Synthesis and antimicrobial activity of new 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, thiopyrane, thiazolidinone, and azepine derivatives

Synthesis and Antimicrobial Activity of New 1, 2, 4-Triazole, 1, 3, 4-Oxadiazole, 1,

, 4-Thiadiazole, Thiopyrane, Thiazolidinone and Azepine Derivatives

3

1, 2*

Ameen Ali Abu-Hashem

1

Photochemistry Department (Heterocyclic Unit), National Research Centre, 12622 Dokki, Giza,

2

Egypt; Chemistry Department, Faculty of Science, Jazan University, 45142 Jazan, Saudi Arabia.

*

Corresponding author: Tel.: +2-01225211700; +966-591363915, Fax: + 202 33370931,

E-mail address: aminaliabuhashem@yahoo.com (A.A.Abu-Hashem)

ABSTRACT: 4-oxo-4-phenylbutanehydrazide 3 was reacted with aryl or alkyl isothiocyanates to

give the corresponding N-substituted-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide

4

a-c. Cyclization of thiosemicarbazides 4a-c with sodium hydroxide led to the formation of 3-(4-

sub-5-thioxo-1, 2, 4-triazol-3-yl)-propanone 5a-c. Desulfurization of thiosemicarbazides 4a-c by

mercuric oxide afforded 3-(5-(sub-amino)-1, 3, 4-oxadiazol-2-yl)-propanone 6a-c. The reaction of

4

a-c with phosphorus oxychloride gave 3-(5-(sub-amino)-1, 3, 4-thiadiazol-2-yl)-propanone 7a-c.

Treatment of 4a-c with ethylbromoacetate or α-bromopropionic acid gave N’-(3-sub-thiazolidin-

-ylidene)-butanehydrazide 8a-c and (N'-(3-sub-oxothiazolidin-2-ylidene)-butanehydrazide 9a-c.

2

Chlorination of oxothiazolidine-hydrazide 9a-c by phosphorus oxychloride afforded N-(3-sub-4-

oxothiazolidine)-butane-hydrazonoyl-chloride 10a-c. The reaction of 10a-c with mercaptoacetyl-

chloride yielded 2-((4-benzoyl-thiopyrane) hydrazono)-3-sub-thiazolidinone 11a-c. Also, reacted

of 10a-c with hydrazine hydrate afforded N''-(3-sub-oxothiazolidine)-butane-hydrazon-hydrazide

1

2a-c. The 3-sub-2-((pyridazine) hydrazono) thiazolidinone 13a-c was obtained by cyclization of

2a-c via refluxing in DMF. The reaction and cyclized of 9a-c with chloroacetyl-chloride in

ethanolic KOH afforded 1-((3-sub-4-oxothiazolidine) amino)-azepine-dione 14a-c. The chemical

structures of the new compounds have been confirmed by diverse spectroscopy analyses such as

IR, NMR, MS and elemental analysis. The synthesized compounds were tested for their

antimicrobial activity and these compounds were considered (Pyridazin-hydrazono-thiazolidinone

1

3a-c, oxothiazolidin-azepinedione 14a-c, N-thiazolidin-hydrazonhydrazide 12a-c and thiopyran-

hydrazono-thiazolidinone 11a-c) the most effective as antimicrobial activity.

Keywords: 1, 2, 4-triazole, 1, 3, 4-oxadiazole, 1, 3, 4-thiadiazole, oxothiazolidine, hydrazide,

thiopyranone, pyridazine, azepine, isothiocyanates, thiosemicarbazides, antimicrobial activity.

This article has been accepted for publication and undergone full peer review but has

not been through the copyediting, typesetting, pagination and proofreading process

which may lead to differences between this version and the Version of Record. Please

cite this article as doi: 10.1002/jhet.4149

1

. INTRODUCTION

A wide diversity of pharmacological characteristic is associated with many heterocyclic

compounds such as; 1, 2, 4-Triazole derivatives are known to their biological activity as

[

1-3]

[4]

[5]

[6]

antimicrobial,

Analgesic, anticonvulsant and anti-inflammatory, anti-tumor, antiviral,

[

7]

and anti-parasitic. Also, 1, 3, 4-oxadiazoles have been famous for eighty years, thus it have

[

8]

[9]

important biological activities such as anti-spasmolytic and hypotensive,

anticonvulsant,

[

10]

[11]

[12]

[13]

antimicrobial,

anti-inflammatory and analgesic,

anticancer,

anti-proliferative,

anti-

[

14]

[15]

allergic,

and hypoglycemic,

. Moreover, the interaction of 1, 3, 4-oxadiazole or 1, 3, 4-

[

16-17]

thiadiazole derivatives with CT-DNA was investigated by different spectroscopic methods,

hence can benefit in understanding the binding mechanism of heterocyclic molecules and the

design of new effective molecules. Also, the interaction of DNA with 1,3,4-oxadiazoles or 1, 3,

4

-thiadiazoles lead to the formation of anti-proliferative cells, anticancer and antitumor agents

[

18-20]

through many scientific studies,

thus these compounds have the ability to the binding to

DNA which makes researchers use these compounds to develop many drugs in the future.

Furthermore, the 1, 3, 4-thiadiazole moiety is one of the most significant and well-known

heterocycles, which is a widespread and complement advantage of an assortment of natural

products and pharmaceutical, thiadiazole ring is existent as a core component in an organized of

drug categories. So, the 1, 3, 4-thiadiazole ring has become an important structure for the

development of new drugs because the 1, 3, 4-thiadiazole derivatives have a broad biological

[

21]

[22]

[23]

activities spectrum such as antimicrobial,

anticancer,

anticonvulsant,

anti-inflammatory

[

24]

[25]

[26]

[27]

and analgesic,

antiviral,

anti-leishmanial,

trypanocidal activity (anti-epimastigote),

[

28]

and carbonic anhydrase inhibitory activity.

Moreover, Thiazolidinone ring systems are known

[

29]

[30]

to possess many pharmacological activities including antioxidant,

antiviral,

antibacterial,

[

31]

[32]

antituberculosis,

lung cancer cell line A549,

and pyrazolo-oxothiazolidines as anti-proliferative agents against human

[

33]

the 2-(acetyloxy)-N-(5-nitro-2-thiazolyl) benz-amide formally

[

34]

known as Nitazoxanide (NTZ) drug (Fig.1) is an antiprotozoal drug. Besides, Azepines (seven-

member ring) is considering heterocyclic compounds containing a nitrogen atom and used to treat

[

35, 36]

[3]

many diseases as the anticancer and tumor metastasis inhibitory activities,

antimicrobial,

[

37]

and carbamazepine is used anti-depressants with anticonvulsant and analgesic properties,

and

mirtazapine is used as an antiemetic in animals, but in humans, it too has antihistaminic,

2

[

38]

insomnia, sedative, antidepressant and anxiolytic activity.

Also, diverse pharmacologically

valuable alkaloids have been specified which displayed a broad range of biological activities

including anticancer, antimalarial, and antiarrhythmic properties, members of the rhazinilam -

leuconoxine - mersicarpine triad of alkaloids occur in the plant family Apocynaceae, recently,

these natural products have been found in the following genera: Leuconotis, Alstonia,

[

39]

Aspidosperma,

shown in (Figure 1).

Fig.1. Chemical structure of many pharmaceutical activities

Moreover, the pyridazine derivatives have diverse types of biological activity such as anti-

[

40]

[41]

[42]

inflammatory and analgesic activity,

antimicrobial,

Also, more scientific researches have been published in the field of

medicinal chemistry containing heterocyclic compounds that possess multiple biological and

anti-tubercular,

and anti-secretory,

[

43]

anti-ulcer, antihistamine.

[

44-50]

pharmaceutical activities.

prepared new heterocyclic compounds such as N- hydrazine-carbothioamides; 1, 2, 4-triazoles; 1,

, 4-oxadiazoles; 1, 3, 4-thiadiazoles; 4-oxothiazolidines; pyridazin-hydrazono-thiazolidinones;

oxothiazolidin-azepine-diones with studying their activities as antimicrobial.

In continuation of our research work in this manuscript, we

3

2

. RESULTS AND DISCUSSION

.1. Chemistry

Treatment of 3-benzoylpropionic acid (1) with absolute ethanol containing 3-4 drops of

[

41]

concentrated H SO gave ethyl 4-oxo-4-phenylbutanoate (2).

However, refluxing (2) with

2

4

hydrazine hydrate for 3-5 hours led to the formation of 4-oxo-4-phenylbutanehydrazide (3), the IR

spectrum of 3 displayed the absence of an ester group and revealed absorption bands at ν 3405-

-1

3

325 cm due to the NH-NH group and 1722 and 1675 cm for the two ketone and amide

2

3

1

carbonyl groups. The H-NMR spectrum of 3 showed two singlet signals at δ 6.10, 9.08 ppm

corresponding to the two and one protons of the (NH ) and (NH) groups (with D O

2

exchangeable), respectively. Moreover, compounds 3 was reacted with isothiocyanate derivatives,

[

20]

namely phenyl-, benzyl-, and ethylisothiocyanate, to afford N-substituted-2-(4-oxo-4-

phenylbutanoyl) hydrazine-1-carbothioamide (4a-c) in good yields. The chemical structures of

a-c were allocated on the basis of their spectral data and elemental analyses. IR spectrum

4

−

1

−1

exhibited absorption bands at ν 3330-3155 cm (3NH), 1725-1718 and 1684-1680 cm (2CO),

−1 1

and the vibration coupling due to N-C=S functions at 1357-1350 cm . H-NMR spectrum of 4a

evidenced three singlet broad signals at δ 9.90, 10.70, 11.60 ppm conforming to the three protons

of the (3NH) group (with D O exchangeable). The MS of 2, 3, 4a, 4b and 4c exposed molecular

2

+

ion peaks at m/z = 206 (M , 100%), 192 (M , 100%), 327 (M , 100%), 341 (M , 90%), 279 (M ,

5%), respectively. All spectral data (IR, NMR, and Mass) and elemental analysis of new

9

compounds were clarified in the experimental section (Scheme 1).

Scheme 1: Synthesis of N-substituted-hydrazine-1-carbothioamide (4a-c) derivatives

Cyclization of N-substituted-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide (4a-c)

[

20]

via refluxing and heating with aqueous sodium hydroxide,

to give the 3-(4-substituted -5-

thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl)-1-phenylpropan-1-one (5a-c), all spectral data of

compounds 5a-c were agreed with the suggested structures. The IR spectrum of compound 5a-c

−

1

designated the existence of broad band absorption at ν 3315-3305 cm of one NH group, 1722-

−

1

−1

1

715 cm of the one carbonyl group and a stretching band in the zone of 1621-1617 cm , special

1

to the C=N of triazole ring. H-NMR of 5a showed one singlet broad signal at δ 12.10 ppm to the

one proton of the (NH) group (with D O exchangeable). Also, Desulfurization of

2

4

[

20]

thiosemicarbazides (4a-c) through yellow mercuric oxide in refluxing and boiling ethanol,

afforded 3-(5-(substituted-amino)-1, 3, 4-oxadiazol-2-yl)-1-phenylpropan-1-one (6a-c) in good

yields. The structures of 6a-c were confirmed on the foundation of elemental analyses, IR, NMR,

and mass spectra. The IR spectra of 6a-c shown the presence of a broad band absorption at ν

−

1

−1

3

265-3255 cm of one NH group, 1726-1723 cm of the one carbonyl group and a vibrational

−

1

band in the region of 1623-1619 cm for the C=N of oxadiazole ring. The mass spectrum of 6a,

+

6

b and 6c showed a molecular ion peaks at m/z = 293 (M , 98%), 307 (M , 90%), 245 (M , 95%).

[

20]

Meanwhile, the treatment of thiosemicarbazides (4a-c) with phosphorus oxychloride,

lead to

the formation of 3-(5-(substituted-amino)-1, 3, 4-thiadiazol-2-yl)-1-phenylpropan-1-one (7a-c).

1

The H-NMR spectrums of 7a showed two triplet signals at 2.83 and 2.93 ppm, J = 5.55 Hz

corresponding to the four protons of the (2CH ) and one singlet signals at 10.70 ppm conforming

2

1

3

to the one proton of the (NH) groups (with D O exchangeable) and the C-NMR spectrum of 7a

2

exposed absorption signals at  27.6 and 37.8ppm, conforming to two carbon atom of the (2CH₂)

groups, and 121.9, 124.3, 127.9, 128.5, 129.8, 132.5, 136.4, 138.2, 155.1 and 161.48 ppm due to

2

fourteen sp carbons atom of the aromatic carbons, and 183.8 ppm corresponding to the one

carbonyl group. Furthermore, Treatment of thiosemicarbazides (4a-c) with ethyl-bromoacetate,

[

20]

afforded the N'-(3-substituted-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutanehydrazide

−

1

(

8a-c), The IR spectra of 8a-c showed the absorption bands at ν 3325-3315 cm of one NH

−

1

group, 1733, 1693 and 1685 cm characteristic for the three carbonyl groups, and H-NMR

spectrum of 8a evidenced one singlet signal at δ 4.25 ppm conforming to the two protons of the

(

CH ) of thiazole ring and one singlet broad signal at δ 10.90 ppm agreeing to the one proton of

2

the (NH) group (with D O exchangeable). The MS of 8a, 8b and 8c discovered molecular ion

2

+

peaks at m/z 367 (M , 100%), 381 (M , 92%), 319 (M , 96%), respectively. Nonetheless,

[

20]

treatment of thiosemicarbazides (4a-c) with α-bromopropionic acid,

produced (N'-(3-

substituted-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane hydrazide (9a-c). The

1

structures of 9a-c were ascertained through spectral data and elemental analyses. H-NMR

spectrum of 9a clearly showed a doublet signals at δ 1.77 ppm, J = 5.80 Hz corresponding to thee

protons of the methyl group and a quartet signals at δ 4.50 ppm, J = 5.77 Hz conforming to the

methine proton of thiazolidinone ring and a broad singlet signal at 10.71 ppm to one proton of NH

group (with D O exchangeable). The mass spectra of 9a, 9b and 9c displayed molecular ion peaks

2

+

at m/z 381 (M , 100%), 395 (M , 88%), 333 (M , 94%) respectively, shown in (Scheme 2).

5

Scheme 2: Synthesis of 1, 2, 4-triazoles; 1, 3, 4-oxadiazoles; 1, 3, 4-thiadiazoles; thiazolidinones

Also, N-(3-substituted-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutanehydrazonoyl

chloride (10a-c) was prepared via gentle heating and refluxing of 9a-c with phosphorus

oxychloride in dry dioxane. The IR spectrum of 10a-c displayed the absence of any absorption

1

3

bands in the (NH) and C=O groups area. The C-NMR spectrum of 10a showed absorption

signals at  24.5, 31.6, 33.9 and 57.2 ppm, conforming to four carbon atoms of the (CH , 2CH

3

2

and CH-thiazole) groups respectively, and 127.8, 128.5, 128.8, 129.2, 132.7, 135.9, 136.6, 152.3

2

and 155.5 ppm due to fourteen sp carbons atom of the aromatic carbons and 172.3, 185.1 ppm

agreeing to the two carbonyl groups. As well, reaction of compounds (10a-c) with mercapto-

6

[

46]

acetyl chloride,

gave the 2-((4-benzoyl-5-oxotetrahydro-2H-thiopyran-2-ylidene) hydrazono)-

3

-substituted-5-methylthiazolidin-4-one (11a-c). Its IR spectrum of 11a revealed absorption

-1

bands around at ν 1724, 1718 and 1682 cm for three carbonyl groups and 1626 cm for (C=N)

1

and the H-NMR spectrum of 11a displayed a doublet signals at δ 1.75 ppm, J = 5.90 Hz agreeing

to thee protons of the methyl group and three a doublet signals at δ 2.70, 4.02 and 4.10 ppm, J =

5

.94 Hz conforming to the four protons of (2CH ) thiopyran ring and a quartet signals at 4.40 ppm

2

to one proton of CH- thiazole ring and a triplet signals at 5.95 ppm to one proton of CH-

thiopyran ring. Moreover, refluxing a mixture of 10a-c and hydrazine hydrate afforded N''-(3-

substituted-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutanehydrazon-hydrazide (12a-

−

1

c). The IR spectrum of 12a-c exhibited absorption bands around at ν 3440-3350 cm (NH-NH )

2

-1

groups and represented absorption bands at ν 1735 and 1688 cm for two carbonyl groups. Its

1

HNMR spectrum of 12a denoted two singlet singles at δ 6.60 and 10.50 ppm showing the

presence of one amino and one (NH) groups (with D O exchangeable). Furthermore, the

2

[41, 49, 50]

compounds 12a-c were condensed with dimethylformamide (DMF/ K CO ) solution,

2

3

stirring and refluxing for a long time under thin layer chromatography (TLC) control afforded 3-

substituted-5-methyl-2-((6-phenyl-4, 5-dihydropyridazin-3(2H)-ylidene) hydrazono) thiazolidin-

4

-one 13a-c in good yield. The IR spectrum of 13a demonstrated absorption bands around at ν

-1

1

3

344 cm for one (NH) and 1682 cm for one carbonyl group. The H-NMR spectrum of 13a

showing one singlet signals at δ 11.30 ppm for the one proton of one (NH) group (D O

2

exchangeable) and The mass spectrum of 13a, 13b and 13c indicated the molecular ion peak at

+

m/z =377 (M , 90%), 391 (M , 86%), 329 (M , 94%), respectively. Additionally, the reaction

mixture of (9a-c) and chloroacetyl-chloride [46] in ethanol with the existence of potassium

hydroxide yielded the corresponding1-((3-substituted-5-methyl-4-oxothiazolidin-2-ylidene)

amino)-6-chloro-5-phenyl-3, 4-dihydro-1H-azepine-2, 7-dione (14a-c). The IR spectra of (14a)

-1

revealed an absorption bands at ν 1690, 1685 and 1680 cm for three carbonyl groups, 1630 cm

-1

1

for (C=N), 1585 cm for (C=C) and 1185 cm for (C-Cl). The H-NMR spectrum of (14a)

exposed one doublet signals appeared at δ 1.69 ppm for three protons of the methyl group and two

triplets at δ 2.02 - 2.22 and 2.27 -2.35 ppm to four protons of (2CH ) groups in the azepine ring

2

and one quartet signals at δ 4.38 ppm for one proton of (CH) group in the thiazole ring. The NMR

and MS spectra supported the suggested structures (cf. experimental and Scheme 3).

7

Scheme 3: Synthesis of thiopyran, thiazolidinone, hydrazon-hydrazide, pyridazine, azepine-2, 7-

dione derivatives

8

3

. BIOLOGICAL ACTIVITIES

.1. Antimicrobial Activity

All compounds were tested in vitro to microbial activity (bacteria and fungi) and all the results

were offered in Tables 1 and 2. Numerous of the compounds were showing the best antimicrobial

-1

activity when compared with cefotaxime sodium (MIC = 1-4 μmol mL ) and nystatin (MIC 2-5

-1

μmol mL ). The new compounds 13a-c, 14a-c, 12a-c and 11a-c proved the better effective as an

antimicrobial activity to against Gram-positive bacteria; Streptococcus pyogenes, Staphylococcus

aureus, and Gram-negative bacteria; Klebsiella pneumoniae, Escherichia coli. The MIC values in

-1

μmol mL to the compounds were as the following: 13a-c (1-5), 14 a-c (1-6), 12a-c (4-8) and

1a-c (6-10). Also, some of the compounds as 10a-c, 9a-c, 8a-c and 5a-c displayed moderate

1

antimicrobial activities. Furthermore, the compounds 14a-c, 13a-c, 12a-c and 11a-c awarded a

3

potent antifungal activity with MIC in μmol /cm of 14a-c (1-5), 13 (2-6), 12a-c (4-8) and 11a-c

-1

(

6-10) when compared with the positive control, nystatin (MIC 2-5 μmol mL ). Some of the

compounds showed moderate antifungal activity when compared with nystatin (MIC 2-5 μmol

-1

mL ): 10a-c (8-12), 9a-c (10-15), 8a-c (13-17) and 5a-c (15-19). The tested fungi were Candida

albicans, Curvularia lunata, Alternaria alternata, and Aspergillus niger.

3

.2. Structure-Activity Relationships (SAR’s)

It is clear that the results as antimicrobial for the compounds synthesized in this manuscript show

the following and can be discussed as follows according to previous studies and new scientific

[

1-3, 10, 21, 31, 34, 41, 48]

articles.

1

- The compounds of 1-4 give less activity as antimicrobial due to the absence of any heterocyclic

ring such as 1, 2, 4-triazoles; 1, 3, 4-oxadiazoles; 1, 3, 4-thiadiazoles or thiazolidine ring.

2

- The compounds of 5-10 given medium activity as antimicrobial due to the presence of a single

heterocyclic ring, such as 1, 2, 4-triazole; 1, 3, 4-oxadiazole; 1, 3, 4-thiadiazole or thiazolidine

ring with a few heteroatoms of different elements, such as nitrogen, sulfur and oxygen atom.

3

- The compounds of 11-14 give higher activity as antimicrobial due to the presence of more than

one ring of the heterocyclic rings such as thiazolidine, thiopyran, pyridazine or azepine ring with

many heteroatoms of different elements such as nitrogen, oxygen and sulfur.

9

Therefore, new heterocyclic compounds were prepared that contain many rings known for their

biological activities as antimicrobial in order to increase the activities of these compounds.

Moreover, the chemical structures of these compounds and its relationship to increasing

biological activity (SAR’s) as antimicrobial can be discussed as follows; the excellent

antimicrobial activities were found to compounds; pyridazin-hydrazono-thiazolidinone (13a-c),

oxothiazolidin-azepine-2,7-dione

(14a-c),

N-oxothiazolidin-hydrazon-hydrazide

(12a-c),

thiopyran-hydrazono-thiazolidin-4-one (11a-c) derivatives against the test microorganisms,

because they contain; pyridazine, thiazolidinone, azepine and thiopyran rings as an essential

nucleus with an increasing number of nitrogen, sulphur and oxygen atoms according to past and

[

3, 31, 34, 41, 48]

new scientific articles.

Also, the same compounds 13a-c, 14a-c, 12a-c and 11a-c

possess highest antimicrobial activities because of the transformation of the thiosemicarbazide,

butane-hydrazide or phenyl-butane-hydrazone-hydrazide groups into pyridazine, thiazolidine,

azepine or thiopyran ring that are linked by the functional groups such as phenyl, benzoyl, ethyl,

methyl, chloro, thioxo, carbonyl and amino group, thus these rings and functional groups are

containing electrons donating that affect the eradication of many types of bacteria and fungi

[

1-3, 10, 21, 31, 34, 41, 48]

according to previous studies.

Also, some of the compounds 10a-c, 9a-c, 8a-c,

5

a-c and 6a-c exhibited moderate antimicrobial activity and the rest of the compounds showed a

weak antimicrobial activity compared to the standard drugs (cefotaxime sodium and nystatin).

Moreover, the pyridazine, thiazolidinone, azepine, thiopyran, 1, 2, 4-triazoles, 1, 3, 4-oxadiazoles

[

1-3,

and 1, 3, 4-thiadiazoles derivatives have effective as antimicrobial agents in previous articles.

1

0, 21, 31, 34, 41, 48]

In this article and previous articles generally, the bacteria and fungi types are

[1-3, 21, 49]

influenced via this category of heterocyclic compounds.

Likewise, past results and our

findings in this article corroborate the promising antimicrobial activity of pyridazin-hydrazono-

thiazolidinone, oxothiazolidin-azepine-dione, N-oxothiazolidin-hydrazon-hydrazide, thiopyran-

hydrazono-thiazolidinone derivatives which can be developed to the highest antimicrobial

activities.

1

0

Table 1: Minimum inhibitory concentrations against bacteria of the new compounds

MIC (µmol mL-1)

Compounds

Microorganisms

Gram-positive bacteria Gram-negative bacteria

Staphylococcus aureus Klebsiella pneumoniae

Streptococcus pyogenes

E. coli

1

2

3

30± 0.009

29± 0.004

28± 0.002

26± 0.006

25± 0.012

27± 0.009

18± 0.015

17± 0.002

18± 0.007

23± 0.012

22± 0.018

24± 0.019

20± 0.009

19± 0.013

21± 0.021

16± 0.027

15± 0.015

17± 0.023

13± 0.013

12± 0.027

14± 0.021

11± 0.031

10± 0.035

12± 0.011

9± 0.025

8± 0.041

9± 0.045

7± 0.047

6± 0.049

7± 0.051

3± 0.055

2± 0.054

4± 0.009

4± 0.052

3± 0.019

5± 0.022

3± 0.005

31± 0.005

30± 0.006

29± 0.001

27± 0.008

26± 0.014

28± 0.015

18± 0.007

18± 0.017

19± 0.005

24± 0.014

23± 0.013

25± 0.011

21± 0.018

20± 0.015

22± 0.023

17± 0.026

16± 0.018

18± 0.026

14± 0.014

13± 0.022

15± 0.025

12± 0.033

11± 0.037

12± 0.034

9± 0.029

9± 0.043

10± 0.047

7± 0.048

7± 0.045

8± 0.054

4± 0.058

3± 0.053

5± 0.011

5± 0.055

4± 0.021

6± 0.034

4± 0.004

29± 0.008

28± 0.003

27± 0.005

25± 0.009

24± 0.013

26± 0.012

16± 0.005

15± 0.014

17± 0.008

22± 0.016

21± 0.012

23± 0.017

19± 0.011

18± 0.013

20± 0.025

14± 0.024

13± 0.021

15± 0.025

11± 0.005

10± 0.029

12± 0.003

9± 0.032

8± 0.036

10± 0.032

7± 0.028

6± 0.042

7± 0.046

5± 0.035

4± 0.043

5± 0.053

1± 0.057

1± 0.055

2± 0.028

2± 0.059

1± 0.028

3± 0.041

1± 0.006

30± 0.006

29± 0.007

28± 0.004

26± 0.002

25± 0.018

27± 0.016

17± 0.013

16± 0.011

18± 0.009

23± 0.015

22± 0.014

24± 0.018

20± 0.012

19± 0.016

21± 0.022

15± 0.025

14± 0.028

15± 0.021

12± 0.008

11± 0.027

13± 0.004

10± 0.034

9± 0.038

11± 0.036

7± 0.026

7± 0.044

8± 0.043

5± 0.029

5± 0.046

6± 0.052

2± 0.056

2± 0.054

3± 0.037

3± 0.024

2± 0.031

4± 0.057

2± 0.009

4

a

4

b

4

5

c

a

5

b

5

6

c

a

6

b

6

7

c

a

7

b

7

8

c

a

8

b

8

9

c

a

9

b

9

c

1

0a

1

0b

1

0c

1a

1

1b

1

1c

2a

1

2b

1

2c

3a

1

3b

1

3c

4a

1

4b

4c

1

Cefotaxime

sodium

Negative

control

NI

DMSO was used as the negative control and as the solvent for test compounds and the reference drug. NI – No

inhibition

1

Table 2: Minimum inhibitory concentrations against fungi of the new compounds

-

1

MIC (µmol mL )

Microorganisms

Compounds

Candida albicans

Aspergillus niger

Curvularia lunata Alternaria alternata

1

2

3

26± 0.005

25± 0.003

24± 0.006

22± 0.012

21± 0.016

23± 0.005

15± 0.019

15± 0.006

16± 0.014

20± 0.021

19± 0.009

20± 0.027

18± 0.029

17± 0.017

18± 0.022

13± 0.031

13± 0.034

14± 0.028

11± 0.035

10± 0.033

12± 0.032

9± 0.042

8± 0.041

9± 0.036

6± 0.028

6± 0.051

7± 0.057

5± 0.058

4± 0.054

5± 0.062

3± 0.065

2± 0.059

4± 0.075

2± 0.055

1± 0.068

2± 0.049

2± 0.008

NI

27± 0.002

26± 0.008

25± 0.003

23± 0.015

22± 0.018

24± 0.019

16± 0.017

16± 0.008

17± 0.012

21± 0.025

20± 0.015

21± 0.029

19± 0.024

18± 0.019

20± 0.026

14± 0.033

14± 0.037

15± 0.019

12± 0.038

11± 0.027

13± 0.035

9± 0.045

9± 0.022

10± 0.046

7± 0.031

7± 0.043

8± 0.059

5± 0.056

5± 0.052

6± 0.055

4± 0.068

3± 0.063

4± 0.061

3± 0.077

2± 0.076

3± 0.057

3± 0.014

NI

28± 0.004

27± 0.009

26± 0.011

24± 0.013

23± 0.014

25± 0.013

17± 0.018

16± 0.012

18± 0.014

22± 0.022

21± 0.026

23± 0.008

20± 0.022

19± 0.021

20± 0.029

16± 0.032

15± 0.035

16± 0.025

13± 0.036

12± 0.015

14± 0.029

10± 0.038

10± 0.043

11± 0.048

9± 0.047

8± 0.052

9± 0.045

7± 0.029

6± 0.058

7± 0.064

5± 0.059

5± 0.052

5± 0.072

3± 0.074

3± 0.059

4± 0.079

4± 0.012

NI

29± 0.006

28± 0.007

27± 0.013

25± 0.018

24± 0.011

26± 0.012

18± 0.015

17± 0.019

19± 0.017

23± 0.023

22± 0.028

24± 0.023

21± 0.025

20± 0.024

21± 0.018

17± 0.021

16± 0.038

17± 0.039

14± 0.034

13± 0.013

15± 0.028

11± 0.041

11± 0.032

12± 0.049

9± 0.042

9± 0.055

10± 0.016

7± 0.057

7± 0.044

8± 0.061

6± 0.042

5± 0.071

6± 0.073

4± 0.066

4± 0.078

5± 0.037

5± 0.007

NI

4

a

b

4

5

c

a

5

b

5

6

c

a

6

b

6

7

c

a

7

b

7

8

c

a

8

b

8

9

c

a

9

b

9

c

1

0a

0b

1

0c

1

1a

1b

1

1c

1

2a

2b

1

2c

1

3a

3b

1

3c

1

4a

4b

1

4c

Nystatin

Negative

control

DMSO was used as the negative control and as the solvent for test compounds and the reference drug. NI- No

inhibition

1

2

4

.1. EXPERIMENTAL SECTION

4

.2. Materials

All materials used were obtained from Sigma Aldrich (Saint Lewis, USA).

.3. Equipment’s

4

All melting points are in degree centigrade (uncorrected) and were determined on Gallenkamp

electric melting point apparatus. TLC analysis was carried out on silica gel 60 F₂₅₄precoated

aluminum sheets. The IR spectra were recorded (KBr) on a Perkin–Elmer 1430 spectrometer (λ,

-1

1

13

cm ) in National Research Centre, Egypt. H and C-NMR Spectra were measured on JEOL-

ECA 500 and JEOL JNM-LA-400 FT NMR Spectrometers at 500, 125 MHz, respectively, using

tetramethylsilane (TMS) as an internal reference and DMSO-d as the solvent at the

6

Microanalytical Center in National Research Centre, Egypt. The mass spectra (EI) were recorded

on GCMS-QP 1000 EX (Shimadzu) at National Research Centre, Egypt. Elemental analyses (C,

H and N) were carried out at the Microanalytical Center in National Research Centre, Egypt. The

elemental analyses were found to agree favorably with the calculated values. Biological

evaluations were done by the antimicrobial unit, Department of Chemistry of Natural and

Microbial Products, National Research Centre, Egypt.

[

41]

4

.4. Synthesis of Ethyl 4-oxo-4-phenylbutanoate (2),

A mixture of 3-benzoylpropionic acid 1 (1.78g, 0.01 mol) in absolute ethanol (40 ml) containing a

few drops of concentrated sulphuric acid was refluxed for 3-5h under control (TLC). The oil

formed was separated by using a rotary system and the purification by sodium sulphate and

-1

chloroform to give compound 2 as a liquid oil in 75% yield, IR (ν, cm ): 3055 (CH aryl), 2960

1

(

CH alkyl), 1790 (C=O), 1750 (C=O), 1570 (C=C). H NMR (DMSO-d , ppm) δ 1.30 (t, 3 H, J =

6

4

6

.20 Hz, CH ), 2.15 (t, 2 H, J = 4.25 Hz, CH ), 3.70 (t, 2 H, J = 4.27 Hz, CH ), 4.12 (q, 2 H, J =

3

2

1

3

.29 Hz, CH ), 7.55-7.92 (m, 5H, phenyl); C NMR (DMSO-d ) δ 20.1 (1C, CH ), 30.5, 34.6,

2

6

3

3.4 (3C, 3CH ), 128.1, 128.5,130.9, 134.8 (6 C, Ar-C), 168.7, 183.5 (2C, 2C=O); MS (70 eV, %)

2

+

m/z 206 (M , 100%); Anal. Calc. (Found) for C H O (206.24): C, 69.89 (69.80); H, 6.84 (6.78).

1

2

14

3

4

.5. Synthesis of 4-oxo-4-phenylbutanehydrazide (3)

A mixture of 2 (2.10 mL, 0.01 mol) and hydrazine monohydrate (0.01 mol) (80-90%) in absolute

ethanol (30 mL) was stirred under refluxed for 2-4h. The reaction mixture was then allowed to

1

3

cool to room temperature. The solid was filtered, washed with methanol, dried, and crystallized

from dioxane as yellow crystals, in 90% yield, m. p. 170-172 °C. IR (KBr): ν _m_a_x= 3405-3325

-1 1

(

brs, NH, NH ), 3045 (CH, aryl), 2952 (CH, alkyl), 1722, 1675 (2C=O), 1578 (C=C) cm ; H

2

NMR (DMSO-d ): δ = 2.22-2.27 (t, 2 H, J = 5.48 Hz, CH ), 3.20-3.25 (t, 2 H, J = 5.49 Hz, CH ),

6

2

6

.10 (br, 2H, NH , D O exchangeable), 7.55-7.92 (m, 5H, Ar-H), 9.08 (br, 1H, NH, D O

2 2 2

1

3

exchangeable). C NMR (DMSO-d ) δ = 30.1, 33.8 (2C, 2CH ), 128.4, 128.9, 131.5, 134.8 (6C,

6

2

+

Ar-C), 174.7, 182.2 (2C, 2C=O); MS (70 eV): m/z = 192 (M , 100%); Anal. Calc. (Found) for

C H N O (192.22): C, 62.49 (62.40); H, 6.29 (6.21); N, 14.57 (14.68).

10

12

2

4

.6. Synthesis of N-substituted-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide (4a-c)

General Procedure: A mixture of 3 (1.92g, 0.01 mol) and the appropriate isothiocyanate (0.01

mol), namely phenyl-, benzyl-, and ethylisothiocyanate, in absolute ethanol (30 mL) was refluxed

for 4-7h and then left to cool. The precipitate formed was filtered off, dried, and crystallized from

the appropriate solvent to give 4a-c.

4

.7. Synthesis of 2-(4-oxo-4-phenylbutanoyl)-N-phenylhydrazine-1-carbothioamide (4a)

The compound was obtained from the reaction of 3 with phenylisothiocyanate (1.20 mL, 0.01

mol), as white crystals, crystallized from methanol in 88% yield, m. p. 215-217 °C. IR (KBr): ν

=

3330, 3240, 3155 (br, 3NH), 3050 (CH aryl), 2960 (CH alkyl), 1725, 1680 (2C=O), 1585

max

-1 1

(

C=C), 1355 (C=S) cm ; H NMR (DMSO-d ): δ = 2.25-2.30 (t, 2 H, J = 5.50 Hz, CH ), 3.05-

6

2

3

.10 (t, 2H, J = 5.56 Hz, CH ), 7.05-7.90 (m, 10 H, Ar-H), 9.90, 10.70, 11.60 (br, 3H, 3NH, D O

2 2

1

3

exchangeable). C NMR (DMSO-d ) δ =31.5, 34.6 (2C, 2CH ), 125.4, 127.2, 128.3, 128.7,

6

2

1

29.1, 132.6, 135.2, 137.8 (12C, Ar-C), 172.3, 178.5 (2C, 2C=O), 182.8 (1C, C=S); MS (70 eV):

+

m/z = 327 (M , 100 %); Anal. Calc. (Found) for C H N O S (327.40): C, 62.37 (62.30); H, 5.23

17

3

2

(5.18); N, 12.83 (12.90).

4

.8. Synthesis of N-benzyl-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide (4b)

The compound was obtained from the reaction of 3 with benzylisothiocyanate (1.32 mL, 0.01

mol), as yellow crystals, crystallized from dioxane in 75% yield, m. p. 198-200 °C. IR (KBr): ν

=

3333, 3242, 3157 (br, 3NH), 3054 (CH aryl), 2963 (CH alkyl), 1720, 1684 (2C=O), 1588

max

-1 1

(

C=C), 1357 (C=S) cm ; H NMR (DMSO-d ): δ = 2.29-2.34 (t, 2H, J = 5.55 Hz, CH ), 3.10-

6

2

1

4

3

.15 (t, 2H, J = 5.58 Hz, CH ), 4.55 (s, 2H, CH ), 7.20-7.95 (m, 10H, Ar-H), 9.82, 10.62, 11.55

2 2

1

3

(

br, 3H, 3NH, D O exchangeable). C NMR (DMSO-d ) δ = 31.3, 34.5, 55.1 (3C, 3CH ), 125.8,

2 6 2

1

26.2, 127.6, 128.9, 129.1, 132.9, 135.5, 138.2 (12C, Ar-C), 172.8, 178.9 (2C, 2C=O), 183.2 (1C,

+

C=S); MS (70 eV): m/z = 341 (M , 90%); Anal. Calc. (Found) for C H N O S (341.43): C,

1

8

19

3

2

6

3.32 (63.25); H, 5.61 (5.68); N, 12.31 (12.24).

.9. Synthesis of N-ethyl-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide (4c)

4

The compound was obtained from the reaction of 3 with ethylisothiocyanate (0.87 mL, 0.01 mol),

as yellowish crystals, crystallized from chloroform in 78% yield, m. p. 185-187 °C. IR (KBr): ν

=

3329, 3239, 3148 (br, 3NH), 3048 (CH aryl), 2958 (CH alkyl), 1718, 1679 (2C=O), 1582

max

-1 1

(

C=C), 1350 (C=S) cm ; H NMR (DMSO-d ): δ = 1.35-1.41 (t, 3H, J = 5.62 Hz, CH ), 2.20-

6

3

2

.26 (t, 2H, J = 5.52 Hz, CH ), 3.01-3.06 (t, 2 H, J = 5.54 Hz, CH ), 4.70 - 4.77 (q, 2H, J = 5.60

2 2

1

3

Hz, CH ), 7.46 -7.95 (m, 5H, Ar-H), 9.75, 10.58, 11.50 (br, 3H, 3NH, D O exchangeable). C

2

NMR (DMSO-d ) δ = 20.1 (1C, CH ), 31.1, 34.2, 50.4 (3C, 3CH ), 128.3, 128.7, 133.5, 136.2

6

3

2

+

(

6C, Ar-C), 170.5, 176.4 (2C, 2C=O), 180.6 (1C, C=S); MS (70 eV): m/z = 279 (M , 95%); Anal.

Calc. (Found) for C H N O S (279.36): C, 55.89 (55.80); H, 6.13 (6.19); N, 15.04 (15.12).

1

3

17

3

2

4

.10. Synthesis of 3-(4-substituted-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl)-1-phenyl

propan-1-one (5a-c)

General Procedure: A mixture of suitable thiosemicarbazides 4a-c (0.01 mol) in aqueous sodium

hydroxide (45 mL, 2N) was heated and refluxed under stirring for 4 -7h. The reaction mixture was

then cooled and neutralized with dilute hydrochloric acid. The solid precipitate obtained was

filtered off, washed with water several times, dried, and crystallized from the appropriate solvent

to give 5a-c.

4

.11. Synthesis of 1-phenyl-3-(4-phenyl-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) propan-1-

one (5a)

The compound was obtained from the reaction of thiosemicarbazides 4a (3.27g, 0.01 mol) with

aqueous sodium hydroxide (2N), as yellowish crystals, crystallized from benzene in 85% yield, m.

p. 237-239 °C. IR (KBr): ν _m_a_x= 3305 (br, NH), 3054 (CH aryl), 2947 (CH alkyl), 1715 (C=O),

-1 1

1

617 (C=N), 1590 (C=C), 1345 (C=S) cm ; H NMR (DMSO-d ): δ = 3.03-3.10 (t, 2H, J = 5.60

6

Hz, CH ), 3.24 -3.31 (t, 2H, J = 5.63 Hz, CH ), 7.28-7.95 (m, 10H, Ar-H), 12.10 (br, 1H, NH,

2

1

5

1

3

D O exchangeable). C NMR (DMSO-d ) δ = 30.1, 33.4 (2C, 2CH ), 128.1, 128.4, 128.6, 129.5,

2

6

2

1

29.9, 131.3, 132.8, 135.6, 150.5 (13C, Ar-C), 168.7 (1C, C=S), 180.8 (1C, C=O); MS (70 eV):

+

m/z = 309 (M , 100%); Anal. Calc. (Found) for C H N OS (309.39): C, 66.00 (66.10); H, 4.89

17

15

3

(4.80); N, 13.58 (13.52).

4

.12. Synthesis of 3-(4-benzyl-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl)-1-phenylpropan-1-

one (5b)

The compound was obtained from the reaction of thiosemicarbazides 4b (3.41g, 0.01 mol) with

aqueous sodium hydroxide (2N), as brownish crystals, crystallized from toluene in 80% yield, m.

p. 225-227 °C. IR (KBr): ν _m_a_x= 3310 (br, NH), 3052 (CH aryl), 2944 (CH alkyl), 1719 (C=O),

-1 1

1

619 (C=N), 1588 (C=C), 1348 (C=S) cm ; H NMR (DMSO-d ): δ = 3.08-3.15 (t, 2H, J = 5.65

6

Hz, CH ), 3.28 -3.35 (t, 2H, J = 5.64 Hz, CH ), 4.82 (s, 2H, CH ), 7.30 -7.97 (m, 10H, Ar-H),

2

1

3

1

2.20 (br, 1H, NH, D O exchangeable). C NMR (DMSO-d ) δ = 30.5, 32.1, 51.7 (3C, 3CH ),

2 6 2

1

26.2, 127.1, 128.3, 128.9, 129.3, 131.7, 133.5, 134.2, 155.3 (13C, Ar-C), 170.2 (1C, C=S), 181.5

+

(

1C, C=O); MS (70 eV): m/z = 323 (M , 92%); Anal. Calc. (Found) for C H N OS (323.41): C,

1

8

17

3

6

6.85 (66.78); H, 5.30 (5.37); N, 12.99 (12.91).

4

.13. Synthesis of 3-(4-ethyl-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl)-1-phenylpropan-1-

one (5c)

The compound was obtained from the reaction of thiosemicarbazides 4c (2.79g, 0.01 mol) with

aqueous sodium hydroxide (2N), as yellowish crystals, crystallized from xylene in 86% yield, m.

p. 207-209 °C. IR (KBr): ν _m_a_x= 3315 (br, NH), 3057 (CH aryl), 2946 (CH alkyl), 1722 (C=O),

-1 1

1

621 (C=N), 1592 (C=C), 1351 (C=S) cm ; H NMR (DMSO-d ): δ = 1.30-1.36 (t, 3H, J = 5.66

6

Hz, CH ), 3.12-3.20 (t, 2H, J = 5.64 Hz, CH ), 3.31 -3.38 (t, 2H, J = 5.67 Hz, CH ), 4.66 - 4.72

3

2

1

3

(

q, 2H, J = 5.69 Hz, CH ), 7.41-7.90 (m, 5H, Ar-H), 12.30 (br, 1H, NH, D O exchangeable). C

2

NMR (DMSO-d ) δ = 21.2 (1C, CH ), 30.8, 32.4, 52.3 (3C, 3CH ), 128.4, 128.7, 132.5, 135.2,

6

3

2

+

1

54.4 (7C, Ar-C), 173.5 (1C, C=S), 184.2 (1C, C=O); MS (70 eV): m/z = 261 (M , 96%); Anal.

Calc. (Found) for C H N OS (261.34): C, 59.75 (59.82); H, 5.79 (5.70); N, 16.08 (16.01).

1

3

15

3

4

.14. Synthesis of 3-(5-(substituted-amino)-1, 3, 4-oxadiazol-2-yl)-1-phenylpropan-1-one (6a-c)

1

6

General Procedure: A mixture of the appropriate thiosemicarbazides 4a-c (0.01mol) and excess

yellow mercuric oxide (3.25g, 0.015mol), in ethanol (40 mL) was refluxed for 6-10h. The

reaction mixture was allowed to cool to room temperature (to allow the sedimentation of the black

mercuric sulphide), was filtered, and the mercuric sulphide was washed with ethanol. The filtrate

and alcoholic washing were combined, treated with water until permenant turbidity existed, and

allowed to stand overnight. The product was separated and crystallized from the proper solvent to

give 6a-c.

4

.15. Synthesis of 1-phenyl-3-(5-(phenylamino)-1, 3, 4-oxadiazol-2-yl) propan-1-one (6a)

The compound was obtained from the reaction of thiosemicarbazides 4a (3.27g, 0.01 mol) with

mercuric oxide (3.25g, 0.015mol), as brownish crystals, crystallized from dioxane in 79% yield,

m. p. 256-258 °C. IR (KBr): ν _m_a_x= 3260 (br, NH), 3058 (CH aryl), 2935 (CH alkyl), 1725

-1 1

(

C=O), 1622 (C=N), 1587 (C=C) cm ; H NMR (DMSO-d ): δ = 2.84-2.90 (t, 2H, J = 5.58 Hz,

6

CH ), 2.95 -3.02 (t, 2H, J = 5.57 Hz, CH ), 7.15-7.92 (m, 10H, Ar-H), 11.20 (br, 1H, NH, D O

2

1

3

exchangeable). C NMR (DMSO-d ) δ = 28.5, 37.2 (2C, 2CH ), 122.7, 123.5, 128.4, 128.8,

6

2

1

29.7, 132.1, 135.6, 137.8, 151.4, 158.5 (14C, Ar-C), 186.1 (1C, C=O); MS (70 eV): m/z = 293

+

(

M , 98%); Anal. Calc. (Found) for C H N O (293.33): C, 69.61 (69.69); H, 5.15 (5.10); N,

1

7

15

3

2

1

4.33 (14.26).

4

.16. Synthesis of 3-(5-(benzylamino)-1, 3, 4-oxadiazol-2-yl)-1-phenylpropan-1-one (6b)

The compound was obtained from the reaction of thiosemicarbazides 4b (3.41g, 0.01 mol) with

mercuric oxide (3.25g, 0.015mol), as yellowish crystals, crystallized from acetone in 72% yield,

m. p. 246-248 °C. IR (KBr): ν _m_a_x= 3265 (br, NH), 3055 (CH aryl), 2940 (CH alkyl), 1723

-1 1

(

C=O), 1623 (C=N), 1588 (C=C) cm ; H NMR (DMSO-d ): δ = 2.80-2.86 (t, 2H, J = 5.56 Hz,

6

CH ), 2.90- 2.97 (t, 2H, J = 5.55 Hz, CH ), 4.74 (s, 2H, CH ), 7.35-7.96 (m, 10H, Ar-H), 10.80

2

1

3

(

br, 1H, NH, D O exchangeable). C NMR (DMSO-d ) δ = 27.8, 36.5, 51.5 (3C, 3CH ), 126.4,

2 6 2

1

27.2, 128.3, 128.7, 129.1, 132.5, 136.2, 138.5, 152.1, 158.8 (14C, Ar-C), 187.3 (1C, C=O); MS

+

(

70 eV): m/z = 307 (M , 90%); Anal. Calc. (Found) for C H N O (307.35): C, 70.34 (70. 25);

18

17

3

2

H, 5.58 (5.50); N, 13.67 (13.75).

4

.17. Synthesis of 3-(5-(ethylamino)-1, 3, 4-oxadiazol-2-yl)-1-phenylpropan-1-one (6c)

1

7

The compound was obtained from the reaction of thiosemicarbazides 4c (2.79g, 0.01 mol) with

mercuric oxide (3.25g, 0.015mol), as yellow crystals, crystallized from methanol in75% yield, m.

p. 230-232 °C. IR (KBr): ν _m_a_x= 3255 (br, NH), 3051 (CH aryl), 2942 (CH alkyl), 1726 (C=O),

-

1 1

1

2

5

619 (C=N), 1586 (C=C) cm ; H NMR (DMSO-d ): δ = 1.25-1.31 (t, 3H, J = 5.62 Hz, CH ),

6 3

.80-2.87 (t, 2H, J = 5.61 Hz, CH ), 2.93 -3.01 (t, 2 H, J = 5.63 Hz, CH ), 4.24 - 4.30 (q, 2H, J =

2

1

3

.64 Hz, CH ), 7.50 -7.96 (m, 5H, Ar-H), 10.40 (br, 1H, NH, D O exchangeable). C NMR

2

(

DMSO-d ) δ = 22.4 (1C, CH ), 27.9, 34.8, 50.2 (3C, 3CH ), 128.1, 128.6, 131.9, 137.4, 155.2,

6 3 2

+

1

58.3 (8C, Ar-C), 185.6 (1C, C=O); MS (70 eV): m/z = 245 (M , 95%); Anal. Calc. (Found) for

C H N O (245.28): C, 63.66 (63.57); H, 6.16 (6.10); N, 17.13 (17.20).

13

15

3

2

4

.18. Synthesis of 3-(5-(substituted-amino)-1, 3, 4-thiadiazol-2-yl)-1-phenylpropan-1-one (7a-c)

General Procedure: Phosphorus-oxychloride (35 mL) was added to the appropriate thiosemi-

carbazides 4a-c (0.01 mol), and the mixture was refluxed for 4-6h. The mixture was then

evaporated in vacuo, and the residue was washed with dilute ammonium hydroxide solution and

water. The solid obtained was filtered off, dried, and crystallized from the suitable solvent to give

7

a-c.

4

.19. Synthesis of 1-phenyl-3-(5-(phenylamino)-1, 3, 4-thiadiazol-2-yl) propan-1-one (7a)

The compound was obtained from the reaction of thiosemicarbazides 4a (3.27g, 0.01 mol) with

phosphorus oxychloride, as yellowish crystals, crystallized from chloroform in 87% yield, m. p.

2

1

2

83-285 °C. IR (KBr): ν _m_a_x= 3245 (br, NH), 3052 (CH aryl), 2944 (CH alkyl), 1727 (C=O),

-1 1

620 (C=N), 1580 (C=C) cm ; H NMR (DMSO-d ): δ = 2.80-2.86 (t, 2H, J = 5.55 Hz, CH ),

6

2

.91-2.95 (t, 2H, J = 5.54 Hz, CH ), 7.20 -7.97 (m, 10H, Ar-H), 10.70 (br, 1H, NH, D O

2

1

3

exchangeable). C NMR (DMSO-d ) δ = 27.6, 37.8 (2C, 2CH ), 121.9, 124.3, 127.9, 128.5,

6

2

1

29.8, 132.5, 136.4, 138.2, 155.1, 161.4 (14C, Ar-C), 183.8 (1C, C=O); MS (70 eV): m/z = 309

+

(

M , 100%); Anal. Calc. (Found) for C H N OS (309.39): C, 66.00 (66.12); H, 4.89 (4.80); N,

1

7

15

3

1

3.58 (13.49).

4

.20. Synthesis of 3-(5-(benzylamino)-1, 3, 4-thiadiazol-2-yl)-1-phenylpropan-1-one (7b)

1

8

The compound was obtained from the reaction of thiosemicarbazides 4b (3.41g, 0.01 mol) with

phosphorus oxychloride, as brownish crystals, crystallized from dimethyl-formamide in 80%

yield, m. p. 274-276 °C. IR (KBr): ν _m_a_x= 3268 (br, NH), 3053 (CH aryl), 2942 (CH alkyl), 1728

-1 1

(

C=O), 1625 (C=N), 1591 (C=C) cm ; H NMR (DMSO-d ): δ = 2.76-2.80 (t, 2H, J = 5.66 Hz,

6

CH ), 2.87 - 2.91 (t, 2H, J = 5.68 Hz, CH ), 4.80 (s, 2H, CH ), 7.30 -7.92 (m, 10H, Ar-H), 10.65

2

1

3

(

br, 1H, NH, D O exchangeable). C NMR (DMSO-d ) δ = 26.9, 37.1, 53.4 (3C, 3CH ), 125.8,

2 6 2

1

27.5, 128.1, 128.6, 129.3, 133.4, 137.5, 139.2, 157.2, 162.1 (14C, Ar-C), 184.2 (1C, C=O); MS

+

(

70 eV): m/z = 323 (M , 84%); Anal. Calc. (Found) for C H N OS (323.41): C, 66.85 (66.75);

1

8

17

3

H, 5.30 (5.38); N, 12.99 (12.90).

4

.21. Synthesis of 3-(5-(ethylamino)-1, 3, 4-thiadiazol-2-yl)-1-phenylpropan-1-one (7c)

The compound was obtained from the reaction of thiosemicarbazides 4c (2.79g, 0.01 mol) with

phosphorus oxychloride, as yellowish crystals, crystallized from ethanol in 84% yield, m. p. 265-

2

67 °C. IR (KBr): ν _m_a_x= 3275 (br, NH), 3057 (CH aryl), 2944 (CH alkyl), 1723 (C=O), 1615

-1 1

(

C=N), 1582 (C=C) cm ; H NMR (DMSO-d ): δ = 1.20-1.27 (t, 3H, J = 5.68 Hz, CH ), 2.77-

6

3

2

.85 (t, 2H, J = 5.69 Hz, CH ), 2.89 -2.95 (t, 2H, J = 5.67Hz, CH ), 4.31 - 4.37 (q, 2H, J = 5.63

2 2

1

3

Hz, CH ), 7.55 -7.98 (m, 5H, Ar-H), 10.52 (br, 1H, NH, D O exchangeable). C NMR (DMSO-

2

d ) δ = 22.8 (1C, CH ), 28.3, 35.9, 50.4 (3C, 3CH ), 128.3, 128.8, 132.2, 136.5, 157.5, 162.7 (8C,

6

3

2

+

Ar-C), 185.9 (1C, C=O); MS (70 eV): m/z = 261 (M , 97%); Anal. Calc. (Found) for C H N OS

1

3

15

3

(261.34): C, 59.75 (59.66); H, 5.79 (5.70); N, 16.08 (16.16).

4

.22. Synthesis of N'-(3-substituted-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutanehydrazide

(8a-c)

General Procedure: A mix of the appropriate thiosemicarbazides 4a-c (0.01 mol), ethylbromo-

acetate (1.67mL, 0.01 mol), and anhydrous sodium acetate (1.23g, 0.015 mol) in absolute ethanol

(35 mL) was refluxed for 5-8h under control (TLC). The reaction mixture was cooled, diluted

with water, and allowed to stand overnight. The solid obtained was filtered off, dried, and

crystallized from the proper solvent to give 8a-c.

4

.23. Synthesis of 4-oxo-N'-(4-oxo-3-phenylthiazolidin-2-ylidene)-4-phenylbutanehydrazide

(8a)

1

9

The compound was obtained from the reaction of thiosemicarbazides 4a (3.27g, 0.01 mol) with

ethyl-bromoacetate, as white crystals, crystallized from n-hexane in 76% yield, m. p. 313-315 °C.

IR (KBr): ν _m_a_x= 3315 (br, NH), 3070 (CH aryl), 2958 (CH alkyl), 1730, 1690, 1683 (3C=O),

-

1 1

1

3

1

617 (C=N), 1592 (C=C) cm ; H NMR (DMSO-d ): δ = 2.70 - 2.77 (t, 2H, J = 5.70 Hz, CH ),

6

2

.25 -3.31 (t, 2H, J = 5.71 Hz, CH ), 4.25 (s, 2H, CH , thiazole), 7.40 -7.98 (m, 10H, Ar-H),

2

1

3

0.90 (br, 1H, NH, D O exchangeable). C NMR (DMSO-d ) δ = 30.1, 31.7, 34.5 (3C, 3CH ),

2

6

2

27.5, 127.8, 128.4, 128.8, 129.2, 132.7, 135.4, 137.1, 146.5 (13C, Ar-C), 165.5, 170.8, 185.4

+

(

3C, 3C=O); MS (70 eV): m/z = 367 (M , 100%); Anal. Calc. (Found) for C H N O S (367.42):

19

17

3

C, 62.11 (62.20); H, 4.66 (4.60); N, 11.44 (11.35).

4

.24. Synthesis of N'-(3-benzyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutanehydrazide (8b)

The compound was obtained from the reaction of thiosemicarbazides 4b (3.41g, 0.01 mol) with

ethyl-bromoacetate, as brownish crystals, crystallized from benzene in 73% yield, m. p. 302-305

°

C. IR (KBr): ν _m_a_x= 3320 (br, NH), 3072 (CH aryl), 2960 (CH alkyl),1733, 1692, 1685 (3C=O),

-

1 1

1

3

1

5

1

615 (C=N), 1595 (C=C) cm ; H NMR (DMSO-d ): δ = 2.66 - 2.73 (t, 2H, J = 5.72 Hz, CH ),

6 2

.28 -3.35 (t, 2H, J = 5.73 Hz, CH ), 4.31 (s, 2H, CH , thiazole), 5.75 (s, 2H, CH ), 7.32 -7.92 (m,

2

1

3

0H, Ar-H), 10.85 (br, 1H, NH, D O exchangeable). C NMR (DMSO-d ) δ = 30.7, 32.2, 35.4,

2

6

1.6 (4C, 4CH ), 126.6, 127.3, 128.1, 128.5, 128.9, 132.4, 135.8, 137.5, 152.7 (13C, Ar-C),

2

+

66.1, 171.3, 185.8 (3C, 3C=O); MS (70 eV): m/z = 381(M , 92%); Anal. Calc. (Found) for

C H N O S (381.45): C, 62.98 (62.90); H, 5.02 (5.08); N, 11.02 (11.10).

20

19

3

4

.25. Synthesis of N'-(3-ethyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutanehydrazide (8c)

The compound was obtained from the reaction of thiosemicarbazides 4c (2.79g, 0.01 mol) with

ethyl-bromoacetate, as yellowish crystals, crystallized from methanol in 74% yield, m. p. 293-295

°

C. IR (KBr): ν _m_a_x= 3325 (br, NH), 3075 (CH aryl), 2965 (CH alkyl),1735, 1695, 1688 (3C=O),

-1 1

1

618 (C=N), 1593 (C=C) cm ; H NMR (DMSO-d ): δ =1.24-1.32 (t, 3H, J = 5.74 Hz, CH ),

6 3

2

.63- 2.70 (t, 2H, J = 5.75 Hz, CH ), 3.31 -3.38 (t, 2H, J = 5.77 Hz, CH ), 4.35 (s, 2H, CH ,

2

thiazole), 4.91- 4.97 (q, 2H, J = 5.73 Hz, CH ), 7.52 -7.95 (m, 5H, Ar-H), 10.75 (br, 1H, NH, D O

2

1

3

exchangeable). C NMR (DMSO-d ) δ = 23.4 (1C, CH ), 30.9, 32.6, 36.1, 37.4 (4C, 4CH ),

6

3

2

1

28.4, 128.9, 131.7, 134.5, 153.2 (7C, Ar-C), 168.1, 172.5, 186.2 (3C, 3C=O); MS (70 eV): m/z =

2

0

+

3

19 (M , 96%); Anal. Calc. (Found) for C H N O S (319.38): C, 56.41 (56.52); H, 5.37 (5.44);

15 17 3 3

N, 13.16 (13.07).

4

.26. Synthesis of (N'-(3-substituted-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenyl

butane hydrazide (9a-c)

General Procedure: A mix of the suitable thiosemicarbazides 4a-c (0.01 mol), α-bromopropionic

acid (0.9 mL, 0.01 mol), and anhydrous sodium acetate (1.23g, 0.015 mol) in absolute ethanol (35

mL) was heated and refluxed for 6-9h. The reaction mixture was cooled, diluted with water, and

allowed to stand overnight. The solid obtained was filtered off, dried, and crystallized from the

appropriate solvent to give 9a-c.

4

.27. Synthesis of N'-(5-methyl-4-oxo-3-phenylthiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazide (9a)

The compound was obtained from the reaction of thiosemicarbazides 4a (3.27g, 0.01 mol) with α-

bromopropionic acid, as yellow crystals, crystallized from methanol in 75% yield, m. p. 322-324

°

C. IR (KBr): ν _m_a_x= 3325 (br, NH), 3075 (CH aryl), 2965 (CH alkyl), 1735, 1693, 1685 (3C=O),

-

1 1

1

2

5

624 (C=N), 1590 (C=C) cm ; H NMR (DMSO-d ): δ = 1.75-1.78 (d, 3H, J = 5.80 Hz, CH ),

6 3

.68-2.74 (t, 2H, J = 5.78 Hz, CH ), 3.28 -3.35 (t, 2H, J = 5.79 Hz, CH ), 4.50 (q, 1H, CH, J =

2

1

3

.77 Hz, thiazole), 7.39 -7.97 (m, 10H, Ar-H), 10.71 (br, 1H, NH, D O exchangeable). C NMR

2

(

DMSO-d ) δ = 24.1 (1C, CH ), 31.8, 34.2 (2C, 2CH ), 57.5 (1C, CH, thiazole), 127.7, 127.9,

6 3 2

1

28.3, 128.7, 129.1, 132.5, 135.8, 136.4, 150.1 (13C, Ar-C), 166.2, 171.1, 186.3(3C, 3C=O); MS

+

(

70 eV): m/z = 381 (M , 100%); Anal. Calc. (Found) for C H N O S (381.45): C, 62.98 (62.90);

2

0

19

3

H, 5.02 (5.10); N, 11.02 (11.11).

4

.28. Synthesis of (N'-(3-benzyl-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazide (9b)

The compound was obtained from the reaction of thiosemicarbazides 4b (3.41g, 0.01 mol) with α-

bromopropionic acid, as yellowish crystals, crystallized from dioxane in 71% yield, m. p. 331-333

°

C. IR (KBr): ν _m_a_x= 3320 (br, NH), 3070 (CH aryl), 2960 (CH alkyl), 1730, 1690, 1680 (3C=O),

-1 1

1

620 (C=N), 1585 (C=C) cm ; H NMR (DMSO-d ): δ = 1.80-1.83 (d, 3H, J = 5.85 Hz, CH ),

6 3

2

1

2

5

.60- 2.66 (t, 2H, J = 5.82 Hz, CH ), 3.31 -3.38 (t, 2H, J = 5.84 Hz, CH ), 4.55 (q, 1H, CH, J =

2 2

.81 Hz, thiazole), 5.70 (s, 2H, CH ), 7.22 -7.90 (m, 10H, Ar-H), 10.76 (br, 1H, NH, D O

2

1

3

exchangeable). C NMR (DMSO-d ) δ = 23.8 (1C, CH ), 32.1, 34.8, 39.2 (3C, 3CH ), 56.2 (1C,

6

3

2

CH, thiazole), 127.2, 127.8, 128.1, 128.5, 128.9, 132.8, 135.4, 136.1, 150.7 (13C, Ar-C), 168.1,

+

1

72.5, 187.4(3C, 3C=O); MS (70 eV): m/z = 395 (M , 88%); Anal. Calc. (Found) for C H N O

2

1

21

3

S (395.48): C, 63.78 (63.70); H, 5.35 (5.42); N, 10.63 (10.70).

4

.29. Synthesis of N'-(3-ethyl-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazide (9c)

The compound was obtained from the reaction of thiosemicarbazides 4c (2.79g, 0.01 mol) with α-

bromopropionic acid, as white crystals, crystallized from tetrahydrofuran in 82% yield, m. p. 341-

3

43 °C. IR (KBr): ν _m_a_x= 3318 (br, NH), 3066 (CH aryl), 2957 (CH alkyl), 1727, 1688, 1678

-1 1

(

3C=O), 1617 (C=N), 1579 (C=C) cm ; H NMR (DMSO-d ): δ = 1.27-1.35 (t, 3H, J = 5.82 Hz,

6

CH ), 1.86 - 1.90 (d, 3H, J = 5.83 Hz, CH ), 2.65 - 2.71 (t, 2H, J = 5.87 Hz, CH ), 3.28 -3.35 (t,

3

2

H, J = 5.87 Hz, CH ), 4.48 (q, 1H, CH, J = 5.86 Hz, thiazole), 4.85 - 4.91 (q, 2H, J = 5.80 Hz,

2

13

CH ), 7.55-7.98 (m, 5H, Ar-H), 10.80 (br, 1H, NH, D O exchangeable). C NMR (DMSO-d ) δ

2

6

=

18.7, 24.5 (2C, 2CH ), 31.9, 34.5, 35.7 (3C, 3CH ), 55.8 (1C, CH, thiazole), 128.3, 128.8,

3 2

+

1

9

32.7, 137.2, 153.4 (7C, Ar-C), 168.6, 172.8, 187.9 (3C, 3C=O); MS (70 eV): m/z = 333 (M ,

4%); Anal. Calc. (Found) for C H N O S (333.41): C, 57.64 (57.55); H, 5.74 (5.80); N, 12.60

1

6

19

3

(12.68).

4

.30. Synthesis of N-(3-substituted-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonoyl chloride (10a-c)

General Procedure: A mixture of 9a (3.81g, 0.01 mol) or 9b (3.95g, 0.01 mol) or 9c (3.33g, 0.01

mol) in dry dioxane (35 mL) was treated with 25 mL of phosphorus oxy-chloride, and the mixture

was stirred under reflux for 6-8h. The reaction mixture was allowed to cool to room temperature.

Then, it was poured into cold water (100 mL), whereby a solid was separated, filtered off, and

crystallized from a suitable solvent to give 10a-c, respectively.

4

.31. Synthesis of N-(5-methyl-4-oxo-3-phenylthiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonoyl chloride (10a)

2

The compound was obtained from the reaction of 9a with phosphorus oxy-chloride, as yellowish

crystals, crystallized from DMF in 90% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3065 (CH aryl),

-1

1

2

960 (CH alkyl), 1732, 1690, (2C=O), 1628 (C=N), 1592 (C=C), 1174 (C-Cl) cm ; H NMR

(

-

DMSO-d ): δ = 1.79 - 1.82 (d, 3H, J = 5.88 Hz, CH ), 2.71 - 2.77 (t, 2H, J = 5.83 Hz, CH ), 3.32

6

3

2

3.39 (t, 2H, J = 5.85 Hz, CH ), 4.45 (q, 1H, CH, J = 5.82 Hz, thiazole), 7.36 -7.94 (m, 10H, Ar-

2

1

3

H); C NMR (DMSO-d ) δ = 24.5 (1C, CH ), 31.6, 33.9 (2C, 2CH ), 57.2 (1C, CH, thiazole),

6

3

2

1

27.5, 127.8, 128.5, 128.8, 129.2, 132.7, 135.9, 136.6, 152.3, 155.5 (14C, Ar-C), 172.3, 185.1

+

(

2C, 2C=O); MS (70 eV): m/z = 399 (M , 100%); Anal. Calc. (Found) for C H ClN O S

2

0

18

3

2

(399.89): C, 60.07 (60.15); H, 4.54 (4.48); N, 10.51 (10.62).

4

.32. Synthesis of N-(3-benzyl-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonoyl chloride (10b)

The compound was obtained from the reaction of 9b with phosphorus oxy-chloride, as brownish

crystals, crystallized from dioxane in 83% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3062 (CH aryl),

-1

1

2

958 (CH alkyl), 1730, 1687, (2C=O), 1625 (C=N), 1588 (C=C), 1170 (C-Cl) cm ; H NMR

(

DMSO-d ): δ = 1.81- 1.85 (d, 3H, J = 5.87 Hz, CH ), 2.75 - 2.82 (t, 2H, J = 5.86 Hz, CH ), 3.35

6

3

2

-

3.42 (t, 2H, J = 5.84 Hz, CH ), 4.47 (q, 1H, CH, J = 5.85 Hz, thiazole), 5.50 (s, 2H, CH ), 7.33-

2

1

3

7

5

.92 (m, 10H, Ar-H); C NMR (DMSO-d ) δ = 24.7 (1C, CH ), 30.8, 32.5, 38.6 (3C, 3CH ),

6 3 2

6.7 (1C, CH, thiazole), 127.1, 127.5, 128.4, 128.7, 128.9, 132.4, 135.2, 136.4, 152.8, 156.1

+

(

14C, Ar-C), 172.6, 185.5 (2C, 2C=O); MS (70 eV): m/z = 413 (M , 90%); Anal. Calc. (Found)

for C H ClN O S (413.92): C, 60.94 (60.85); H, 4.87 (4.80); N, 10.15 (10.24).

2

1

20

3

2

4

.33. Synthesis of N-(3-ethyl-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonoyl chloride (10c)

The compound was obtained from the reaction of 9c with phosphorus oxy-chloride, as yellowish

crystals, crystallized from acetone in 85% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3069 (CH aryl),

-1

1

2

962 (CH alkyl), 1733, 1684, (2C=O), 1627 (C=N), 1582 (C=C), 1172 (C-Cl) cm ; H NMR

(

DMSO-d ): δ = 1.30-1.38 (t, 3H, J = 5.95 Hz, CH ), 1.92-1.96 (d, 3H, J = 5.92 Hz, CH ), 2.73 -

6

3

2

.80 (t, 2H, J = 5.90 Hz, CH ), 3.38 -3.45 (t, 2H, J = 5.89 Hz, CH ), 4.50 (q, 1H, CH, J = 5.91

2 2

1

3

Hz, thiazole), 4.90-4.96 (q, 2H, J = 5.92 Hz, CH ), 7.51-7.95 (m, 5H, Ar-H); C NMR (DMSO-

2

d ) δ = 19.1, 24.2 (2C, 2CH ), 29.7, 31.8, 37.2 (3C, 3CH ), 56.4 (1C, CH, thiazole), 128.5, 128.9,

6

3

2

3

+

1

32.8, 136.4, 152.5, 156.4 (8C, Ar-C), 172.3, 188.2 (2C, 2C=O); MS (70 eV): m/z = 351 (M , 98

); Anal. Calc. (Found) for C H ClN O S (351.85): C, 54.62 (54.54); H, 5.16 (5.24); N, 11.94

%

1

6

18

3

2

(11.85).

4

.34. Synthesis of 2-((4-benzoyl-5-oxotetrahydro-2H-thiopyran-2-ylidene) hydrazono)-3-

substituted-5-methylthiazolidin-4-one (11a-c)

General Procedure: A mixture of 10a-c (0.01 mol) mercaptoacetyl-chloride (1.10 g, 0.01 mol),

and anhydrous potassium carbonate (2.08 g, 0.015 mol) in dry acetone (35 mL) was refluxed for

8

-14h. The reaction mixture was allowed to cool to room temperature. Water (40 mL) was added

and then the solid that separated was filtered off, dried and crystallized from the suitable solvent

to give 11a-c.

4

.35. Synthesis of 2-((4-benzoyl-5-oxotetrahydro-2H-thiopyran-2-ylidene) hydrazono)-5-methyl-

-phenylthiazolidin-4-one (11a)

3

The compound was obtained from the reaction of 10a (3.99g, 0.01 mol) with mercaptoacetyl-

chloride, as white crystals, crystallized from methanol in 82% yield, m. p. >350 °C. IR (KBr): ν

-

1

=

3052 (CH aryl), 2949 (CH alkyl), 1724, 1718, 1682, (3C=O), 1626 (C=N), 1584(C=C) cm ;

max

1

H NMR (DMSO-d ): δ = 1.73-1.77 (d, 3H, J = 5.90 Hz, CH ), 2.68-2.74 (d, 2H, J = 5.95 Hz,

6

3

CH , thiopyran), 4.02 (d, 1H, J = 5.93 Hz, CH , thiopyran), 4.10 (d, 1H, J = 5.95 Hz, CH ,

2

thiopyran), 4.40 (q, 1H, J = 5.89 Hz, CH, thiazole), 5.95 (t, 1H, J = 5.91 Hz, CH, thiopyran),

1

3

7

.40 -7.98 (m, 10H, Ar-H); C NMR (DMSO-d ) δ = 25.1 (1C, CH ), 28.5, 35.7 (2C, 2CH ),

6 3 2

5

1.2, 58.4 (2C, 2CH), 127.3, 127.9, 128.4, 128.7, 129.1, 132.4, 134.7, 135.9, 155.5, 160.2 (14C,

+

Ar-C), 173.6, 187.1, 195.5 (3C, 3C=O); MS (70 eV): m/z = 437 (M , 100%); Anal. Calc. (Found)

for C H N O S (437.53): C, 60.39 (60.47); H, 4.38 (4.30); N, 9.60 (9.70).

2

19

3

3 2

4

.36. Synthesis of 2-((4-benzoyl-5-oxotetrahydro-2H-thiopyran-2-ylidene) hydrazono)-3-benzyl-

-methylthiazolidin-4-one (11b)

5

The compound was obtained from the reaction of 10b (4.13g, 0.01 mol) with mercaptoacetyl-

chloride, as yellow crystals, crystallized from dioxane in 78% yield, m. p. >350 °C. IR (KBr): ν

-

=

3050 (CH aryl), 2947 (CH alkyl), 1725, 1720, 1685, (3C=O), 1622 (C=N), 1580 (C=C) cm

max

1

;

H NMR (DMSO-d ): δ = 1.70 - 1.74 (d, 3H, J = 5.92 Hz, CH ), 2.65-2.71 (d, 2H, J = 5.94 Hz,

6 3

2

4

CH , thiopyran), 4.05 (d, 1H, J = 5.96 Hz, CH , thiopyran), 4.12 (d, 1H, J = 5.97 Hz, CH ,

2

thiopyran), 4.43 (q, 1H, J = 5.90 Hz, CH, thiazole), 5.55 (s, 2H, CH ), 5.90 (t, 1H, J = 5.94 Hz,

2

1

3

CH, thiopyran), 7.30 -7.95 (m, 10H, Ar-H); C NMR (DMSO-d ) δ = 25.6 (1C, CH ), 28.2, 35.4,

6

3

8.9 (3C, 3CH ), 51.5, 58.7 (2C, 2CH), 126.8, 127.4, 128.3, 128.5, 128.9, 132.7, 134.3, 135.6,

2

+

1

55.2, 160.7 (14C, Ar-C), 173.2, 186.9, 195.8 (3C, 3C=O); MS (70 eV): m/z = 451 (M , 90%);

Anal. Calc. (Found) for C H N O S (451.56): C, 61.18 (61.24); H, 4.69 (4.60); N, 9.31 (9.37).

23

21

3

3 2

4

.37. Synthesis of 2-((4-benzoyl-5-oxotetrahydro-2H-thiopyran-2-ylidene) hydrazono)-3-ethyl-5-

methylthiazolidin-4-one (11c)

The compound was obtained from the reaction of 10c (3.51g, 0.01 mol) with mercaptoacetyl-

chloride, as yellowish crystals, crystallized from benzene in 80% yield, m. p. >350 °C. IR (KBr):

ν _m_a_x= 3055 (CH aryl), 2945 (CH alkyl), 1722, 1723, 1680, (3C=O), 1627 (C=N), 1586 (C=C)

-1 1

cm ; H NMR (DMSO-d ): δ = 1.25-1.33 (t, 3H, J = 5.93 Hz, CH ), 1.66 - 1.70 (d, 3H, J = 5.97

6

3

Hz, CH ), 2.75-2.81 (d, 2H, J = 5.90 Hz, CH , thiopyran), 4.09 (d, 1H, J = 5.92 Hz, CH ,

3

2

thiopyran), 4.17 (d, 1H, J = 5.94 Hz, CH , thiopyran), 4.47 (q, 1H, J = 5.96 Hz, CH, thiazole),

2

4

.82- 4.88 (q, 2H, J = 5.95 Hz, CH ), 5.99 (t, 1H, J = 5.98 Hz, CH, thiopyran), 7.58 -7.99 (m, 5H,

2

1

3

Ar-H); C NMR (DMSO-d ) δ = 19.5, 25.9 (2C, 2CH ), 28.8, 35.1, 38.5 (3C, 3CH ), 51.7, 58.9

6

3

2

(2C, 2CH), 128.4, 128.8, 132.9, 135.7, 156.5, 161.2 (8C, Ar-C), 174.1, 187.3, 194.9 (3C, 3C=O);

+

MS (70 eV): m/z = 389 (M , 95%); Anal. Calc. (Found) for C H N O S (389.49): C, 55.51

1

8

19

3

3 2

(55.60); H, 4.92 (4.85); N, 10.79 (10.71).

4

.38. Synthesis of N''-(3-substituted-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazon- hydrazide (12a-c)

General Procedure: A mixture of 10a-c (0.01 mol), and hydrazine hydrate (99-100 %, 10 mL)

was stirred under reflux in dioxane (35 mL) and ethanol (5 mL) for 10-15h. The reaction mixture

was allowed to cool to zero ℃ for 6 h, and the solid was collected by filtration and crystallized

from the appropriate solvent to give 12a-c.

4

.39. Synthesis of N''-(5-methyl-4-oxo-3-phenylthiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonhydrazide (12a)

2

5

The compound was obtained from the reaction of 10a (3.99g, 0.01 mol) with hydrazine hydrate,

as a pale yellow crystals, crystallized from dioxane in 91% yield, m. p. >350 °C. IR (KBr): ν _m_a_x

=

3

1

430-3355 (br s, NH-NH ), 3045 (CH aryl), 2940 (CH alkyl), 1732, 1688, (2C=O), 1630 (C=N),

2

-1 1

578(C=C) cm ; H NMR (DMSO-d ): δ = 1.75- 1.79 (d, 3H, J = 5.95 Hz, CH ), 2.74- 2.80 (t, 2

6

3

H, J = 5.91 Hz, CH ), 3.28-3.35 (t, 2H, J = 5.90 Hz, CH ), 4.49 (q, 1H, J = 5.95 Hz, CH,

2

thiazole), 6.60 (br, NH , D O exchangeable), 7.38 -7.97 (m, 10H, Ar-H), 10.50 (br, NH, D O

2

1

3

exchangeable); C NMR (DMSO-d ) δ = 24.9 (1C, CH ), 29.7, 33.5 (2C, 2CH ), 56.8 (1C, CH,

6

3

2

thiazole), 127.6, 128.2, 128.4, 128.6, 128.8, 132.7, 135.6, 136.5, 155.7, 159.4 (14C, Ar-C), 171.5,

+

1

84.8 (2C, 2C=O); MS (70 eV): m/z = 395 (M , 100%); Anal. Calc. (Found) for C H N O S

2

0

21

5

2

(395.48): C, 60.74 (60.82); H, 5.35 (5.28); N, 17.71 (17.64).

4

.40. Synthesis of N''-(3-benzyl-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonhydrazide (12b)

The compound was obtained from the reaction of 10b (4.13g, 0.01 mol) with hydrazine hydrate,

as yellow crystals, crystallized from DMF in 84% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3435-

3

358 (br s, NH-NH ), 3049 (CH aryl), 2945 (CH alkyl), 1733, 1690, (2C=O), 1632 (C=N), 1580

2

-1 1

(

C=C) cm ; H NMR (DMSO-d ): δ = 1.78 - 1.82 (d, 3H, J = 5.93 Hz, CH ), 2.77 - 2.83 (t, 2H, J

6

3

=

5.96 Hz, CH ), 3.31 -3.38 (t, 2H, J = 5.97 Hz, CH ), 4.51 (q, 1H, J = 5.92 Hz, CH, thiazole),

2 2

5

.60 (s, 2H, CH ), 6.70 (br, NH , D O exchangeable), 7.32 -7.94 (m, 10H, Ar-H), 10.60 (br, NH,

2 2 2

1

3

D O exchangeable); C NMR (DMSO-d ) δ = 25.3 (1C, CH ), 28.2, 32.4, 38.5 (3C, 3CH ), 56.3

2

6

3

2

(1C, CH, thiazole), 127.1, 127.5, 128.2, 128.5, 128.7, 132.9, 135.8, 136.8, 155.9, 159.7 (14C, Ar-

+

C), 170.8, 183.9 (2C, 2C=O); MS (70 eV): m/z = 409 (M , 98%); Anal. Calc. (Found) for

C H N O S (409.51): C, 61.59 (61.50); H, 5.66 (5.71); N, 17.10 (17.03).

21

23

5

2

4

.41. Synthesis of N''-(3-ethyl-5-methyl-4-oxothiazolidin-2-ylidene)-4-oxo-4-phenylbutane

hydrazonhydrazide (12c)

The compound was obtained from the reaction of 10c (3.51g, 0.01 mol) with hydrazine hydrate,

as yellowish crystals, crystallized from ethanol in 87% yield, m. p. >350 °C. IR (KBr): ν _m_a_x

=

3

1

3

440-3350 (br s, NH-NH ), 3052 (CH aryl), 2950 (CH alkyl), 1735, 1692, (2C=O), 1634 (C=N),

2

-1 1

582 (C=C) cm ; H NMR (DMSO-d ): δ = 1.28-1.36 (t, 3H, J = 5.98 Hz, CH ), 1.81 - 1.85 (d,

6

3

H, J = 5.97 Hz, CH ), 2.80 - 2.86 (t, 2H, J = 5.94 Hz, CH ), 3.33 -3.40 (t, 2H, J = 5.91 Hz, CH ),

3

2

6

4

.55 (q, 1H, J = 5.93 Hz, CH, thiazole), 4.93 - 4.99 (q, 2H, J = 5.94 Hz, CH ), 6.80 (br, NH , D O

2 2 2

1

3

exchangeable), 7.55 -7.96 (m, 5H, Ar-H), 10.72 (br, NH, D O exchangeable); C NMR (DMSO-

2

d ) δ = 20.1, 26.3 (2C, 2CH ), 28.6, 32.7, 39.1 (3C, 3CH ), 56.8 (1C, CH, thiazole), 128.4, 128.9,

6

3

2

+

1

33.3, 136.2, 156.1, 158.8 (8C, Ar-C), 170.5, 183.7 (2C, 2C=O); MS (70 eV): m/z = 347 (M , 99

); Anal. Calc. (Found) for C H N O S (347.44): C, 55.31 (55.40); H, 6.09 (6.01); N, 20.16

%

16

21

5

2

(20.24).

4

.42. Synthesis of 3-substituted-5-methyl-2-((6-phenyl - 4, 5-dihydropyridazin-3(2H)-ylidene)

hydrazono) thiazolidin-4-one (13a-c)

General Procedure: The compounds 12a-c (0.01 mol), was refluxed in dimethylformamide (45

mL) and anhydrous potassium carbonate (2.08g, 0.015 mol) for 15-18h (under TLC control). The

reaction was cooled; the deposited precipitate was filtered off, washed with ethanol and dried, and

crystallized from appropriate solvent to produce 13a-c in good yield.

4

.43. Synthesis of 5-methyl-3-phenyl-2-((6-phenyl-4, 5-dihydropyridazin-3(2H)-ylidene)

hydrazono) thiazolidin-4-one (13a)

The compound was obtained from the reaction of 12a (3.95g, 0.01 mol) with DMF, as yellow

crystals, crystallized from benzene in 79% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3340 (br. s,

-1 1

NH), 3070 (CH aryl), 2960 (CH alkyl), 1682, (C=O), 1636 (C=N), 1583(C=C) cm ; H NMR

(DMSO-d ): δ = 1.72- 1.76 (d, 3H, J = 6.01 Hz, CH ), 2.10 - 2.18 (t, 2H, J = 6.04 Hz, CH ), 2.20

6 3 2

-

2.27 (t, 2H, J = 6.03 Hz, CH ), 4.53 (q, 1H, J = 6.05 Hz, CH, thiazole), 7.22 -7.65 (m, 10H, Ar-

2

1

3

H), 11.30 (br, NH, D O exchangeable); C NMR (DMSO-d ) δ = 24.5(1C, CH ), 26.1, 28.4 (2C,

2

6

3

2

1

CH ), 55.7 (1C, CH, thiazole), 127.1, 127.5, 127.8, 128.2, 128.5, 128.7, 134.9, 137.4, 144.7,

2

+

57.3, 159.8 (15C, Ar-C), 174.7 (1C, C=O); MS (70 eV): m/z = 377 (M , 90%); Anal. Calc.

(

Found) for C H N OS (377.47): C, 63.64 (63.55); H, 5.07 (5.13); N, 18.55 (18.62).

20 19 5

4

.44. Synthesis of 3-benzyl-5-methyl-2-((6-phenyl-4, 5-dihydropyridazin-3(2H)-ylidene)

hydrazono) thiazolidin-4-one (13b)

The compound was obtained from the reaction of 12b (4.09g, 0.01 mol) with DMF, as yellowish

crystals, crystallized from toluene in 72% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3345 (br. s,

-1

1

NH), 3072 (CH aryl), 2963 (CH alkyl), 1684 (C=O), 1632 (C=N), 1581(C=C) cm ; H NMR

2

7

(

DMSO-d ): δ = 1.74 - 1.78 (d, 3H, J = 6.07Hz, CH ), 2.13 - 2.21 (t, 2 H, J = 6.06 Hz, CH ), 2.24

6 3 2

-

2.31 (t, 2H, J = 6.08 Hz, CH ), 4.58 (q, 1H, J = 6.09 Hz, CH, thiazole), 5.52 (s, 2H, CH ), 7.20-

2

1

3

7

.63 (m, 10H, Ar-H), 11.25 (br, NH, D O exchangeable); C NMR (DMSO-d ) δ = 24.8(1C,

2 6

CH ), 26.5, 28.7, 39.4 (3C, 3CH ), 55.9 (1C, CH, thiazole), 127.3, 127.7, 127.9, 128.4, 128.7,

3

2

1

28.9, 135.1, 138.2, 144.5, 157.8, 160.2 (15C, Ar-C), 175.1 (1C, C=O); MS (70 eV): m/z = 391

+

(

M , 86%); Anal. Calc. (Found) for C H N OS (391.49): C, 64.43 (64.34); H, 5.41 (5.35); N,

2

1

21

5

1

7.89 (17.95).

.45. Synthesis of 3-ethyl-5-methyl-2-((6-phenyl-4, 5-dihydropyridazin-3(2H)-ylidene)

4

hydrazono) thiazolidin-4-one (13c)

The compound was obtained from the reaction of 12c (3.47g, 0.01 mol) with DMF, as white

crystals, crystallized from dioxane in 76% yield, m. p. >350 °C. IR (KBr): ν _m_a_x= 3348 (br. s,

-1

1

NH), 3075 (CH aryl), 2966 (CH alkyl), 1688 (C=O), 1635 (C=N), 1584(C=C) cm ; H NMR

(

DMSO-d ): δ = 1.22-1.30 (t, 3H, J = 6.01 Hz, CH ), 1.79 - 1.83 (d, 3H, J = 6.03 Hz, CH ), 2.12 -

6 3 3

2

.20 (t, 2H, J = 6.04 Hz, CH ), 2.28 -2.35 (t, 2H, J = 6.02 Hz, CH ), 4.60 (q, 1H, J = 6.08 Hz,

2 2

CH, thiazole), 4.85- 4.92 (q, 2H, J = 6.05 Hz, CH ), 7.25-7.40 (m, 5H, Ar-H), 11.20 (br, NH, D O

2

1

3

exchangeable); C NMR (DMSO-d ) δ = 21.2, 26.7 (2C, 2CH ), 28.9, 33.1, 39.5 (3C, 3CH ),

6

3

2

5

6.2 (1C, CH, thiazole), 127.4, 128.3, 128.6, 136.8, 144.3, 155.7, 159.1 (9C, Ar-C), 173.4 (1C,

+

C=O); MS (70 eV): m/z = 329 (M , 94%); Anal. Calc. (Found) for C H N OS (329.42): C, 58.34

1

6

19

5

(58.26); H, 5.81 (5.74); N, 21.26 (21.33).

4

.46. Synthesis of 1-((3-substituted-5-methyl-4-oxothiazolidin-2-ylidene) amino)-6-chloro-5-

phenyl-3, 4-dihydro-1H-azepine-2, 7-dione (14a-c)

General Procedure: A mixture of 9a-c (0.01mol) and chloro-acetyl-chloride (1.12 g, 0.01mol)

was refluxed in ethanol (50 mL) in the presence of potassium hydroxide (0.01mol) for 16-19h.

The reaction mixture was cooled with water; the deposited precipitate was filtered off, washed

with ethanol, dried, and crystallized from the suitable solvent to afford 14a-c.

4

.47. Synthesis of 6-chloro-1-((5-methyl-4-oxo-3-phenylthiazolidin-2-ylidene) amino)-5-phenyl-

, 4-dihydro-1H-azepine-2, 7-dione (14a)

3

2

8

The compound was obtained from the reaction of 9a (3.81g, 0.01 mol) with chloro-acetyl

chloride, as yellowish crystals, crystallized from dimethylformamide in 74% yield, m. p. >350 °C.

IR (KBr): ν _m_a_x= 3070 (CH aryl), 2960 (CH alkyl), 1690, 1685, 1680 (3C=O), 1630 (C=N), 1585

-1 1

(

C=C), 1185 (C-Cl) cm ; H NMR (DMSO-d ): δ = 1.69 (d, 3H, J = 6.10 Hz, CH ), 2.02 - 2.22

6 3

(

t, 2H, J = 6.12 Hz, CH ), 2.27 -2.35 (t, 2H, J = 6.14 Hz, CH ), 4.38 (q, 1H, CH, J = 6.13 Hz,

2

1

3

thiazole), 7.06-7.92 (m, 10H, Ar-H). C NMR (DMSO-d ) δ = 21.3 (1C, CH ), 23.3, 32.9 (2C,

6

3

2

1

9

CH ), 61.8 (1C, CH, thiazole), 117.7 (1C,C-Cl), 123.9, 126.4, 129.9, 131.9, 132.5, 132.9, 135.4,

2

+

41.9, 148.9, 155.1 (14C, Ar-C), 161.3, 167.6, 168.1 (3C, 3C=O); MS (70 eV): m/z = 439 (M ,

00 %); Anal. Calc. (Found) for C H ClN O S (439.91): C, 60.07 (60.15); H, 4.12 (4.20); N,

2

18

3

.55 (9.46).

4

.48. Synthesis of 1-((3-benzyl-5-methyl-4-oxothiazolidin-2-ylidene) amino)-6-chloro-5-phenyl-

, 4-dihydro-1H-azepine-2, 7-dione (14b)

3

The compound was obtained from the reaction of 9b (3.95g, 0.01 mol) with chloro-acetyl

chloride, as yellow crystals, crystallized from dioxane in 70% yield, m. p. >350 °C. IR (KBr): ν

=

3075 (CH aryl), 2965 (CH alkyl), 1693, 1688, 1682(3C=O), 1632 (C=N), 1587 (C=C), 1182

max

-1 1

(

C-Cl) cm ; H NMR (DMSO-d ): δ = 1.75 (d, 3H, J = 6.08 Hz, CH ), 2.05- 2.25 (t, 2 H, J = 6.09

6

3

Hz, CH ), 2.26 -2.34 (t, 2H, J = 6.07 Hz, CH ), 4.40 (q, 1H, CH, J = 6.05 Hz, thiazole), 5.60 (s,

2

1

3

2

H, CH ), 7.05-7.90 (m, 10H, Ar-H). C NMR (DMSO-d ) δ = 24.6 (1C, CH ), 27.7, 30.8, 38.5

2 6 3

(

3C, 3CH ), 58.5 (1C, CH, thiazole), 119.8 (1C,C-Cl), 126.5, 127.1, 127.4, 127.8, 128.4, 128.7,

2

1

35.8, 137.9, 150.7, 154.1 (14C, Ar-C), 162.2, 168.3, 169.4 (3C, 3C=O); MS (70 eV): m/z = 453

+

(

M , 90%); Anal. Calc. (Found) for C H ClN O S (453.94): C, 60.86 (60.94); H, 4.44 (4.51); N,

2

3

20

3

9

.26 (9.16).

4

.49. Synthesis of 6-chloro-1-((3-ethyl-5-methyl-4-oxothiazolidin-2-ylidene) amino)-5-phenyl-3,

-dihydro-1H-azepine-2, 7-dione (14c)

4

The compound was obtained from the reaction of 9c (3.33g, 0.01 mol) with chloro-acetyl

chloride, as yellowish crystals, crystallized from dimethylformamide in 73% yield, m. p. >350 °C.

IR (KBr): ν _m_a_x= 3079 (CH aryl), 2968 (CH alkyl), 1695, 1690, 1684(3C=O), 1635 (C=N), 1590

-1 1

(

C=C), 1180 (C-Cl) cm ; H NMR (DMSO-d ): δ = 1.27-1.35 (t, 3H, J = 6.04 Hz, CH ), 1.80 (d,

6

3

H, J = 6.02 Hz, CH ), 2.08 - 2.27(t, 2H, J = 6.01 Hz, CH ), 2.28 -2.37 (t, 2H, J = 6.06 Hz, CH ),

3 2 2

2

9

4

.45 (q, 1H, CH, J = 6.08 Hz, thiazole), 4.77- 4.84 (q, 2H, J = 6.03 Hz, CH ), 7.02 -7.40 (m, 5H,

2

1

3

Ar-H). C NMR (DMSO-d ) δ = 20.5, 25.9 (2C, 2CH ), 27.8, 32.9, 38.7 (3C, 3CH ), 58.9 (1C,

6

3

2

CH, thiazole), 119.5 (1C,C-Cl), 126.8, 128.1, 128.8, 138.4, 151.2, 154.5 (8C, Ar-C), 162.6, 166.5,

+

1

70.1 (3C, 3C=O); MS (70 eV): m/z = 391 (M , 95%); Anal. Calc. (Found) for C H ClN O S

1

8

18

3

(391.87): C, 55.17 (55.25); H, 4.63 (4.70); N, 10.72 (10.64).

4

.50. MATERIAL AND METHODS

.51. Biological screening

The antimicrobial activity of the newly prepared compounds was tested in vitro against Gram-

positive bacteria Streptococcus pyogenes, Staphylococcus aureus, Gram-negative bacteria

Klebsiella pneumoniae, Escherichia coli, and the fungi Candida albicans, Curvularia lunata,

Alternaria alternate and Aspergillus niger. The newly prepared compounds were dissolved in

dimethyl sulfoxide (DMSO) and tested for their antimicrobial activity by the agar disk diffusion

[

1-3, 21, 36, 49]

technique. Cefotaxime sodium and nystatin,

were used as the standard drugs for

-1

antibacterial and antifungal assays, respectively. A solution of 100 μg mL of the tested

compound was practical and microplate-wells, 1 cm in diameter, were used. Zones of inhibition

were measured with calipers or automated scanners and were paralleled with those of the

-1

standards. Cefotaxime sodium (0.15μmol mL ) and nystatin (0.037 μmol mL ) were used as the

standard drugs for antibacterial and antifungal activity, respectively. Compound-impregnated

disks were placed on an agar plate containing a standard suspension of microorganisms. The plate

was incubated for 24 h at 37 °C. For the assessment of the minimum inhibitory concentration

[

1-3, 21, 36, 49]

(MIC) by the serial plate dilution way,

5 mg of each tested compound was dissolved in

1

mL of DMSO separately to prepare stock solutions. Serial dilutions were prepared from each

stock solution. The plates were incubated at 37 °C for 24 h. MIC is defined as the lowest

-

1

concentration (μmol mL ) of the tested compound that results in no visible growth on the plates.

DMSO was used as the solvent control to ensure that the solvent had no effect on bacterial

growth. Notice: This experiment was repeated three times on the same prepared compounds and

the ideal drugs according to the same conditions with calculation an average of the minimum

inhibitory concentration (MIC).The results are shown in Tables 1 and 2.

3

0

Article Doi

Synthesis and antimicrobial activity of new 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, thiopyrane, thiazolidinone, and azepine derivatives

DOI: 10.1002/jhet.4149

Source and publish data:

Authors:

Article abstract of DOI:10.1002/jhet.4149

Full text of DOI:10.1002/jhet.4149

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