.56, 156.73, 160.02, 162.52, 167.47 (C ¼ O). For
C27H24N6O4S2 calculated: 57.84% C, 4.32% H, 14.99% N,
11.41% O, 11.44% S; found: 57.69% C, 4.33% H, 14.91% N,
11.45% O, 11.48% S. HRMS (m/z): [M-H]ꢁ calcd for
C27H24N6O4S2: 559.1228; found: 559.1216.
Conflict of interest
The author confirms that this article content has no conflict
of interest.
N-(5-acetyl-4-methylthiazol-2-yl)-2-[[4-phenyl-5-((quinolin-
8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5i)
m. p. 267 ꢀC, yield 81%. 1H-NMR (300 MHz, DMSO-d6,
ppm) d 2.48 (s, 3H, CH3), 2.58 (s, 3H, carbonyl-CH3), 4.30
(s, 2H, S-CH2), 5.27 (s, 2H, O-CH2), 7.20 (d, J ¼ 7.51, 1H,
Ar-H), 7.41–7.45 (m, 4H, Ar-H), 7.53–7.56 (m, 2H, Ar-H),
7.62–7.64 (m, 2H, Ar-H), 8.31 (d, J ¼ 7.35 Hz, 1H, Ar-H),
8.86–8.87 (m, 1H, Ar-H), 12.84 (brs, 1H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 18.56 (CH3), 30.57 (carbonyl-
CH3), 35.86 (S-CH2), 61.20 (O-CH2), 111.85, 121.55, 122.41,
126.04, 127.00, 127.59, 129.50, 130.11, 130.56, 132.79,
136.33, 140.22, 149.83, 151.75, 152.36, 153.56, 154.84,
159.81, 167.36 (C ¼ O), 191.17 (thiazole-C ¼ O). For
C26H22N6O3S2 calculated: 58.85% C, 4.18% H, 15.84% N,
9.05% O, 12.08% S; found: 58.68% C, 4.19% H, 15.82% N,
9.08% O, 12.11% S. HRMS (m/z): [M-H]ꢁ calcd for
C26H22N6O3S2: 529.1122; found: 529.1115.
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