(2024) 18:138
El‑Saghier et al. BMC Chemistry
https://doi.org/10.1186/s13065-024-01237-9

BMC Chemistry

RESEARCH

Open Access

Synthesis, docking
and characterization of some novel
5‑(S‑alkyl)‑1.3.4‑thiadiazole‑2‑carboxamide
derivatives as anti‑inflammatory
and antibacterial agents
Ahmed M. El‑Saghier1*, Asmaa Abdul‑Baset1, Omer M. El‑Hady1, Walaa M. Abd El‑Raheem2 andAsmaa M. Kadry1

Abstract
Because of the great pharmacological and industrial significance of 1,3,4-thiadiazole and its related compounds,
researchers are still very interested in them. For this reason, in this study, we looked at ways to create new hybrid
compounds containing carboxamide and 1,3,4-thiadiazole moieties. The thioxoacetamide derivatives used to makethese compounds were reacted with various alkylated reagents to produce multiple S-alkyl groups. Additionally,
these compounds were reacted with aldehydes to form novel derivatives known as 5-(substituent)-N-phenyl-1,3,4thiadiazole-2-carboxamide. Here, we used the agar well diffusion method to examine the antibacterial activity of all
the produced compounds against a few pathogenic bacteria that were resistant to multiple drugs. Additionally,
look into their capacity to lower inflammation through the use of bovine serum albumin in the protein denatura‑tion procedure. The substances were characterized by spectral analysis (IR, 1HNMR, 13CNMR and Elemental Analysis),and efficient as antibacterial agents against all the tested bacterial strains, except for Escherichia coli. Compounds
4a and 8c showed the highest level of inhibition zone against Gram-positive bacteria (Staph. aureus, Bacillus subtilis)
at concentration 0.3, 0.4 and 0.5 mg/ml compared with ciprofloxacin at the same concentrations. The results demon‑
strated that every compound has significant anti-inflammatory activity. At a concentration of 250 µg/ml, compounds
3a, 4c and 8c had the highest percentage inhibition of protein denaturation when (83.24%, 86.44% and 85.14%,
respectively) compared to other compounds and diclofenac sodium as reference drug. Comparing compounds 4c
and 8c to ciprofloxacin and diclofenac sodium, they showed powerful antibacterial and anti-inflammatory action.
Furthermore, an investigation using molecular docking against DHPS from S. aureus (PDB ID: 6CLV) showed a strong
connection with the intended protein and an elevated docking score, making it a prime candidate for antibiotics.
Keywords Carboxamide, Thioxoacetamide, 1,3,4-thiadiazole, Thiohydrazides, Antimicrobial, Anti-inflammatory agent*Correspondence:
Ahmed M. El‑Saghierel.saghier@science.sohag.edu.eg
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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El‑Saghier et al. BMC Chemistry(2024) 18:138

Background
Microbiological diseases are the most critical issue facing
the economy and the world’s health [1]. It has recently
become more challenging to treat bacterial infections
with conventional medicines [2]. Growing concern isbeing expressed throughout the world over the growth ofbacterial resistance to well-known treatments and hospital-acquired illnesses [3]. In actuality, the development of
microbial resistance to commercially accessible antibacterial medications is the main cause of illness and mortality [4]. Microbiological disorders that have recently
caused a great deal of pain for humans include the epidemic of the plague, diphtheria, cholera, typhoid fever, a
respiratory infection, and tuberculosis [5]. Additionally,some recent clinical studies mention the growth in enterococci that are resistant to vancomycin, Staphylococcus
epidermidis, and methicillin-resistant Staphylococcus
aureus (MRSA), which are the most prevalent bacterial infections that cause death in the majority wealthy
countries [6, 7]. As per the World Health Organisation(WHO), traditional antibiotic therapy typically fails totreat diseases caused by resistant germs, which increases
the risk of mortality and lengthens suffering [8]. Therefore, the development of novel antimicrobial drugs thatdiffer from the widely used categories of antibacterial
agents is still necessary [9]. Moreover, one potential solution to the problem of overloaded multidrug resistance(MDR) is the development of novel drugs with distinctive mechanisms of action to prevent cross-resistancewith currently available therapies [10]. Because of theirbroad range of biological functions, heterocyclic ring
structures in organic compounds continue to garner alot of research. Numerous synthetic compounds thatexhibit appealing biological effects such as antiviral [11],anticancer [12], cytotoxic [13], anticonvulsant [14], antihyperlipedemic [15], anti-inflammatory [16], analgesic[17], antidepressant [18], antioxidant [19], anti-pesticide[20], anti-COVID [21], antileishmanial [22], and antituberculosis [23] properties commonly use the scaffold
1,3,4-thiadiazole.
Many thiadiazole compounds have found extensive
usage in chemotherapeutics as antimicrobial and antibacterial agents [24] that are effective against a wide
range of pathogenic bacteria and resistant mycobacterium, such as compounds A and B. Moreover, mycobacterial activity has been observed to be significantly
inhibited by compound B ­(IC50 = 0.23 g/ml) [25]. Compound C was discovered to be superior to the industry
standard (pyrimethanil) when the synthetic 1,3,4-thiadiazole scaffolds were tested using the mycelial growth rate
method against a few fungus strains [26]. However, scaffolds D have anti-inflammatory activity and demonstrate
COX-2 selectivity in the J774A.1 murine macrophage

Page 2 of 21

cell line [27]. (Fig. 1). The impressive anti-inflammatory
properties of both heterocycles and carboxamide units
have been demonstrated. As a result, a lot of research
has focused on creating and studying oxicam derivatives
as pharmacological agents. The success of the nonsteroidal anti-inflammatory medicines (NSAIDs) piroxicam(Feldene®), meloxicam (Mobic®), and tenoxicam stimulated research in this topic (Fig. 1). Additionally, Rimonabant exerted high activity via the inhibition of COX-2(inducible) induced at sites of inflammation [28, 29].
As part of our ongoing efforts to produce anti-infective
medicines [30–35]. In this study, we design and synthesize several new prototypes containing two pharmacophores, carboxamide and 1,3,4-thiadiazole inside one
structural framework using environmentally friendly processes starting with 2-hydrazinyl-N-phenyl-2-thioxoacetamide derivatives [36]. We tested their anti-bacterial andanti-inflammatory activity for bioactive compounds.

Result and discussion
Chemistry

As a continuation of our strategy is to determine methods to utilize these molecules as the basis for the synthesis of many different five, six, and seven-membered rings[37–41]. Reaction of thioxoacetamide derivatives 1a–d
with carbon disulfide and potassium hydroxide in ethanol at room temperature considered an efficient method
to synthesis potassium 5-(phenylcarbamoyl)-1,3,4-thiadiazole-2-thiolate derivatives (2a–d), which treated withconcentrated hydrochloric acid until pH 2–3 to afford
novel moiety of 1,3,4-thiadiazole derivatives 3a–d thatcan be used as a building block of some new 1,3,4-thiadiazole analogous (Scheme 1). The IR spectrum of compound 3a–d revealed the disappearance of ­NH2 group.
1
HNMR for compound 3a showed new singles at 15.06
for ­NHthiadiazole group, disappeared by ­D2O, at the sametime the peaks for amino group are disappeared. All thecompounds show a new peak above 190 ppm in 13C NMR
which come back to C=S of the formed 1,3,4-thiadiazole
rings.
Moreover, compounds 2a–c reacted with active halocompounds namely, methyl iodide ethyl iodide, 1-bromo2-methylbutane and (bromomethyl)benzene at low temperature to give the corresponding S-alkyl derivatives
with a substantial output, economical, gentle, straightforward, and environmentally friendly approach that produces suitable behaviors, see Scheme 2. Structures of therecently obtained compounds were verified based upon
their IR, 1H-NMR, 13C-NMR, and elemental analyses.
The IR spectra of compounds 4–7 exhibited the presence of broad band: at 3234–3537 ­cm−1 corresponding to NH groups, at 1660–1680 ­cm−1 corresponding
to alkyl groups. The 1H-NMR spectrum, for example, ofEl‑Saghier et al. BMC Chemistry(2024) 18:138

Page 3 of 21

Fig. 1 Strategy employed for designing 1.3.4-thiadiazole-2-carboxamide derivatives

compound 4a–c revealed the presence of a broad bandat 10.60–11.03 ppm characterized to NH group, a singlet
signal at 2.24–2.84 ppm corresponding to S-alkyl group.
13
CMR spectrum of compound 4a revealed the following
signals: 165.29, 156.32 (2C, thiadiazole), 173.51 (C=O),
four signals at 138.12, 129.18, 125.11, 121.27 ppm for
5C of Aromatic group and singlet signal at 17.37 ppm of
methylthiol group.
Nevertheless, alkylation reaction of compounds
2a–d with chloroacetone, ethyl chloroacetate, chloroacetic acid and ethyl chloroformate, afforded thecorresponding 5-(S-alkyl) sulfanyl-1,3,4-thiadiazole2-carboxamide derivatives 8a–c, 9a, 10a and 11a,
respectively. Additionally, it was easily to synthesis
compound 9a by another way through conversion ofacidic group in compound 10a into ester group in compound 9a, see Scheme 3. The structures of the obtained5-(S-alkyl)-1.3.4-thiadiazole-2-carboxamide derivatives
8–11 were distinguished by their spectral and elemental data. For instance, the IR spectrum of compound
9a had peak absorption for the NH group at 3537 ­cm−1
and another distinctive band for the novel C=O group

El‑Saghier et al. BMC Chemistry(2024) 18:138

Scheme 1 Synthesis of N-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide derivatives

Scheme 2 Synthesis of 5-(S-alkyl)-1.3.4-thiadiazole-2-carboxamide derivatives

Scheme 3 Synthesis of 5-(S-alkyl)-1.3.4-thiadiazole-2-carboxamide derivatives

Page 4 of 21

El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 5 of 21

Scheme 4 Synthesis of 5-(substituent)-N-phenyl-1,3,4-thiadiazole-2-carboxamide derivatives

at 1737 ­cm−1. Where the 1H-NMR spectrum of thiscompound showed a singlet signal at 11.05 ppm for
NH group which disappeared by ­D2O, a multiples signals between 7.15 and 7.83 ppm for aromatic protons,
singlet signal at 4.35 ppm for S–CH2– group, quartet
signal at 4.20–4.14 ppm and a triplet signal at 1.23–
1.20 ppm with coupling constant equals to 7.08 Hz,
which could be assigned for ­C H2CH3 groups. The signals of 13CNMR confirmed the expected structure
by appearance of new carbonyl group at 168.08 ppm.
Finally, the DEPT-135 obviously distinguished between
the –CH2– (62.12 ppm) and –CH3 (14.56 ppm) of theethyl chain where, it showed one C­ H3 with a positive
phase and two ­C H2 with a negative one.
Reaction of compound 1a with different aldehydes
namely, cinnamaldehyde, p-N, N dimethylaminobenzaldehyde, 3,4,5-trimethoxy-benzaldehyde, 1-naphthaldehyde, pipreonal, p methylbenzaldehyde and glyoxal toafford; 5-(substituent)-N-phenyl-1,3,4-thiadiazole-2-carboxamide derivatives (12a–18a), respectively, Scheme 4.
IR spectrum of compounds 12a–18a showed the disappearance of ­NHNH2 group absorption bands. The
1
H-NMR spectrum for compound 12a showed signal at
10.70 ppm for NH group (disappeared by D­ 2O), between

El‑Saghier et al. BMC Chemistry(2024) 18:138

Fig. 2 Antibacterial activity of the tested compounds

Page 6 of 21

El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 7 of 21

Fig. 2 continued

7.85–7.08 ppm for aromatic protons and 6.68 ppm for
the –CH=CH– group. The signals of 13C NMR spectrum
confirmed the expected structure by appearance of newgroup signals at 163.20, 158.13 (2-S–C=N) and 120.74,
112.13 ppm for CH=CH– group. The 1H-NMR spectrum
for compound 13a showed signal at 11.31 ppm for NH
group (disappeared by ­D2O), between 8.23–7.09 ppm foraromatic protons and a new singlet signal at 2.84 ppm
for the two methyl groups. The signals of 13CNMR spectrum confirmed the expected structure by appearance of
new group signals at 171.33 (C=O), 166.60, 162.53 (2C,
thiadiazole) and 36.42 ppm (­2CH3). In the case of compound 18a, its 1H-NMR spectrum showed two signals at
10.19 and 9.04 ppm for NH groups (disappeared by ­D2O),
between 7.74–7.06 ppm for aromatic protons and new
singlet signal at 5.53 for the two -CH groups. The signalsof 13CNMR spectrum confirmed the expected structure
by appearance of new signal at 159.13 (C=O), 139.04(C, Thiadiazole), 138.66, 129.05, 124.29, 120.74 for aromatic ring and 76.13 ppm for quaternary carbon atom.
Also, its Dept -135 spectrum showed signals at 129.09,
124.31, 120.74 ppm for aromatic ring and 75.98 ppm­(CHthiadiazole) in the positive phase.

Biological evaluation
Antimicrobial screening

Antimicrobial activity of the tested compounds wasinvestigated against multidrug pathogenic bacteria. The
tested compounds showed potential antibacterial effectagainst Staph. aureus, Bacillus subtilis and K. pneumonia and no inhibitory effect against E. coli. Ciprofloxacin is used in this investigation as a control. In clinic andhospital settings, ciprofloxacin is a widely used broadspectrum antibiotic. The closest compounds to ciprofloxacin were 4c and 8c, which were more effective against
Gram-positive bacteria (Staph. aureus, Bacillus subtilis)
at concentration 0.3, 0.4 and 0.5 mg/ml. Furthermore,compounds 3a, 4a and 6a showed potential antibacterial
effect against Staph. Aureus and Bacillus subtilis, respectively, as shown in (Table S1(supplementary file), Fig. 2).
Statistical results of antimicrobial screening

Nineteen compounds studied with different concentrations on both Gram-positive and Gram-negative bacteria, formed four subsets in accordance with the zone of
inhibition values. A one-way ANOVA was conductedto compare the effect of in-vitro antibacterial activity

El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 8 of 21

Table 1 In-vitro antibacterial activity of tested compounds
Bacteria

Test compound

Mean of the size of the inhibitionzone (mm)Std. deviation
Deviation

p-value*

S. aureus

3a

31.55

5.45

0.0001

3b

29.91

3.15

Bacillus sp.

3c

25.17

4.63

3d

22.16

4.36

4a

30.68

3.02

5a

18.87

5.89

8a

18.67

4.05

10a

14.21

2.75

9a

12.65

7.05

7a

24.08

3.85

11a

21.47

5.92

4c

30.41

4.80

8b

27.08

5.31

8c

33.27

4.73

7b

19.79

7.73

6a

19.98

5.95

13a

4.30

5.54

18a

14.34

3.47

Ciprofloxacin

43.97

4.28

3a

10.77

7.19

3b

20.76

5.80

3c

11.62

6.83

3d

19.04

6.80

4a

15.80

4.83

5a

16.73

5.16

8a

21.51

5.95

10a

15.59

8.35

9a

10.71

5.60

7a

18.59

2.37

11a

15.99

4.19

4c

31.54

4.76

8b

23.43

2.61

8c

36.43

4.04

7b

17.59

4.36

6a

32.07

5.04

13a

13.85

4.32

18a

14.11

2.58

Ciprofloxacin

33.15

7.18

0.0001El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 9 of 21

Table 1 (continued)
Bacteria

Test compound

Mean of the size of the inhibitionzone (mm)Std. deviation
Deviation

p-value*

K. pnemoniae

3a

15.17

2.43

0.0001

3b

17.47

3.37

3c

14.84

2.29

E. coli

3d

19.89

5.96

4a

19.26

6.11

5a

20.32

6.38]

8a

15.44

8.25

10a

0.00

0.00

9a

6.53

5.61

7a

20.23

2.55

11a

11.42

6.05

4c

19.24

3.10

8b

13.55

8.43

8c

26.32

7.10

7b

15.40

4.35

6a

0.00

0.00

13a

0.00

0.00

18a

15.24

10.91

Ciprofloxacin

38.16

9.46

3a

0.00

0.00

3b

0.00

0.00

3c

0.60

2.32

3d

0.00

0.00

4a

0.00

0.00

5a

0.00

0.00

8a

0.00

0.00

10a

0.00

0.00

9a

0.00

0.00

7a

0.00

0.00

11a

0.00

0.00

4c

4.25

5.49

8b

0.00

0.00

8c

6.02

5.27

7b

0.00

0.00

6a

0.00

0.00

13a

0.00

0.00

18a

0.00

0.00

Ciprofloxacin

45.02

11.25

* p < 0.05 (significant), p < 0.01 (highly significant), p < 0.001 (very highly significant), NS: Non significant p > 0.05

0.0001El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 10 of 21

Fig. 3 Shows a comparison between test compounds and ciprofloxacin with the size of the inhibition zone of Bacillus (gram +ve) strain of bacteriaof compounds (Table 1). From Table 1, we have founda statistically significant result. It is observed that thein-vitro antibacterial activity of compounds 19 (Ciprofloxacin), 8c, 6a, and 4c significantly different from allother compounds. But Ciprofloxacin is used as standard. It is evident from the ANOVA that the compounds(8c, 6a, and 4c), exhibited significantly high antibacterial activity compare to the all other synthesized
tested compounds and also with standard. As shownin Table 1, compound 8c exhibit significantly highantibacterial activity against S. aureus (33.26 ± 4.73)
and significantly excellent antibacterial effect against
Bacillus strain (36.44 ± 4.05) (Fig. 3). Moreover, compound 6a, 4c had exhibit significantly high antibacterial effect against Bacillus strain as mean = 32.66, 31.54
respectively.

heating [42]. In this study all compounds were shownto have strong anti-inflammatory action by employing a protein denaturation inhibition technique atconcentration of 50, 100, 150, 200 and 250 µg/ml ina concentration-dependent manner (Table 2). In
comparison to other compounds, the compounds 3a,4c and 8c showed the highest levels of inhibition atconcentrations of 250 µg/ml with percentage inhibition 83.24%, 86.44% and 85.14%, respectively. At thesame concentrations, compounds 3b and 8b exhibited
significant anti-inflammatory activity with percentage inhibition 81.99% and 80.99%. These substances
could therefore be a viable substitute for agents thathave anti-inflammatory properties. Hence, it could bea valuable medicinal ingredient for the treatment ofbacterial infections and inflammation.

Anti‑inflammatory activity of the tested compounds

Statistical results of anti‑inflammatory activity

Proteins eliminate their tertiary and secondary structures when exposed to an external stressor or substance, such as a powerful base or acid, a highly
concentrated inorganic salt, an organic solvent, or
heating. This process is referred to as denaturation.
The expected process of denaturation is a modification in electrostatic, hydrogen, hydrophobic, anddisulphide coupling. There is a dose-dependentcapacity of certain anti-inflammatory medications
to avoid denaturation of proteins brought about by

All synthesized compounds were screened for in-vitro
anti-inflammatory activity by inhibition of protein denaturation method using diclofenac as a standard drug.
From Table 2, we have found a statistically significant
result in all concentration (50, 100, 150, 250 µg /ml) incomparison to different test compounds. It is evident
from the ANOVA that the compounds 3a, 4c, 8c, 3b

El‑Saghier et al. BMC Chemistry(2024) 18:138

and 8b, exhibited significantly high anti-inflammatorycompare to the all-other synthesized tested compounds.
Compound 8c showed significant effect mean 65.23 compering with 70.85 for Diclofenac sodium.at concentrations of 50 µg/ml as shown in Fig. 4.

Conclusion
Synthesis, characterization, and investigation of some
1,3,4-thiadiazole derivatives which prepared from thioxoacetamide derivatives were studied, their reactions
with some alkyl halides to make alkylation reaction andwith some aldehydes to form novel 5-(substituent)N-phenyl-1,3,4-thiadiazole-2-carboxamide
derivatives
were investigated. Finally, we studied the possibility of
1,3,4-dihydrothiadiazole derivatives as antimicrobial
potential on some multidrug-resistant pathogenic bacteria. Gram-positive and Gram-negative bacteria are bothtargets of antimicrobial action using the agar well diffusion method then screening data is subjected to statistical analysis using one way ANOVA technique. The
compounds exhibited antibacterial efficacy against all
tested bacterial strains except Escherichia coli. Also, theresult revealed that all compounds possessed potent significant anti-inflammatory activity. In deep study, compounds 4c and 8c possess significant antimicrobial andanti-inflammatory activity as compared to ciprofloxacin
and diclofenac sodium. Additionally, a study employing
molecular docking against DHPS from S. aureus (PDB
ID: 6CLV) found that it is a great option for antibiotics
since it is used by nearly all bacterial strains to synthesize nucleic acids. The molecular docking study exhibited
positive interaction with the target protein and a highdocking score especially for compounds 3a, 4c, 8d and18a. According to the study’s findings, the substances inquestion have strong antibacterial and anti-inflammatory
properties. The overall results of this study can be considered as very promising in the perspective of new antimicrobial drugs, especially when the medical importance oftested microorganisms is considered. However, pharmacological and toxicological studies, will be necessary toconfirm this hypothesis.

Page 11 of 21

Table 2 Anti-denaturation activity of the tested compounds
and positive control
Concentrations
µg/ml
50

100

Test
compoundMean ofinhibition%Std.
deviation

p-value*

0.0001

3a

63.19

0.00

3b

59.25

0.00

3c

58.44

0.00

3d

58.63

0.00

4a

30.60

0.00

5a

2.76

0.00

8a

1.39

0.00

10a

2.12

0.00

9a

4.76

0.00

7a

35.22

0.00

11a

34.72

0.00

4c

64.13

0.00

8b

59.75

0.00

8c

65.23

0.00

7b

32.72

0.00

6a

30.60

0.0

13a

35.22

0.0

18a

6.76

0.0

Diclofenac
sodium

70.85

0.0

3a

73.46

0.0

3b

68.42

0.0

3c

67.33

0.0

3d

68.45

0.0

4a

35.15

0.0

5a

9.32

0.0

8a

6.37

0.0

10a

8.54

0.0

9a

9.78

0.0

7a

40.78

0.0

11a

41.15

0.0

4c

74.40

0.0

8b

68.84

0.0

8c

74.46

0.0

7b

40.66

0.0

6a

39.15

0.0

Methods/Experimental

13a

40.78

0.0

18a

10.72

0.0

Chemistry

Diclofenac
sodium79.55

0.0

Thin layer chromatography (TLC) was employed to track
all reactions utilizing percolated dishes of silica gel G/

0.0001El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 12 of 21

Table 2 (continued)

Table 2 (continued)

Concentrations
µg/ml

Test
compoundMean ofinhibition%Std.
deviation

p-value*

Concentrations
µg/ml

Test
compoundMean ofinhibition%Std.
deviation

p-value*

150

3a

78.44

0.0

0.0001

250

3a

83.24

0.0

0.0001

3b

75.14

0.0

3b

81.99

0.0

3c

72.50

0.0

3c

79.65

0.0

3d

73.80

0.0

3d

78.00

0.0

4a

41.31

0.0

4a

51.43

0.0

200

5a

16.87

0.0

5a

29.12

0.0

8a

11.42

0.0

8a

21.86

0.0

10a

14.37

0.0

10a

23.12

0.0

9a

18.47

0.0

9a

29.76

0.0

7a

44.32

0.0

7a

64.62

0.0

11a

46.31

0.0

11a

60.43

0.0

4c

77.64

0.0

4c

85.14

0.0

8b

74.14

0.0

8b

80.99

0.0

8c

78.64

0.0

8c

86.44

0.0

7b

45.52

0.0

7b

60.77

0.0

6a

43.31

0.0

6a

55.43

0.0

13a

48.30

0.0

13a

70.62

0.0

18a

17.47

0.0

18a

33.76

0.0

Diclofenac
sodium82.64

0.0

Diclofenac
sodium

97.85

0.0

3a

81.72

3b

78.00

0.0001
0.0

3c

74.66

0.0

3d

74.43

0.0

4a

46.65

0.0

5a

22.93

0.0

8a

16.62

0.0

10a

20.93

0.0

9a

25.33

0.0

7a

58.00

0.0

11a

52.65

0.0

4c

82.02

0.0

8b

78.56

0.0

8c

82.72

0.0

7b

52.43

0.0

6a

49.65

0.0

13a

62.21

0.0

18a

25.63

0.0

Diclofenac
sodium85.46

0.0* p < 0.05 (significant), p < 0.01 (highly significant), p < 0.001 (very highly
significant), NS: Non significant p > 0.05

UV-254 with a 0.25 mm thickness (Merck 60F254) andUV light (254 nm/365 nm) enable visualization. The
uncorrected Kofeler melting point instrument was used
to record all melting points. On an FT-IR spectrophotometer, KBr pellets were used to analyses IR spectra. At
Sohag University, spectral characterizations of the compounds, Bruker Avance III at 400 MHz and 100 MHz
for 1H and 13CNMR (DMSO-d6, δ ppm), respectively
were used. Tetramethylsilane (TMS) was selected as
the standard for internal measurement and its chemical shifts (δ) were expressed in parts per million (ppm).
TMS (= 0 ppm) or DMSO (= 39.51 ppm) were employed
as internal standards for 13C NMR. A Perkin-Elmer CHN
analyzer model provided elemental analyses as shown insupplementary file.

El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 13 of 21

Fig. 4 Shows a comparison between test compounds with 50 µg/ml concentration with % of inhibition

General synthesis of N‑phenyl‑5‑thioxo‑4,5‑dihydro‑1,3,4‑thiadiazole‑2‑carboxamide derivatives (3a–d)

2-Hydrazino-N-Phenyl-2-thioxoacetamide(1a–d)(0.01 mmol), potassium hydroxide (0.03 mmol), carbon
disulfide (0.03 mmol) was stirring in ethanol at room
temperature for 6 h., then was poured in 20 ml distilledwater. Concentrated hydrochloric acid was added until
pH 2–3, precipitated formed crystallized with ethanol,
see Figure (S1–S10).
N-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazole2-carboxamide (3a): White crystals, yield 93%, mp. 180–
182 °C; FT-IR (ATR) δmax: 3345, 3191 (2NH str.), 3104­(CHarom str.), 1678 (C=O str.), 1659 (C=N str.), 1236 (C=Sstr.); 1H NMR: δ 15.06 (s, H, N
­ Hthiadiazole, exchangeable by­D2O), 10.79 (s, H, NH, exchangeable by D­ 2O), 7.77–7.14(m, 5H, ArH) ppm; 13C NMR: δ 190.78 (C=S), 157.25(C=O), 155.34, 137.91 (2C, Thiadiazole), 129.20, 125.23,
121.34 ppm (C of Arom.). Anal. Calcd. for C­ 9H7N3OS2(237.30): C, 45.55; H, 2.91; N, 17.71; S, 27.02% Found: C,
45.65; H, 2.81; N, 17.61; S, 27.12%.
5-Thioxo-N-(o-tolyl)-4,5-dihydro-1,3,4-thiadiazole2-carboxamide (3b): Orange crystals, yield 91%, mp.
177–179 °C; FT-IR (ATR) δmax: 3342, 3311 (2NH str.),3057 ­(CHarom str.), 1681 (C=O str.), 1648 (C=N str.),
1222 (C=S str.); 1H NMR: δ 15.06 (s, H, N
­ Hthiadiazole),
10.79 (s, H, NH), 7.39–7.19 (m, 4H, ArH), 2.24 ppm(s, 3H, C­ H3); 13C NMR: δ 190.55 (C=S), 157.25 (C=O),
155.15, 137.91 (2C, Thiadiazole), 134.62, 132.10, 129.20,
125.23, 121.34 (Arom.), 18.54 ppm ­(CH3). Anal. Calcd.

for ­C10H9N3OS2 (251.33): C, 47.79; H, 3.61; N, 16.72; S,
25.52% Found: C, 47.35; H, 3.95; N, 16.52; S, 25.31%.
N-(4-methoxyphenyl)-5-thioxo-4,5-dihydro-1,3,4thiadiazole-2-carboxamide (3c): Orange crystals,
yield 88%, mp. 193–195 °C; FT-IR (ATR) δmax: 3348,
3316 (2NH str.), 3132 ­(CHarom str.), 1675 (C=O str.),
1659 (C=N str.), 1236 (C=S str.); 1H NMR: δ 15.06 (s,H, ­NHthiadiazole), 10.79 (s, H, NH), 7.77–7.35 (dd, 4H,
ArH, J = 8.08Hz), 4.18 (s, 3H, O­ CH3) ppm; 13C NMR:
δ 201.67 (C=S), 170.85 (C=O), 165.93 (C, Thiadiazole)
137.94, 129.25, 125.29, 121.31 (Arom.), 54.21 (OCH3)
ppm.Anal. Calcd. for ­C10H9N3O2S2 (267.33): C, 44.93;
H, 3.39; N, 15.72; S, 23.99% Found: C, 44.57; H, 3.75; N,
16.30; S, 23.58%.
N-(4-nitrophenyl)-5-thioxo-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (3d): Orange crystals, yield 70%,
mp. 201–203 °C; FT-IR (ATR) δmax: 3351, 3327 (2NHstr.), 3136 (­CHarom str.), 1678 (C=O str.), 1666 (C=Nstr.), 1350, 1555 (­NO2 str.), 1225 (C=S str.); 1H NMR:δ 15.01 (s, H, ­NHthiadiazole), 10.79 (s, H, NH), 7.77–7.35
ppm (dd, 4H, ArH, J = 8.08Hz) ppm; 13C NM: δ 190.78(C=S), 157.25 (C=O), 155.15 (C, Thiadiazole) 144.07,
129.25, 129.20, 125.23, 121.34 ppm (Arom.) Anal.
Calcd. for C­ 9H6N4O3S2 (282.30): C, 38.29; H, 2.14; N,
19.85; S, 22.72% Found: C, 38.17; H, 2.24; N, 19.15; S,
22.52%.

El‑Saghier et al. BMC Chemistry(2024) 18:138

General synthesis of 5‑(S‑alkyl)‑1.3.4‑thiadiazole‑2‑carboxamide derivatives

A mixture of N-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide derivatives (2a–d) (0.01 mmol),potassium hydroxide (0.03 mmol) and alkyl halide (0.015mmol) were added and stirred in ethanol for 2 h. The
formed precipitate was collected and crystallized fromethanol.
5-(Methylthio)-N-phenyl-1,3,4-thiadiazole-2-carboxamide (4a): White crystals, yield 97%, mp. 160–162 °C;
FT-IR (ATR) δmax: 3381 (NH str.), 3156 ­(CHarom str.),2923 ­(CH3 alip str.), 1673 (C=O str.), 1659 (C=N str.); 1H
NMR: δ 11.03 (s, H, NH), 7.85–7.14 (m, 5H, ArH), 2.83
ppm (s, 3H, S­ CH3); 13C NMR: δ 173.51 (C=O), 165.29,
156.32 (2C, Thiadiazole), 138.12, 129.18, 125.11, 121.27(Arom.), 17.37 ppm ­(SCH3). Anal. Calcd. for ­C10H9N3OS2(251.33): C, 47.79; H, 3.61; N, 16.72; S, 25.52% Found: C,
47.99; H, 3.41; N, 16.42; S, 25.80%.
5-(Methylthio)-N-(o-tolyl)-1,3,4-thiadiazole-2-carboxamide (4b): White crystals, yield 87%, mp. 155–157°C; FT-IR (ATR) δmax: 3383 (NH str.), 3107 ­(CHarom str.),
2988, 2963 (­CH3 str.), 1679 (C=O str.), 1609 (C=N str.);
1
H NMR: δ 10.60 (s, H, NH), 7.39–7.19 (m, 4H, ArH),
2.30 (s, 3H, ­CH3 Arom), 2.24 (s, 3H, ­SCH3) ppm; 13C
NMR: δ 170.71 (C=O), 165.69, 156.44 (2C, Thiadiazole),
135.25, 134.08, 130.93, 127.11, 126.64, 125.23 (Arom.),
28.93 ­(SCH3), 25.28) ppm ­(CH3 Arom.). Anal. Calcd.
for ­C11H11N3OS2 (265.35): C, 49.79; H, 4.18; N, 15.84; S,
24.17% Found: C, 49.63; H, 4.22; N, 15.76; S, 24.16%.
N-(4-methoxyphenyl)-5-(methylthio)-1,3,4-thiadiazole-2-carboxamide (4c): Orange crystals, yield 66%,
mp. 198–200 °C; FT-IR (ATR) δmax: 3379 (NH str.), 3251­(CHarom str.), 2996, 2985 (­CH3alip str.), 1675 (C=O str.),1605 (C=N str.); 1H NMR: δ 11.07 (s, H, NH), 7.83–7.38(dd, 4H, ArH, J=8.08Hz), 4.04 (s, 3H, O­ CH3), 2.31 ppm(s, 3H, S­ CH3); 13C NMR: δ 170.85, 165.93, 155.15, 137.94,
129.25, 125.29, 121.31 Arom, 54.21 (OCH3), 24.64 ppm(SCH3). Anal. Calcd. for ­C11H11N3O2S2 (281.35): C, 46.96;
H, 3.94; N, 14.93; S, 22.79% Found: C, 46.77; H, 3.89; N,
15.03; S, 22.64%.
5-(Ethylthio)-N-phenyl-1,3,4-thiadiazole-2-carboxamide (5a): White crystals, yield 73%, mp. 157–159 °C;
FT-IR (ATR) δmax: 3336.85 (NH str.), 3061 ­(CHarom str.),
2979–2870 ­(CH2CH3alip str.), 1670 (C=Oamidic str.),1599(C=N str.); 1H NMR: δ 11.04 (s, H, NH), 7.84–7.15 (m,5H, ArH), 3.41, 3.40, 3.38, 3.36 (q, 2H, ­SCH2, J = 6.6 Hz),
1.45, 1.43, 1.41 ppm (t, 3H, ­CH3, J = 6.6 Hz); 13C NM: δ
171.47(C=O), 165.37, 156.31 (2C, Thiadiazole), 138.06,
131.87, 125.18, 121.28 (Arom.), 29.18 ­(CH2), 14.64 ppm­(CH3). Dept -135 NMR; 129.35,124.90,121.31 Arom,
29.36, 14.57 ppm. Anal. Calcd. for C­ 11H11N3OS2 (265.03):
C, 49.79; H, 4.18; N, 15.84; S, 24.17% Found: C, 49.39; H,
4.18; N, 15.98; S, 24.03%.

Page 14 of 215-((2-Methylbutyl) thio)-N-phenyl-1,3,4-thiadiazole2-carboxamide (6a): White crystals, yield 84%, mp.
150–152 °C; FT-IR (ATR) δmax: 3340 (­ NHamidic str.), 3061­(CHarom str.), 2961–2869 (­ CHaliphatic str.), 1667 (C=Oamidicstr.), 1599 (C=N str.); 1H NMR: δ 11.04 (s, H, NH), 7.82–
7.10 (m, 5H, ArH), 3.33, 3.31 (d, 2H,SCH2), 1.62, 1.60,
1.59, 1.53, 1.50 (m, 3H, (CH(CH3)CH2)), 0.87, 0.86, 0.82
ppm (t, 6H, CH3)CH2CH3); 13C NMR: δ 171.90 (C=O),
165.44, 156.25 (2C, Thiadiazole), 138.06, 129.15, 125.11,
121.21 (Arom.), 44.50, 37.88, 32.79, 27.40, 22.40 ppm.
Anal. Calcd. for C­ 14H17N3OS2 (307.43): C, 54.69; H, 5.57;
N, 13.67; S, 20.86% Found: C, 54.46; H, 5.77; N, 13.58; S,
20.73%.
5-(Benzylthio)-N-phenyl-1,3,4-thiadiazole-2-carboxamide (7a): White crystals, yield 95%, mp. 237–239 °C;
FT-IR (ATR) δmax: 3223 (NH str.), 3056 ­(CHarom str.), 2958­(CH2alip str.), 1667 (C=Oamidic str.), 1625 (C=N str.); 1H
NMR δ 11.05 (s, H, NH), 7.83–7.15(m, 10H, ArH), 4.67(s,2H, ­SCH2) ppm; 13C NMR δ 171.19 (C=O), 165.87,156.26(2C, Thiadiazole), 138.03, 136.40, 129.66, 129.25, 129.11,
128.32, 125.23, 121.25 (Arom.), 38.109 ppm (­ CH2). Dept135 NMR; 129.61, 129.25, 129.11, 128.32, 125.28, 121.31(Arom.), 38.20 ppm (­ CH2). Anal. Calcd. for C­ 16H13N3OS2(327.42): C, 58.69; H, 4.00; N, 12.83; S, 19.59% Found: C,
58.66; H, 4.28; N, 12.19; S, 19.89%.
5-(Benzylthio)-N-(o-tolyl)-1,3,4-thiadiazole-2-carboxamide (7b): White crystals, yield 78%, mp. 211–213°C; FT-IR (ATR) δmax: 3345 (NH str.), 3105 ­(CHaromstr.), 2971 ­(CH3 str.), 1662 (C=O str.), 1605 (C=N str.);
1
H NMR: δ 11.05 (s, H, NH), 7.83–7.15 (m, 9H, ArH),
4.67(s, 2H, ­SCH2), 1.21 ppm (s, 3H, CH3); 13C NMR: δ
171.19 (C=O), 165.87, 156.26 (2C, Thiadiazole), 140.98,
136.40, 133.74, 129.25, 129.11, 128.32, 125.23, 121.25(Arom.), 38.10 ­(CH2), 23.09 ppm ­(CH3). Anal. Calcd.
for ­C17H15N3OS2 (341.45): C, 59.80; H, 4.43; N, 12.31; S,
18.78% Found: C, 59.87; H, 4.33; N, 12.37; S, 18.54%.
5-((2-Oxopropyl)
thio)-N-phenyl-1,3,4-thiadiazole2-carboxamide (8a): White crystals, yield 93.5%, mp.
217–219 °C; FT-IR (ATR) δmax: 3332 (NH str.), 3060­(CHarom str.), 2917 (­CH3 alip str.), 1710 (C=O str.) 1661
(C=Oamidic str.), 1622 (C=N str.); 1H NMR: δ 11.03 (s,H, NH), 7.83–7.17 (m, 5H, ArH), 4.52 (s, 2H, ­SCH2),
2.31 ppm (s, 3H, ­CH3); 13C NMR: δ 201.67 (C=O),
170.85(C=Oamidic), 165.93, 1 56.31 (2C, Thiadiazole),
137.94, 129.25, 125.29, 121.06, 44.64 (­CH2), 29.18 ppm­(CH3), Dept-135; 129.34, 125.19, 121.39 (Arom.), 44.59­(SCH2), 29.02 ppm ­(CH3). Anal. Calcd. for ­C12H11N3O2S2(293.36): C, 49.13; H, 3.78; N, 14.32; S, 21.86% Found: C,
49.53; H, 3.68; N, 14.39; S, 21.69%.
5-((2-Oxopropyl) thio)-N-(o-tolyl)-1,3,4-thiadiazole2-carboxamide (8b): White powder, yield 81.5%, mp.
205–207 °C; FT-IR (ATR) δmax: 3325 (NH str.), 3060­(CHarom str.), 2957(CH3alip str.), 1713 (C=O str.), 1667

El‑Saghier et al. BMC Chemistry(2024) 18:138(C=Oamidic str.), 1606 (C=N str.); 1H NMR: δ 10.61 (s, H,NH), 7.39–7.19 (m, 4H, ArH), 4.52 (s, 2H, S­ CH2), 2.30
(s, 3H, ­COCH3), 2.24 (s, 3H, ­CH3 ArH) ppm; 13C NMR:
δ 201.57 (C=O), 170.71 (C=Oamidic), 165.69, 156.44,(2C, Thiadiazole), 135.85, 130.93, 127.11, 126.66, 126.64(Arom.), 44.64 ­(SCH2), 28.93 (COCH3), 18.10 ppm (­CH3
Arom). Anal. Calcd. for ­C13H13N3O2S2 (307.39): C, 50.79;
H, 4.26; N, 13.67; S, 20.86% Found: C, 50.33; H, 4.87; N,
13.47; S,20.71%.
N-(4-methoxyphenyl)-5-((2-oxopropyl)
thio)-1,3,4thiadiazole-2-carboxamide (8c): White crystals, yield
72%, mp. 267–269 °C; FT-IR (ATR) δmax: 3343 (NH),3067 ­(CHarom), 2949–2854 (­CH2CH3alip), 1710 (C=O),
1661 (C=Oamidic), 1622 (C=N str.); 1H NMR: δ 10.07(s, H, NH), 7.83–7.38 (dd, 4H, ArH, J = 8.08 Hz), 4.52
(s, 2H, SCH2), 4.09 (s,3H, ­COCH3)), 2.31 ppm (s, 3H,­OCH3); 13C NMR:δ 201.67 (C=O), 170.85 (C=Oamidic),
165.93, 156.31 (2C, Thiadiazole), 137.94, 129.25, 125.29,
121.31 (Arom.), 57.13 (OCH3), 44.64 ­(SCH2), 29.35 ppm­(COCH3). Anal. Calcd. for ­C13H13N3O3S2 (323.39): C,
48.28; H, 4.05; N, 12.99; S, 19.83% Found: C, 48.65; H,
4.35; N, 12.78; S, 19.48%.
N-(4-nitrophenyl)-5-((2-oxopropyl)
thio)-1,3,4-thiadiazole-2-carboxamide (8d): White crystals, yield 66%,
mp. 280–282 °C; FT-IR (ATR) δmax: 3345 (NH str.), 3191­(CHarom str.), 3104–2921 (­CH2, ­CH3alip str.), 1762 (C=Ostr.), 1678 (C=Oamidic str.), 1659 (C=N str.), 1536,1341­(NO2 str.); 1H NMR: δ 11.15 (s, H, NH), 7.89–7.44 (dd,
4H, ArH, J = 8.08 Hz), 4.67 (s, 2H, S­ CH2), 2.15 ppm (s,3H, ­CH3); 13C NMR:δ 202.02 (C=O), 171.89 (C=Oamidic),
166.54, 157.13 (2C, Thiadiazole), 138.11, 129.66, 125.51,
121.82 (Arom.), 44.69 (­SCH2), 29.67 ppm (­COCH3).
Anal. Calcd. for C­ 12H10N4O4S2 (338.36): C, 42.60; H, 2.98;
N, 16.56; S, 18.95% Found: C, 42.63; H, 2.95; N, 16.59; S,
18.94%.
Ethyl
2-((5-(phenylcarbamoyl)-1,3,4-thiadiazol2-yl) thio) acetate (9a): White crystals, yield 64%, mp.
133–13; FT-IR (ATR) δ max: 3537 ­(NHamidic str.), 3142­(CHarom str.), 2983–2905 (­CH2, ­C H3alip str.), 1737.94(C=O str.), 1664.28 (C=Oamidic str.), 1605 (C=N str.);
1
H NMR: δ 11.05 (s, H, NH), 7.83–7.15 (m, 5H, ArH),
4.35 (s, 2H, S­ CH2), 4.20, 4.18, 4.16, 4.14 (q, 2H, ­C H2,
J = 7.08 Hz), 1.23, 1.22, 1.20 ppm (s, 3H, C­ H3, J = 7.08Hz); 13C NMR: δ 170.42 (C=O), 168.08, (C=O amidic),
166.38, 156.55 (2C, Thiadiazole), 137.87, 128.85,
125.61, 121.2 (Arom.), 3,62.19, 36.23, 14.34 ppm­(CH3). Dept-135; 129.31, 125.21, 121.40 (Arom.),
62.12, ­(SCH2), 35.67 (COOCH2), 14.56 ppm ­(CH3).
Anal. Calcd. for ­C13H13N3O3S2 (323.39): C, 48.28; H,
4.05; N, 12.99; S, 19.83% Found: C, 48.50; H, 4.17; N,
12.58; S, 19.48%.
2-((5-(Phenylcarbamoyl)-1,3,4-thiadiazol-2-yl)thio)acetic acid (10a): White crystals, yield 90%, mp.

Page 15 of 21

199–201 °C; FT-IR (ATR) δmax: 3322 ­(NHamidic str.),3104 (br OH str.), 3061 ­(CHarom str.), 2979–2926­(CH2CH3alip str.), 1721 (C = O str.) 1665 (C=Oamidicstr.), 1599 (C=N str.); 1H NMR: δ 15.11 (s, H, COOH),
11.04 (s, H, NH), 7.81 -7.18, (m, 5H, ArH), 4.52 (s,2H, ­SCH2) ppm; 13C NMR: δ 170.63 (C=O), 169.39(C=Oamidic), 165.95, 156.33 (2C, Thiadiazole), 137.86,
129.28, 125.36, 121.35 (Arom.), 36.36 ppm ­(CH2).
Dept-135; 129.32, 125.50, 121.40 (CH Arom), 36.27
ppm ­(CH2). Anal. Calcd. for C­ 11H9N3O3S2 (295.34): C,
44.73; H, 3.07; N, 14.23; S, 21.71% Found: C, 44.33; H,
3.37; N, 14.43; S, 21.53%.
O-ethyl
S-(5-(phenylcarbamoyl)-1,3,4-thiadiazol2-yl) carbonothioate (11a): White powder, yield 53%,
mp. 166–168 °C; FT-IR (ATR) δmax: 3349 ­(NHamidicstr.), 3055 (­CHarom str.), 2984–2870 (­CH2CH3alip str.),
1729.32 (C=O str.) 1682 (C=Oamidic str.), 1641 (C=Nstr.); 1H NMR: δ 11.23 (s, H, NH), 7.82 -7.15 (m, 5H,
ArH), 4.76–4.67 (q, 2H, ­C H2, J = 10.88 Hz), 1.05–1.00
ppm (t, 3H, ­C H3, J = 10.88 Hz); 13C NMR: δ 168.75(C=O), 164.29 (C=O), 158.51, 155.86 (2C,Thiadiazole),
137.87, 129.20, 125.20, 121.35 (Arom.), 56.53 ­(CH2),
18.86 ppm (­CH3). Anal. Calcd. for C­12H11N3O3S2(309.36): C, 46.59; H, 3.58; N, 13.58; S, 20.73% Found:C, 46.44; H, 3.81; N, 13.78; S, 20.55%.
General synthesis of 5‑(substituent)‑N‑phenyl‑1,3,4‑thiadiazole‑2‑carboxamide derivatives 12a–18a

A mixture of 2-hydrazinyl-N-phenyl-2-thioxoacetamide (1a) (1.0 mmol) and an aldehyde namely; cinnamaldehyde, p-N, N dimethylaminobenzaldehyde,
3,4,5-trimethoxy-benzaldehyde,
1-naphthaldehyde,
pipreonal, p methylbenzaldehyde and glyoxal (1.0mmol) was refluxed for 3 h. in acetic acid. The solid
product was filtrated and crystallized from ethanol, see
Figure (S55–S71).
N-phenyl-5-styryl-1,3,4-thiadiazole-2-carboxamide(12a): Yellow crystals, yield 71%, mp. 226–228 °C FT-IR(ATR) δmax: 3328 (NH str.), 3108 ­(CHarom str.), 3057–
2923 (CH=CHalip str.), 1685 (C=O str.), 1599 (C=Nstr.); 1H NMR: δ 10.70 (s, H, NH, exchangeable by D­ 2O),
7.85–7.08 (m, 10H, ArH), 6.68 (s, 2H, CH=CH) ppm;
13
C NMR: δ 167.81 (C=O), 163.20, 158.13 (2C, Thiadiazole), 144.36, 141.98, 139.27, 139.04, 138.66, 133.38,
129.05, 124.05, 120.74, 112.13 (Arom.) ppm. Anal. Calcd.
for ­C17H13N3OS (307.37): C, 66.43; H, 4.26; N, 13.67; S,
10.43% Found: C, 66.38; H, 4.31; N, 13.61; S, 10.45%.
5-[4-(Dimethylamino)
phenyl]-N-phenyl-1,3,4-thiadiazole-2-carboxamide (13a): Red crystals, yield 91%,
mp. 210–212 °C FT-IR (ATR) δmax: 3327 (NH str.), 3087­(CHarom str.), 2983–2874 (­ CH3 str.), 1664 (C=O str.), 1625
(C=N str.); 1H NMR: δ 11.31 (s, H, N
­ Hamidic, exchangeable

El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 16 of 21

Table 3 Docking data

5a

8a

10a

9a

7a

11a

8b

8d

7b

4b

6a
4a

3a

4c

LigandReceptor

Interaction

Distance

E (kcal/mol)

S (kcal/mol)

N7

MET 37

H-donor

3.880− 1.090− 5.783

S 15

ALA 73H-donor3.300− 1.190

O9

ARG 176H-acceptor

2.430− 4.100

6-ring

ARG 204

pi-H

3.420

− 1.080

S 11

MET 37

H-donor3.730− 1.130

S 11

ASP 38H-donor

3.990− 1.160

S 11

ASP 38H-donor

3.640− 1.200

S 15

ASP 38H-donor3.410− 1.290

S 15

ASP 38H-donor3.440− 1.130

O 18

ARG 52

H-acceptor

2.750− 1.340

S 11

THR 214

H-donor

2.920− 1.720

S 15

THR 214

H-donor3.230− 1.530

O 19

ASP 42H-donor

2.500− 5.910

6-ring

LYS 203

pi-H

3.330

− 1.700

N7

MET 37

H-donor3.210− 2.220

S 15

ARG 202

H-donor

3.530− 1.510O9

ARG 176H-acceptor

2.630− 2.300

5-ring

ARG 204

pi-H

3.880

− 1.3805-ring

ARG 204

pi-H

3.030

− 1.160

S 11

MET 37

H-donor

2.610− 1.960

S 11

ALA 41

H-donor

3.160− 1.710N 14

THR 214

H-acceptor

2.700− 2.800

S 11

ASP 38H-donor3.640− 1.140

S 15

ASP 38H-donor

2.730− 1.390

O 18

LYS 248

H-acceptor

3.040− 1.700

S 11

ASP 38H-donor

2.710− 2.200

S 15

ASP 38H-donor

3.010− 1.600

O 19

TYR 212H-acceptor

2.920− 1.620S 11

ASP 42H-donor

2.750− 2.540

O 21

TYR 212H-acceptor

2.540− 1.810O 22

LYS 248

H-acceptor

3.060− 1.630

5-ringASP 213

pi-H

3.320

− 1.850

5-ring

THR 214

pi-H

3.990

− 1.140

S 11

ASP 42H-donor2.750− 1.830

S 15

ASP 78H-donor3.950− 1.510

6-ring

MET 37

pi-H

3.690

− 0.600

S 11

ASP 38H-donor2.790− 1.130

S 15

ASP 38H-donor

3.080− 1.400

6-ringTYR 212

pi-H

3.730

− 1.170

S 15

MET 37

H-donor2.320− 1.140

O9

LYS 248

H-acceptor

2.840− 1.600

N7

MET 37

H-donor

3.120− 2.800

N 14

MET 37

H-donor

3.160− 1.130

S 15

ASP 38H-donor

3.560− 1.810S 15

ASP 38H-donor

3.570− 0.740O9

ARG 176H-acceptor

2.710− 1.820N7

MET 37

H-donor

3.860− 1.350

S 15

ALA 73H-donor

3.160− 1.300

O9

ARG 176H-acceptor

2.560− 2.600

N7

THR 214

H-donor

2.740− 1.560

S 11

ASP 42H-donor

2.760− 2.430

S 15

ALA 41

H-donor

2.830− 1.980− 5.809− 5.560− 5.616− 6.098− 6.368− 6.431− 6.814− 6.315− 5.463− 5.817− 6.498− 6.821− 6.809El‑Saghier et al. BMC Chemistry(2024) 18:138

Page 17 of 21

Table 3 (continued)

13a

18a

LigandReceptor

Interaction

Distance

E (kcal/mol)

S (kcal/mol)

S 14

GLU39

H-donor3.22− 0.80− 6.670

O 10

LYS3

H-acceptor

3.12− 1.406-ring

GLU39

pi-H

4.18

− 0.60N9

ASP38

H-donor2.91− 1.60

O 22

LYS248H-acceptor

2.93− 7.606-ring

THR214pi-H

4.12− 0.60by ­D2O), 8.23–7.09 (m, 9H, ArH), 2.84 (s, 6H, 2­ CH3);
13
C NMR: δ 171.33 (C=O), 166.60, 162.53 (2C, Thiadiazole), 156.24, 137.00, 135.08, 133.21, 129.07, 125.90,
125.34, 121.20 (Arom.), 36.42 ppm ­(2CH3). Anal. Calcd.
for ­C17H16N4OS (324.40): C, 62.94; H, 4.97; N, 17.27; S,
9.88% Found: C, 62.85; H, 4.98; N, 17.29; S, 9.89%.
N-Phenyl-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole-2-carboxamide (14a): White crystals, yield 76%,
mp. 199–201 °C FT-IR (ATR) δmax3278 (NH str.), 3146­(CHarom str.), 2998–2874 ­(OCH3 str.), 1671 (C=O str.),
1625 (C=N str.); 1H NMR: δ 10.21 (s, H, NH, exchangeable by ­D2O), 7.99–7.12 (m, 7H, ArH), 3.94 (s, 9H,­3OCH3) ppm; 13C NMR: δ 173.54 (C=O), 167.53, 162.81(2C, Thiadiazole), 151.80, 147.37, 135.70, 130.09, 126.28,
124.31, 122.13, 120.55 (Arom.), 56.56, 48.97 (­3OCH3)
ppm. Anal. Calcd. for C­ 18H17N3O4S (371.41): C, 58.21; H,
4.61; N, 11.31; S, 8.63% Found: C, 58.25; H, 4.62; N, 11.28;
S, 8.58%.
5-(Naphthalen-1-yl)-N-phenyl-1,3,4-thiadiazole-2-carboxamide (15a): Pale yellow crystals, yield 67%, mp.
245–247 °C FT-IR (ATR) δmax: 3317 (NH str.), 3037–2985­(CHarom str.), 1673 (C=O str.), 1625 (C=N str.); 1H NMR:δ 10.52 (s, H, ­NHamidic, exchangeable by ­D2O), 7.81–7.09
ppm (m, 12H, ArH) ppm; 13C NMR: δ 171.96 (C=O),
164.76, 156.81 (2C, Thiadiazole), 135.95, 135.38, 133.68,
132.99, 129.43, 129.21, 129.25, 128.36, 128.21, 128.05,
121.29, 120.61, 119.76, 117.78 (Arom.) ppm. Anal. Calcd.
For ­C19H13N3OS (331.39): C, 68.91; H, 3.93; N, 12.64; S,
9.68% Found: C, 68.86; H, 3.95; N, 12.68; S, 9.66%.
5-(Benzo[d][1,3]dioxol-5-yl)-N-phenyl-1,3,4-thiadiazole-2-carboxamide (16a): White crystals, yield 74%,
225–227 °C FT-IR (ATR) δmax: 3330 (NH str.), 3059­(CHarom str.), 2962 ­(CH2alip str.), 1690 (C=O str.), 1622
(C=N str.); 1H NMR: δ 10.20 (s, H, NH, exchangeable by­D2O), 7.75–6.93 (m, 8H, ArH), 6.58 (s, 2H, C­ H2 piprenal)
ppm; 13C NMR: δ 171.05 (C=O), 161.88, 158.45 (2C, Thiadiazole), 147.37, 146.15, 141.08, 139.21, 129.71, 127.85,
125.36, 121.57, 133.05, 111.04 (Arom.), 101.04 ­(CH2 piprenal) ppm. Anal. Calcd. for ­C16H11N3O3S (325.34): C,
59.07; H, 3.41; N, 12.92; S, 9.86% Found: C, 59.20; H, 3.38;
N, 12.81; S, 9.84%.

− 7.380

N-phenyl-5-(p-tolyl)-1,3,4-thiadiazole-2-carboxamide(17a): Pale yellow, yield 77%, mp. 233-235°C FT-IR (ATR)
δmax: 3322 (NH str.), 3125 ­(CHarom str.), 2976 ­(CH3alip str.),
1677 (C=O str.), 1625 (C=N str.); 1H NMR: δ 10.20 (s, H,
NH, exchangeable by ­D2O), 7.89–7.13 (m, 9H, ArH), 3.41 (s,3H, ­CH3) ppm; 13C NMR: δ 172.26 (C=O), 166.02, 156.66(2C, Thiadiazole), 153.95, 141.17, 138.14, 129.24, 125.22,
124.85, 121.40, 105.40 (Arom.), 19.02 ppm (­CH3). Anal.
Calcd. For ­C16H13N3OS (295.36): C, 65.06; H, 4.44; N, 14.23;
S, 10.86% Found: C, 64.98; H, 4.46; N, 14.21; S, 10.88%.
N,N-diphenyl-2,2’,3,3’-tetrahydro[2,2’-bi(1,3,4thiadiazole)]-5,5’-dicarboxamide (18a): Orange crystals,
yield 81%, mp. 187–189 °C FT-IR (ATR) δmax3321, 3255
(2NH str.), 3079 ­(CHarom str.), 2968 ­(CHthiadiazole str.),
1693 (C=O str.), 1625 (C=N str.); 1H NMR: δ 10.19 (s, H,­NHamidic, exchangeable by ­D2O), 9.04 (s, H, N
­ Hthiadiazole,exchangeable by D­ 2O), 7.74–7.06 (m, 5H, ArH), 5.53 (s,2H, ­CHthiadiazole) ppm; 13C NMR: δ 159.13 (C=O), 139.04(C, Thiadiazole), 138.66, 129.05, 124.29, 120.74 (Arom.),
76.13 ppm (­ CHthiadiazole); Dept-135 NMR; 129.09, 129.25,
124.31, 120.74 (Arom.), 75.98 ppm ­(CHthiadiazole) Anal.
Calcd. for C­ 18H16N6O2S2 (412.49): C, 52.41; H, 3.91; N,
20.37; S, 15.55% Found: C, 52.46; H, 3.90; N, 20.39; S,
15.52%.
Biological evaluation
Antimicrobial screening

According to the antibacterial activity of several compounds was screened using the agar well diffusion
method [43]. Ciprofloxacin was utilized to compare theresults as a positive control. Dimethylsulfoxide (DMSO)
solution (10% v/v) was used as a negative control.
In‑vitro anti‑inflammatory activity (protein denaturation)of the tested compounds

For the test compounds and the reference medication,
diclofenac sodium, 0.05 mL of various concentrations(50, 100, 150, 200, and 250 µg/ml) were used, respectively.
Then all tubes were combined with 0.45 ml (0.5% w/v) of
BSA. The samples were heated for 3 min to maintain atemperature of 57 °C after being incubated at 37 °C forEl‑Saghier et al. BMC Chemistry

3D(2024) 18:138

Page 18 of 21

2D

8b

3a

8d
4a

9a

4b

10a

4c

11a

5a

13a

6a

7a

7b

8a

Fig. 5 2D and 3D views of the docked compounds with DHPS

18a

El‑Saghier et al. BMC Chemistry(2024) 18:138

20 min. Add 2.5 ml of phosphate buffer to the aforementioned solutions after cooling. At 660 nm, a UV–Visible
spectrophotometer was used to detect the absorbance.
Protein denaturation at 100% is represented by the control. A positive control drug called diclofenac sodium wasused to compare the outcomes [44]. Calculations can bemade to determine the degree of protein denaturation
inhibition.

% inhibition of denaturation = 100 × (1 − A2/A1)
A2 = Absorbance of the test sample, A1 = Absorbanceof control.
Statistical analysis

Analysis was performed using Statistical Program forSocial Science (SPSS) version 26 (Armonk, NY: IBM
Crop). The gathering of data was recorded and evaluatedon an IBM-compatible computer. One-way ANOVA wasused to determine if there was any statistically significant
difference. P value ≤ 0.05 was considered significant.

Molecular docking
To predict the binding style and interactions of theaforementioned drugs with dihydropteroate synthase,molecular docking experiments were carried out to better understand their efficacy (DHPS). This last one is a
crucial enzyme in the prokaryotic biosynthesis of folicacid and a crucial cofactor in the pathways that almost all
bacterial strains use to synthesize nucleic acids, making
it a prime candidate for antibiotics [45, 46]. Thus, crystal
structure of DHPS in complex with pterin-sulfonamide
conjugates [47]. PDB ID 6CLV, from S. aureus organism, was employed as a binding site in molecular docking simulations and downloaded from the RCSB protein
data library. The docking results showed strong interactions with high docking scores (S) (more negative) ofstudied compounds to DHPS from S. aureus. The negative values of the calculated docking scores (S) for studied compounds, Table 3, demonstrates that the bindingis spontaneous, and the chemicals are suitable for use as
drugs [48, 49].
The subject compounds had a strong docking scorefrom − 6.821 (3a), − 6.814 (8d), − 6.809 (4c), and− 6.498 (4a), to − 5.560 (10a), and − 5.463 (4b) Kcal/
mol toward the DHPS from S. aureus as can be shown
from (Table 3). Due to their high docking score, 3a,8d and 4c seem to be the most active. Compound 3a
revealed three hydrogen bonds interactions between N
7 with MET 37, S 15 with ALA 73, and O 9 with ARG
176; and 8d revealed three hydrogen bonds interactions
between S 11 with ASP 42, O 21 with TYR 212, and O
22 with LYS 248; furthermore, 4c revealed three hydrogen bonds interactions between N 7 with THR 214, S

Page 19 of 21

11 with ASP 42, S 15 with ALA 41. The docking results
showed good interactions of the investigated 13a, and18a compounds to DHPS from S. aureus (PDB ID:
6CLV). The subject 13a, and 18a compounds had gooddocking scores as − 6.670 kcal/mol, and − 7.380 kcal/
mol, respectively. The 13a revealed one H-donor, one
H-acceptor, and one pi-H interactions between S14GLU39, O10-LYS3, and 6-ring-GLU39, with distance of
3.22, 3.12, and 4.18 Angstrom, respectively, While, 18arevealed one H-donor, one H-acceptor, and one pi-H
interactions between N9-ASP38, O22-LYS248, and6-ring-THR214, with distance of 2.91, 2.93, and 4.12
Angstrom, respectively (Fig. 5).

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s13065-​024-​01237-9.
Supplementary Material 1.
Acknowledgements
The Faculty of Science, Sohag University, Egypt, have supplied the authors
with facilities and support, and they are sincerely grateful.
Author contributions
A.M.E.: Formal analysis, data collection, funding procurement, first draught
writing, writing reviews, and editing. A.A.: Writing the first draught, Writing
the review and editing. O.M.E.: Writing (first draught), writing (review andediting), approach, resources, formal analysis, data curation, and writing(original draught). W.M.A. writing an initial draught, reviewing, and editing thatdraught. A.M.K. Original draughts of writing, reviewing and correcting written
work, formal analysis, data collection and resources. The work’s published form
has been read by all authors and received their approval.
Funding
Open access funding provided by The Science, Technology & Innovation
Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank
(EKB).
Data availability
The authors declare that the data supporting the findings of this study areavailable within the paper and its Supplementary Information files. Should
any raw data files be needed in another format they are available from thecorresponding author upon reasonable request.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Chemistry Department, Faculty of Science, Sohag University, Sohag 82524,
Egypt. 2 Botany and Microbiology Department, Faculty of Science, Sohag
University, Sohag 82524, Egypt.
Received: 18 November 2023 Accepted: 28 June 2024

El‑Saghier et al. BMC Chemistry(2024) 18:138

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