Design and synthesis of novel 2,4,5-thiazole derivatives as 6-APA mimics and antimicrobial activity evaluation

Article abstract of DOI:10.1080/10426507.2021.1946537

Nine new thiazole derivatives were synthesized considering 6-acetyl penicillanic acid (6-APA) and investigated for their antimicrobial activity. Ethyl 2-(2-mercaptoacetamido)-4-methylthiazole-5-carboxylate derivatives (3a–3i) were gained with a two-step synthetic method using conventional Hantzsch thiazole synthesis. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR spectral data and HRMS. All compounds were tested on eleven bacteria and sixteen fungi species and minimum inhibitory concentration (MIC) was determined for each. Compounds 3d (4-methyl-2-(2-((5-methyl-1,3,4-thiadiazol-2-yl), 3f (4-methyl-2-(2-((5-nitro-1H-benzimidazol-2-yl) and 3g (4-methyl-2-(2-((5-methyl-4H-1,2,4-triazol-3-yl) bearing thiazole, 5-nitrobenzimidazole and triazole rings respectively exhibited high antimicrobial activity against most of the strains. In silico physicochemical properties were calculated for the compounds and it was detected that they comply with the rules of drug availability.

Full text of DOI:10.1080/10426507.2021.1946537

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Design and synthesis of novel 2,4,5-thiazole
derivatives as 6-APA mimics and antimicrobial
activity evaluation
Demokrat Nuha, Asaf Evrim Evren, Meral Yılmaz Cankılıç & Leyla Yurttaş
To cite this article: Demokrat Nuha, Asaf Evrim Evren, Meral Yılmaz Cankılıç & Leyla
Yurttaş (2021): Design and synthesis of novel 2,4,5-thiazole derivatives as 6-APA mimics and
antimicrobial activity evaluation, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2021.1946537
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2021.1946537
Design and synthesis of novel 2,4,5-thiazole derivatives as 6-APA mimics
and antimicrobial activity evaluation
Demokrat Nuhaa, Asaf Evrim Evrenb,c, Meral Yılmaz Cankılıc¸d, and Leyla Yurttas¸b
b
aDepartment of Chemistry, Faculty of Science, Eskisehir Technical University, Eskis¸ehir, Turkey; Department of Pharmaceutical Chemistry,
c
Faculty of Pharmacy, Anadolu University, Eskis¸ehir, Turkey; Vocational School of Health Services, Bilecik Seyh Edebali University, Bilecik,
d
Turkey; Department of Biology, Faculty of Science, Eskisehir Technical University, Eskis¸ehir, Turkey
ABSTRACT
ARTICLE HISTORY
Received 5 February 2021
Accepted 18 June 2021
Nine new thiazole derivatives were synthesized considering 6-acetyl penicillanic acid (6-APA) and
investigated for their antimicrobial activity. Ethyl 2-(2-mercaptoacetamido)-4-methylthiazole-5-carb-
oxylate derivatives (3a–3i) were gained with a two-step synthetic method using conventional
Hantzsch thiazole synthesis. The structural elucidation of the compounds was performed by 1H-
NMR, 13C-NMR spectral data and HRMS. All compounds were tested on eleven bacteria and six-
teen fungi species and minimum inhibitory concentration (MIC) was determined for each.
Compounds 3d (4-methyl-2-(2-((5-methyl-1,3,4-thiadiazol-2-yl), 3f (4-methyl-2-(2-((5-nitro-1H-benzi-
midazol-2-yl) and 3g (4-methyl-2-(2-((5-methyl-4H-1,2,4-triazol-3-yl) bearing thiazole, 5-nitrobenzi-
midazole and triazole rings respectively exhibited high antimicrobial activity against most of the
strains. In silico physicochemical properties were calculated for the compounds and it was
detected that they comply with the rules of drug availability.
KEYWORDS
Thiazole; 6-APA;
antibacterial activity;
antifungal activity;
physicochemical prop-
erty prediction
GRAPHICAL ABSTRACT
Introduction
new resistant bacteria was published recently [13]. These
cautions denote that we will need new antimicrobial agents
to heal patients or to prevent them from infections
very soon.
Since chemotherapeutics including the thiazole moiety
are commonly used in several chronic diseases including
cancer [14–16], hypertension [17], diabetes [18], Parkinson’s
and/or Alzheimer’s diseases [19], analgesic [20], anxiety
[21], and also various infections [22–26]. Thus, we examined
the antimicrobial properties of this ring. For this purpose,
our research group aimed to design new thiazole derivatives
that may show cytotoxicity against pathogenic microbes.
There is a great concern in the clinical setting due to devel-
oping resistance against antimicrobial agents which occurs
in several phenotypes such as multi-drug, extended-drug,
and pan-drug resistance [1–3]. As the development of anti-
microbial resistance (AMR) interrupts not only the treat-
ment of infections but also the treatment of any kind of
disease [4], antimicrobial studies have been prioritized.
Hence, many kinds of antimicrobial studies such as develop-
ing new (potential) drugs and searching for new pathways
were published in the literature [5–9]. In the past decades
depending on antibiotics misuse, scientists did not approach
the future optimistically [10–12]. Unfortunately, a list of Inspired by the core structures of penicillin derivatives, since
CONTACT Demokrat Nuha
demokratnuha@gmail.com
Department of Chemistry, Faculty of Science, Eskisehir Technical University, 26555 Eskis¸ehir, Turkey.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2021.1946537.
ß 2021 Taylor & Francis Group, LLC

2
D. NUHA ET AL.
aromatic protons of the aromatic rings. The 13C-NMR spec-
tra of compounds showed signals at d 17.47–18.05 ppm for
4-methyl thiazole carbon (CH3), at d 14.64–14.87 ppm for
ethoxy carbon (CH3), and at d 59.84–61.04 ppm for ethoxy
carbon (CH2), at d 35.52–40.48 ppm for acetamide (CH2), at
d
97.44–165.42 ppm for aromatic carbon and at
167.22–172.96 for carbonyl (C ¼ O) carbon. HRMS data
confirmed the molecular formulae as expected.
ADME parameters
Figure 1. The core structure of penicillin derivatives (a) (6-APA), the core struc-
ture of the designed molecules (b), and overlay of 6-acetyl penicillanic acid
(pink carbons) and designed compounds (green carbons) without R groups (c)
[overlay module was performed via Discovery Studio Visualizer (DSV,
2017.R2) [27]].
The computational results were shown in Table 1. According
to these results, there was no violation of Lipinski’s rule of
five [30]. These scores are in line with the activity potential
of those compounds. It is thought that the synthesized com-
pounds might have a good pharmacokinetic profile. Thus, the
drug-likeness of the compounds was dedicated to positive.
the thiazole side is substituted with dimethyl and carboxylic
acid groups (Figure 1), our core structure is formed of car-
boxylic acid ester and methyl substitutions. Also, the aceta-
mide structure was preserved but it linked to the other ring
system with a sulfur atom. Although ß-lactam moiety is
defined as a pharmacophore, we thought that the acetamide
linkage may mimic it, since the carbonyl oxygen is close to
thiazole in our design.
According to the above information and based on the
need to develop new and effective antimicrobial agents,
novel 2-acetamidethiazole derivatives were synthesized and
evaluated for their antibacterial and antifungal activity.
Antimicrobial activity evaluation
The antimicrobial activity of the compounds was tested on
various types of microorganisms. The tested bacteria strains
are B. cereus, B. subtilis, M. luteus, and S. aureus as Gram-
positive species, E. faecalis, P. vulgaris, K. pneumoniae, E. coli,
S. typhimurium, Y. enterocolitica, and E. aerogenes as Gram-
negative species, and the results were given as minimum
inhibitory concentration (MIC) as shown in Table S1
(Supplemental Materials). In general, the tested compounds
were more active against Gram-negative than Gram-positive
strains. None of the compounds showed activity against B.
subtilis and B. cereus. Compound 3g exhibited the same
potency as that of the standard drug chloramphenicol
whereas compound 3f showed half of the potency of the
standard drug against M. luteus. Likewise, compound 3f
exhibited half the activity against S. aureus. Remarkably, com-
pounds 3d and 3g exhibited fourfold antibacterial activity
(MIC: 31.25 mg/mL), whereas 3f (MIC: 62.50 mg/mL) showed
twofold activity compared to chloramphenicol (MIC: 125 mg/
mL). Among Gram-negative bacterial strains, E. coli and S.
typhimurium were the most resistant types. Compounds 3d
and 3g inhibited P. vulgaris and E. aerogenes at 31.25 mg/mL
and compound 3f inhibited the same bacteria at 62.50 mg/mL
concentration while chloramphenicol had a MIC value of
125 mg/mL. K. pneumoniae was the most susceptible bacteria
to which compounds 3d and 3f exhibited twofold activity,
whereas compounds 3c and 3g showed the same potency as
that of the standard drug. Against Y. enterocolitica, MIC
value was determined 31.25mg/mL for compound 3f, whereas
compounds 3d, 3e, and 3g had MIC values of 62.50 mg/mL
which were similar to that of chloramphenicol.
Results and discussion
Chemistry
The compounds 3a–3i were synthesized as summarized in
Scheme 1.
In this study, we synthesized nine new compounds which
included the ethyl 2-(2-mercaptoacetamido)-4-methylthia-
zole-5-carboxylate nucleus in their core structures. The
structures of the synthesized compounds (3a–3i) were con-
firmed by 1H-NMR, 13C-NMR, and high-resolution mass
spectroscopy (HRMS). In the first step, ethyl 2-chloro-3-
oxobutanoate and thiourea were reacted at room tempera-
ture for ring closure to obtain ethyl 2-amino-4-methylthia-
zole-5-carboxylate (1) [28]. Then compound
1
was
acetylated with chloroacetyl chloride according to a method
reported [29]. Finally, the obtained product ethyl 2-(2-chlor-
oacetamido)-4-methylthiazole-5-carboxylate (2) was reacted
with 2-mercapto azole derivatives to gain the final products
ethyl 2-(2-mercaptoacetamido)-4-methylthiazole-5-carboxyl-
ate derivatives (3a–3i) as shown in Scheme 1. All the syn-
thesized compounds were characterized by analytical and
1
spectral data. The H-NMR spectra of compounds showed
The antifungal activity of the compounds was tested
against four Candida, five Aspergillus, four Penicillium, two
Fusarium, and one Alternaria species and the findings were
represented in Table S2 (Supplemental Materials). Among
Candida strains, C. parapsilosis was the most sensitive type
that compounds 3c and 3d showed twofold activity of that
that ethoxy protons were observed at d 1.24–1.27 ppm
(CH3) as a triplet and at d 4.15–4.23 ppm (CH2) as a quar-
tet, at d 2.46–2.55 ppm (CH3) for 4-methyl thiazole protons
which were singlet peaks. Acetamide protons were observed
at d 3.96–4.44 ppm (CH2) as a singlet. A broad singlet peak
seen at d 12.78–12.86 ppm indicated the acetamide N–H
proton. The appearance of a pair of singlet, doublets, trip- of the standard drug whereas 3g exhibited similar potency
lets, and/or multiplets at d 6.73–8.56 ppm was due to the to ketoconazole. Compounds 3d and 3g inhibited C.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 1. The synthesis diagram of the compounds 3a–3i. Reagents and conditions: (a) EtOH, r.t., 15 h; (b) TEA, THF, ClCOCH2Cl, 0–5 ꢀC, then r.t 3 h; (c) Acetone,
Potassium carbonate, r.t., 6 h
Table 1. Physicochemical, pharmacokinetic, and medicinal chemistry properties of the final compounds (by SwissAdme) 3a–3i.
Physicochemical properties
Pharmacokinetics
Medicinal chemistry
HBA
HBD
TPSA
Log Po/w
Log S
GIA
Log Kp
RoF (V)
SA
3a
3b
3c
3d
3e
3f
3g
3h
3i
7
5
5
6
6
7
6
5
5
1
1
1
1
2
2
1
2
1
165.43
139.65
159.49
175.85
159.74
196.33
152.54
150.51
162.96
1.30
1.82
2.17
2.46
2.75
2.00
1.44
2.79
3.59
ꢁ4.72
ꢁ4.64
ꢁ5.49
ꢁ6.18
ꢁ6.56
ꢁ7.18
ꢁ4.30
ꢁ6.40
ꢁ7.58
Low
High
Low
Low
Low
Low
Low
Low
Low
ꢁ7.23
ꢁ6.90
ꢁ6.63
ꢁ6.48
ꢁ6.28
ꢁ6.47
ꢁ7.32
ꢁ6.08
ꢁ5.55
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
3.24
3.18
3.49
3.32
3.32
3.37
3.25
3.22
3.29
RF-1
RF-2
5
5
3
0
115.38
69.06
0.53
3.55
ꢁ3.16
High
High
ꢁ7.46
Yes (0)
Yes (1)
2.78
4.45
ꢁ5.51
ꢁ6.46
HBA: H-bond acceptor, HBD: H-bond donor, TPSA: Topologic polar surface area (Å2) Log Po/w: Lipophiplicity, Consensus Log Po/w (Average of all five predictions),
Log S: Water Solubility, GIA: Gastrointestinal absorption, Log Kp: skin permeation (cm/s) RoF (V): Lipinski’s Rule of Five (violation number), SA: Synthetic acces-
sibility from 1 (very easy) to 10 (very difficult). RF- 1: Chloramphenicol, RF-2: Ketoconazole.
albicans at the same MIC value of 62.50 mg/mL while com- Compounds 3d and 3g showed equipotent activity to the
pound 3d inhibited C. glabrata at half the potency of the standard drug against A. ochraceus which was a clinic iso-
standard drug. Compounds 3d and 3g attracted attention late. Among Penicillium species, P. chrysogenum was the
due to their inhibition potential as in other mold species. toughest kind whereas P. notatum was the most sensitive
Among Aspergillus strains, A. niger was the most resistant one to which compounds 3c, 3d, 3e, 3f, 3h, and 3i exhibited
mold, while A. fumigatus was the most susceptible kind. equipotent and 3g twofold antifungal activity compared to
Compounds 3d and 3h displayed antifungal activity at two- the standard drug. Against P. citrinum, compounds 3d and
fold activity whereas compounds 3f and 3g showed the 3e showed significant activity while compound 3g inhibited
same potency as that of ketoconazole against A. fumigatus. P. expansum, distinctively. All compounds except 3a, 3b,

4
D. NUHA ET AL.
and 3i executed satisfying antifungal activity against both spectrometer (Bruker Bioscience, Billerica, MA, USA) in
Fusarium strains that against F. moniliforme compounds 3c, DMSO-d6, respectively. In the NMR spectra, splitting pat-
3d, and 3g and against F. solani compound 3g exhibited terns were designated as follows: s: singlet; d: doublet; t:
twofold antifungal activity. None of the compounds showed triplet; m: multiplet. Coupling constants (J) were reported as
activity against A. alternata.
Hertz. High-resolution mass spectrometric (HRMS) studies
Nine ethyl 4-methyl-2-(2-((heteroaryl)thio)acetamido)- were performed using an LC/MS-IT-TOF system (Shimadzu,
thiazole-5-carboxylate (3a–3i) derivatives were tested for Kyoto, Japan). The Supplemental Materials file contains
their antimicrobial activity potential. Thiazole derivatives antimicrobial activity assay, the antibacterial and antifungal
were widely studied molecules focusing on many pharmaco- activity of the compounds (Tables S1–S2), and sample
logical aspects and they were known with antimicrobial HRMS, 1H and 13C-NMR spectra for products
effect profile, particularly. The thiazole ring exists in the (Figures S2–S28).
structure of many active compounds in the market and the
3
literature [31]. When the compounds were evaluated struc-
turally, it was seen that the compounds 3d, 3f, and 3g were
active on both Gram-positive and Gram-negative bacteria in
General synthesis of ethyl 2-amino-4-methylthiazole-5-
carboxylate (1)
terms of antibacterial activity. These compounds carry 5-
methyl-1,3,4-thiadiazole, 5-nitrobenimidazole and 4-methyl-
triazole, respectively. When the compounds were evaluated
in terms of antifungal activity, similarly it was observed that
the compounds 3d and 3g were prominent with higher effi-
ciency, but it was also determined that the compounds 3c
bearing 2-thiazoline and 3e bearing 5-methoxybenzimidazole
had widespread antifungal effects. Additionally, compounds
3f and 3h exhibited activity comparable to the standard
drug, especially prominent in some genres. No significant
activity was observed for compounds 3a, 3b, and 3i, except
for exceptions. No clear correlation was detected when the
virtual physicochemical parameters and biological findings
were considered together.
Also, it was concluded that all compounds have a good
pharmacokinetic profile considering values of log P and vio-
lations of Ro5.
For future studies, the design of molecules should be
improved according to the following suggested points. The
thiazole ring system may be reduced to a non-aromatic
form. The sulfur atom at the chain may be changed to oxy-
gen or nitrogen atoms. The end rings [(benz)azoles] may be
changed with the phenyl derivatives. The ester may be con-
Ethyl 2-chloro-3-oxobutanoate (2.38 g, 14.45 mmol) was
added to a solution of thiourea (1 g, 13.14 mmol) in ethanol
(40 mL) at room temperature. The mixture was stirred for
15 h at 80 ꢀC. The reaction was monitored with TLC
(EtOAc:PET ¼ 1:2). After the reaction was completed, etha-
nol was removed, and the crude product was washed with
cold ethanol and crystallized from ethanol. m. p. 173–175 ꢀC
[28], yield 82%.
The synthesis of ethyl 2-(2-chloroacetamido)-4-
methylthiazole-5-carboxylate (2)
Triethylamine (2.45 g, 24.19 mmol) was added to a solution
of ethyl 2-amino-4-methylthiazole-5-carboxylate (1) (3 g,
16.12 mmol) in THF (80 mL) in an ice bath. 2-chloroacetyl
chloride (1.52 g, 19.35 mmol) mixed with THF (10 mL) and
added dropwise to the mixture. The mixture was stirred for
3 h in an ice bath. The reaction was monitored with TLC
(EtOAc:PET ¼ 1:1). After the reaction was completed, THF
was removed, and the crude product was washed with water.
Yield 85% [29].
verted to a carboxylic acid or its derivatives. As a pharmaco- General synthesis of ethyl 2-(2-mercaptoacetamido)-4-
phore residue, the ß-lactam ring should be added to methylthiazole-5-carboxylate derivatives (3a–3i)
molecules. The positions of the carboxyl side and hydropho-
Mercapto derivatives (1.14 mmol) were added to a solution
bic side may be changed to each other as in penicillin
of ethyl 2-(2-chloroacetamido)-4-methylthiazole-5-carboxyl-
derivatives.
ate (2) (0.3 g, 1.14 mmol) in acetone (25 mL). K2CO3 (0.23 g,
1.71 mmol) was added to the mixture and the mixture was
stirred for 6 h at room temperature. The reaction was moni-
tored with TLC (EtOAc:PET ¼ 1:3). After the reaction was
completed, acetone was removed, and the crude product
was washed with water and recrystallized from ethanol.
Materials and methods
Chemistry
All chemicals used in the syntheses were purchased either
from Merck Chemicals (Merck KGaA, Darmstadt, Germany)
or Sigma-Aldrich Chemicals (Sigma-Aldrich Corp., St.
Louis, MO, USA). The reactions and the purities of the
compounds were observed by thin-layer chromatography
Ethyl 4-methyl-2-(2-((1-methyl-1H-tetrazol-5-
yl)thio)acetamido)thiazole-5-carboxylate (3a)
1
(TLC) on silica gel 60 F254 aluminum sheets obtained from m. p. 177–178 ꢀC, yield 78%, H-NMR (300 MHz, DMSO-
Merck (Darmstadt, Germany). Melting points of the synthe- d6, ppm) d 1.24 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.46 (s,
sized compounds were recorded by MP90 digital melting 3H, thiazole-CH3), 3.97 (s, 3H, tetrazole-CH3), 4.14 (s, 2H,
point apparatus (Mettler Toledo, Ohio, USA) and were pre- S-CH2), 4.15–4.19 (m, 2H, O-CH2-CH3). 13C-NMR
sented as uncorrected. H-NMR and 13C-NMR spectra were (75 MHz, DMSO-d6, ppm) d 14.86 (O-CH2-CH3), 17.99
1
recorded by a Bruker 300 MHz and 75 MHz digital FT-NMR (thiazole-CH3), 34.02 (tetrazole-CH3), 40.48 (S-CH2), 59.86

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
(O-CH2-CH3), 110.60, 154.66, 157.25, 163.43, 169.62, 170.94. 157.09, 163.04, 165.42, 170.88. HRMS (m/z): [M þ H]þ cal-
[M þ H]þ
calculated
343.0642;
culated 407.0842; found 407.0851.
HRMS
found 343.0646.
(m/z):
Ethyl 4-methyl-2-(2-((5-nitro-1H-benzo[d]imidazol-2-
yl)thio)acetamido)thiazole-5-carboxylate (3f)
Ethyl 4-methyl-2-(2-((1-methyl-1H-imidazol-2-
yl)thio)acetamido)thiazole-5-carboxylate (3b)
1
m. p. 216–217 ꢀC, yield 85%, H-NMR (300 MHz, DMSO-
1
m. p. 165–166 ꢀC, yield 81%, H-NMR (300 MHz, DMSO-
d6, ppm) d 1.27 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.53 (s,
3H, thiazole-CH3), 3.59 (s, 3H, imidazole-CH3), 3.96 (s, 2H,
S-CH2), 4.23 (q, J ¼ 7.12 Hz, 2H, O-CH2-CH3), 6.94 (d,
J ¼ 1.20 Hz, 1H, Ar-H), 7.26 (d, J ¼ 1.18 Hz, 1H, Ar-H). 13C-
NMR (75 MHz, DMSO-d6, ppm) d 14.66 (O-CH2-CH3),
17.48 (thiazole-CH3), 33.46 (imidazole-CH3), 37.52 (S-CH2),
60.96 (O-CH2-CH3), 114.52, 124.16, 129.11, 139.51, 156.73,
160.13, 162.53, 168.49. HRMS (m/z): [M þ H]þ calculated
341.0737; found 341.0743.
d6, ppm) d 1.26 (t, J ¼ 7.08 Hz, 3H, O-CH2-CH3), 2.52 (s,
3H, thiazole-CH3), 4.14 (s, 2H, S-CH2) 4.21 (q, J ¼ 7.08 Hz,
2H, O-CH2-CH3), 6.16 (s, 1H, benzoimidazole-NH), 7.41 (d,
J ¼ 8.82 Hz, 1H, Ar-H), 7.88 (dd, J1¼ 2.31 Hz, J2¼ 6.51 Hz,
1H, Ar-H), 8.21 (d, J ¼ 2.25 Hz, 1H, Ar-H). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 14.68 (O-CH2-CH3), 17.62
(thiazole-CH3), 35.52 (S-CH2), 60.80 (O-CH2-CH3), 110.72,
113.92, 115.65, 140.14, 144.34, 150.61, 156.96, 161.36,
162.70, 170.10. HRMS (m/z): [M þ H]þ calculated 422.0587;
found 422.0588.
Ethyl 4-methyl-2-(2-((4-methyl-4H-1,2,4-triazol-3-
yl)thio)acetamido)thiazole-5-carboxylate (3g)
Ethyl 2-(2-((4,5-dihydrothiazol-2-yl)thio)acetamido)-4-
methylthiazole-5-carboxylate (3c)
1
m. p. 256–257 ꢀC, yield 79%, H-NMR (300 MHz, DMSO-
1
m. p. 133–134 ꢀC, yield 85%, H-NMR (300 MHz, DMSO-
d6, ppm) d 1.27 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.54 (s,
3H, thiazole-CH3), 3.59 (s, 3H, triazole-CH3), 4.15 (s, 2H, S-
CH2), 4.23 (q, J ¼ 7.08 Hz, 2H, O-CH2-CH3), 8.56 (s, 1H,
Ar-H), 12.78 (brs, 1H, -NH). 13C-NMR (75 MHz, DMSO-d6,
ppm) d 14.65 (O-CH2-CH3), 17.47 (thiazole-CH3), 31.31
(triazol-CH3), 36.64 (S-CH2), 61.04 (O-CH2-CH3), 114.72,
146.84, 148.70, 156.72, 159.73, 162.47, 167.67. HRMS (m/z):
[M þ H]þ calculated 342.0689; found 342.0694.
d6, ppm) d 1.27 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.53 (s,
3H, thiazole-CH3), 3.46 (t, J ¼ 7.92 Hz, 2H, dihydrothiazole),
4.09 (t, J ¼ 8.07 Hz, 2H, dihydrothiazole), 4.17 (s, 2H, S-
CH2), 4.23 (q, J ¼ 7.08 Hz, 2H, O-CH2-CH3). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 14.66 (O-CH2-CH3), 17.50
(thiazole-CH3), 36.17(dihydrothiazole), 36.30 (S-CH2), 60.92
(O-CH2-CH3), 64.36 (dihydrothiazole), 114.39, 156.71,
160.46, 162.55, 162.94, 167.62. HRMS (m/z): [M þ H]þ cal-
culated 346.0348; found 346.0349.
Ethyl 2-(2-((1H-benzo[d]imidazol-2-yl)thio)acetamido)-4-
methylthiazole-5-carboxylate (3h)
Ethyl 4-methyl-2-(2-((5-methyl-1,3,4-thiadiazol-2-
yl)thio)acetamido)thiazole-5-carboxylate (3d)
1
m. p. 223–224 ꢀC, yield 81%, H-NMR (300 MHz, DMSO-
d6, ppm) d 1.25 (t, J ¼ 7.08 Hz, 3H, O-CH2-CH3), 2.48 (s,
3H, thiazole-CH3), 4.03 (s, 2H, S-CH2) 4.15 (q, J ¼ 7.11 Hz,
2H, O-CH2-CH3), 7.08 ꢁ 7.12 (m, 2H, Ar-H), 7.42 ꢁ 7.45
(m, 2H, Ar-H) . 13C-NMR (75 MHz, DMSO-d6, ppm) d
14.87 (O-CH2-CH3), 18.05 (thiazole-CH3), 38.76 (S-CH2),
59.84 (O-CH2-CH3), 110.59, 114.27, 121.57, 140.12, 152.02,
157.38, 163.47, 169.75, 172.96. HRMS (m/z): [M þ H]þ cal-
culated 377.0737; found 377.0738.
1
m. p. 254–255 ꢀC, yield 87%, H-NMR (300 MHz, DMSO-
d6, ppm) d 1.27 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.55 (s,
3H, thiazole-CH3), 2.67 (s, 3H, thiadiazole-CH3), 4.23 (q,
J ¼ 7.08 Hz, 2H, O-CH2-CH3), 4.37 (s, 2H, S-CH2), 12.86
(brs, 1H, -NH). 13C-NMR (75 MHz, DMSO-d6, ppm) d
14.64 (O-CH2-CH3), 15.66 (thiazole-CH3), 17.48 (thiadia-
zole-CH3), 37.04 (S-CH2), 61.04 (O-CH2-CH3), 114.76,
156.74, 159.77, 162.46, 164.16, 166.45, 167.22. HRMS (m/z):
[M þ H]þ calculated 359.0301; found 359.0306.
Ethyl 2-(2-(benzo[d]thiazol-2-ylthio)acetamido)-4-
methylthiazole-5-carboxylate (3i)
Ethyl 2-(2-((5-methoxy-1H-benzo[d]imidazol-2-
yl)thio)acetamido)-4-methylthiazole-5-carboxylate (3e)
1
m. p. 155–156 ꢀC, yield 88%, H-NMR (300 MHz, DMSO-
d6, ppm) d 1.24 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.52 (s,
3H, thiazole-CH3), 4.19 (q, J ¼ 7.08 Hz, 2H, O-CH2-CH3),
4.44 (s, 2H, S-CH2), 7.32–7.37 (m, 1H, Ar-H), 7.41–7.47 (m,
1H, Ar-H), 7.79 (d, J ¼ 8.22 Hz, 1H, Ar-H), 8.01 (d,
J ¼ 7.89 Hz, 1H, Ar-H) . 13C-NMR (75 MHz, DMSO-d6,
ppm) d 14.68 (O-CH2-CH3), 17.62 (thiazole-CH3), 37.85 (S-
CH2), 60.66 (O-CH2-CH3), 113.51, 121.52, 122.31, 124.94,
126.84, 135.23, 152.98, 156.88, 162.67, 162.73, 166.56,
168.39. HRMS (m/z): [M þ H]þ calculated 394.0348;
1
m. p. 178–179 ꢀC, yield 89%, H-NMR (300 MHz, DMSO-
d6, ppm) d 1.25 (t, J ¼ 7.11 Hz, 3H, O-CH2-CH3), 2.51 (s,
3H, thiazole-CH3), 3.76 (s, 3H, O-CH3), 4.14 (s, 2H, S-CH2)
4.18 (q, J ¼ 7.08 Hz, 2H, O-CH2-CH3), 6.73 (dd, J1¼
2.43 Hz, J2¼ 6.27 Hz, 1H, Ar-H), 6.96 (d, J ¼ 2.34 Hz, 1H,
Ar-H), 7.32 (d, J ¼ 8.70 Hz, 1H, Ar-H). 13C-NMR (75 MHz,
DMSO-d6, ppm) d 14.76 (O-CH2-CH3), 17.81 (thiazole-
CH3), 37.37 (S-CH2), 55.90 (O-CH3) 60.34 (O-CH2-CH3),
97.44, 110.76, 112.36, 115.10, 135.01, 140.16, 149.88, 155.66, found 394.0348.

6
D. NUHA ET AL.
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Prediction of the physicochemical properties
The physicochemical, pharmacokinetic, and medicinal chem-
istry properties of the compounds were calculated, virtually
by using SwissAdme software [32]. HBA as H-bond
acceptor, HBD as H-bond donor, TPSA as Topologic polar
surface area (Å2), Log Po/w as consensus Log Po/w
(Average of all five predictions), Log S as water solubility,
GIA as Gastrointestinal absorption, Log Kp as skin perme-
ation (cm/s), RoF (V) as Rule of Five (violation number),
SA as Synthetic accessibility from 1 (very easy) to 10 (very
difficult) were predicted for final molecules and standard
drugs chloramphenicol and ketoconazole.
Conclusions
In this study, nine new ethyl 2-(2-mercaptoacetamido)-4-
methylthiazole-5-carboxylate derivatives (3a–3i) were
obtained using thiourea and ethyl 2-chloro-3-oxobutanoate
as starting materials. After acetylation reaction, the final
compounds were gained. Ethyl 2-(2-mercaptoacetamido)-4-
methylthiazole-5-carboxylate was the core structure that
overlaid the 6-APA molecule. All final compounds were
tested on twenty-seven microorganism strains. Among the
compounds, 3f (5-nitrobenzimidazole), 3g (N-methyltria-
zole), and 3h (benzimidazole) exhibited high antibacterial
activity whereas 3g and 3h showed prominent antifungal
activity compared to the standard drugs. K. pneumoniae, A.
fumigatus and F. moniliforme were the most suscep-
tible genres.
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Acknowledgment
We gratefully thank Anadolu University DOPNA Laboratory for ana-
lyzing the synthesized compounds.
Aromatase
Enzyme;
4-(Aryl/Heteroaryl)-2-(Pyrimidin-2-
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1986–1995. DOI: 10.1016/j.bmc.2018.02.048.
Disclosure statement
[16] Evren, A. E.; Yurttas, L.; Ekselli, B.; Akalin-Ciftci, G. Synthesis
and Biological Evaluation of 5-Methyl-4-Phenyl Thiazole
Derivatives as Anticancer Agents. Phosphorus Sulfur Silicon
Relat Elem 2019, 194, 820–828. DOI: 10.1080/10426507.2018.
1550642.
[17] Harari, S.; Elia, D.; Humbert, M. Pulmonary Hypertension in
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The author confirms that this article’s content has no conflict
of interest.
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