Synthesis, antimicrobial, and anti-inflammatory activities of novel 5-(1-adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles and related derivatives

Molecules 2010, 15, 2526-2550; doi:10.3390/molecules15042526

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molecules

ISSN 1420-3049

www.mdpi.com/journal/molecules

Article

Synthesis, Antimicrobial, and Anti-inflammatory Activities of

Novel 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4-

triazoles and Related Derivatives

Mohamed A. Al-Omar ¹, Ebtehal S. Al-Abdullah ¹, Ihsan A. Shehata ¹, Elsayed E. Habib ²,

Tarek M. Ibrahim ³and Ali A. El-Emam ^1,*

1

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh

11451, Saudi Arabia

2

Department of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516,

Egypt

3

Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Mansoura,

Mansoura 35516, Egypt

* Author to whom correspondence should be addressed; E-Mail: aelemam@ksu.edu.sa;

Tel.: +966-1-4677350; Fax: +966-1-4676220.

Received: 8 March 2010; in revised form: 29 March 2010 / Accepted: 2 April 2010 /

Published: 9 April 2010

Abstract: The reaction of 5-(1-adamantyl)-4-amino-3-mercapto-1,2,4-triazole (5) with

various aromatic aldehydes in ethanol or acetic acid yielded the corresponding 4-

arylideneamino derivatives 6a–v. Treatment of the 4-(2,6-difluoro- and

dichlorobenzylideneamino) derivatives 6o and 6q with 1-substituted piperazines, and

formaldehyde solution in ethanol afforded good yields of the corresponding 5-(1-

adamantyl)-4-(2,6-dihalobenzylideneamino-2-(4-substituted-1-piperazinylmethyl)-1,2,4-

triazoline-3-thiones 7a–p. 5-(1-Adamantyl)-4-arylideneamino-2-(4-ethoxycarbonyl-1-

piperidylmethyl)-1,2,4-triazoline-3-thiones 8a–n, were similarly prepared via the reaction

of the corresponding arylideneamino derivative with ethyl 4-piperidinecarboxylate and

formaldehyde solution in ethanol. Compounds 6a–v, 7a–p and 8a–n were tested for in

vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-

like pathogenic fungus Candida albicans. Several derivatives showed good or moderate

activities, particularly against the tested Gram-positive bacteria. In addition, the in vivo

anti-inflammatory activity of 21 compounds was determined using the carrageenan-

Molecules 2010, 15

induced paw oedema method in rats. Compounds 7d, 7g, 7i, 7j, 7l, 8c, 8e and 8l showed

2527

good or moderate dose-dependent activity in this area.

Keywords: 1-adamantyl derivatives; 1,2,4-triazoles; antimicrobial activity; anti-

inflammatory activity

1. Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics,

primarily for the treatment of pain and inflammation in arthritis. The development of microbial

resistance has necessitated the search for new potent antibacterial and antifungal agents. Derivatives of

adamantane which have long been known for their antiviral activity against the influenza [1–3] and

HIV viruses [4–7], were also associated with central nervous [8–10], antimicrobial [11–15] and anti-

inflammatory activities [14–18]. 1,2,4-Triazole derivatives were reported to possess diverse biological

activities, such as antibacterial [19-21] and anti-inflammatory [22–25] properties. In addition, several

5-substituted-4-arylideneamino-3-mercapto-1,2,4-triazoles and their piperazinomethyl derivatives were

reported to exhibit significant antimicrobial activity [26–28]. In continuation to our interest in the

chemical and pharmacological properties of adamantane derivatives [6,11,14–16], we report herein the

synthesis, antimicrobial and anti-inflammatory activities of a new series of 5-(1-adamantyl)-4-

arylideneamino-3-mercapto-1,2,4-triazoles and their piperazinomethyl and piperidinomethyl

Mannich bases.

2. Results and Discussion

2.1. Chemistry

5-(1-Adamantyl)-4-amino-3-mercapto-1,2,4-triazole (5) was prepared starting from adamantane-1-

carboxylic acid (1) via esterification with methanol to yield the methyl ester 2, which was

subsequently reacted with hydrazine to yield adamantane-1-carboxylic acid hydrazide (3). Treatment

of 3 with carbon disulphide in ethanolic potassium hydroxide yielded the corresponding potassium N'-

(1-adamantylcarbonyl)dithiocarbazate (4), which was cyclized by heating with hydrazine to yield 5-(1-

adamantyl)-4-amino-3-mercapto-1,2,4-triazole (5) in good overall yield [29]. Treatment of compound

5 with the appropriate aromatic aldehydes under reflux in ethanol for 5 h yielded the corresponding

arylideneamino derivatives 6a-v in reasonable yields. In the cases of the reactions with 2-nitro-, 4-

nitro-, 2,4-dichloro-, 3,4-dichloro-, 2,4-dinitro-, or 4,5-dimethoxy-2-nitrobenzaldehyde, the yields were

very poor. This may be attributed to the poor solubility of these aldehydes in ethanol. However,

carrying out the reaction in acetic acid, in which these aldehydes are freely soluble, in addition to its

higher boiling point, greatly increased the yield (Scheme 1, Table 1).

The 2,6-difluoro- and dichlorobenzylideneamino derivatives 6o and 6q were reacted with several 1-

substituted piperazines and formaldehyde solution in ethanol to yield the corresponding N-Mannich

bases 7a–p in good yields. The reaction was carried out by heating the reactants in ethanol for

15 min to enhance the solubility of compounds 6o and 6q. On monitoring the reaction with thin layer

Molecules 2010, 15

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chromatography (TLC), the starting compounds 6o and 6q disappeared completely after 15 minutes

and the products either precipitated on standing or after addition of water. The 5-(1-adamantyl)-4-

arylideneamino-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-triazoline-3-thione N-Mannich bases

8a–n were similarly prepared via the reaction of the corresponding 5-(1-adamantyl)-4-arylideneamino-

3-mercapto-1,2,4-triazole with ethyl 4-piperidinecarboxylate and formaldehyde solution by heating the

reactants in ethanol for 20 min (Scheme 2, Tables 2 and 3). The structures of newly synthesized

compounds 6a–v, 7a–p and 8a–n were confirmed by ¹H-NMR, ¹³C-NMR and mass spectra.

Scheme 1. Synthetic Pathway for Compounds 6a–v.

CH₃OH

H₂SO₄

H

NH₂NH₂

O

N

COOH

NH₂

CH₃

O

2

3

1

CS₂/ KOH

EtOH, r.t.

N

ArCHO

N

S

H

NH₂NH₂

N

SH

N

H

N

S^-K⁺

SH

N

6a-v

O

H₂N

5

4

R

Table 1. Melting points, crystallization solvents, yields, molecular formulae and molecular

weights of compounds 6a–v.

Yield

(%)

Molecular Formula

(Mol. Wt.)

Comp. No.

R

Mp (ºC)

Cryst. Solv.

6a

6b

6c

6d

6e

6f

6g

6h

6i

6j

6k

6l*

6m*

6n

6o

6p

6q

6r*

6s*

6t

H

2-F

4-F

2-Cl

4-Cl

4-Br

2-OH

4-OH

4-CH₃

2-OCH₃

4-OCH₃

2-NO₂

4-NO₂

4-(CH₃)₂N

2,6-F₂

222-224

226-228

255-257

223-225

207-209

228-230

238-240

264-266

208-210

226-228

214-216

226-228

242-244

223-225

241-243

219-221

207-209

233-235

237-239

191-193

245-247

145-147

EtOH/H₂O

EtOH

81

74

71

75

68

59

79

82

80

77

81

52

50

66

68

62

49

62

69

86

49

68

C₁₉H₂₂N₄S (338.47)

C₁₉H₂₁FN₄S (356.46)

C₁₉H₂₁ClN₄S (372.91)

C₁₉H₂₁BrN₄S (417.37)

C₁₉H₂₂N₄OS (354.47)

C₂₀H₂₄N₄S (352.50)

C₂₀H₂₄N₄OS (368.50)

C₁₉H₂₁N₅O₂S (383.47)

C₂₁H₂₇N₅S (381.54)

C₁₉H₂₀F₂N₄S (374.45)

C₁₉H₂₀ClFN₄S (390.91)

C₁₉H₂₀Cl₂N₄S (407.36)

C₂₁H₂₆N₄O₂S (398.52)

C₁₉H₂₀N₆O₄S (428.46)

C₂₁H₂₅N₅O₄S (443.52)

EtOH

AcOH

EtOH/H₂O

EtOH

EtOH/H₂O

EtOH

AcOH

EtOH

2-Cl,6-F

2,6-Cl₂

2,4-Cl₂

3,4-Cl₂

3,4-(CH₃O)₂

2,4-(NO₂)₂

2-NO₂,4,5-(CH₃O)₂

EtOH

DMF

AcOH

EtOH

AcOH

6u*

6v*

* Prepared by method B.

Molecules 2010, 15

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Table 2. Melting points, crystallization solvents, yields, molecular formulae and molecular

weights of compounds 7a–p.

Yield

(%)

54

Molecular Formula

(Mol. Wt.)

Comp. No.

X

R

Mp (°C)

Cryst. Solv.

7a

7b

7c

7d

7e

7f

F

CH₃

C₂H₅

102-104

169-171

156-158

151-153

140-142

132-134

184-186

148-150

109-111

117-119

136-138

170-172

184-186

159-161

139-141

178-180

EtOH/H₂O

EtOH

C₂₅H₃₂F₂N₆S (486.62)

C₂₆H₃₄F₂N₆S (500.65)

C₂₇H₃₄F₂N₆O₂S (544.66)

C₃₀H₃₄F₂N₆S (548.69)

C₃₀H₃₃F₃N₆S (566.68)

C₃₁H₃₃F₅N₆S (616.69)

C₃₁H₃₆F₂N₆OS (578.72)

C₃₁H₃₆F₂N₆S (562.72)

C₂₅H₃₂Cl₂N₆S (519.53)

C₂₆H₃₄Cl₂N₆S (533.56)

C₂₇H₃₄Cl₂N₆O₂S (577.57)

C₃₀H₃₄Cl₂N₆S (581.60)

C₃₀H₃₃Cl₂FN₆S (599.59)

C₃₁H₃₃Cl₂F₃N₆S (649.60)

C₃₁H₃₆Cl₂N₆OS (611.63)

C₃₁H₃₆Cl₂N₆S (595.63)

89

F

COOC₂H₅

C₆H₅

82

F

79

F

4-FC₆H₄

3-CF₃C₆H₄

2-CH₃OC₆H₄

C₆H₅CH₂

CH₃

EtOH/H₂O

EtOH/CHCl₃

EtOH

80

F

88

7g

7h

7i

F

85

F

80

Cl

EtOH/H₂O

EtOH

68

7j

C₂H₅

75

7k

7l

COOC₂H₅

C₆H₅

72

83

7m

7n

7o

7p

4-FC₆H₄

3-CF₃C₆H₄

2-CH₃OC₆H₄

C₆H₅CH₂

EtOH

85

EtOH

86

EtOH

67

EtOH

80

Scheme 2. Synthetic Pathway for Compounds 7a–p and 8a–n.

N

R

N

SH

HN

N R

S

N

6

CH₂O/EtOH

7a-p

X

R

COOEt

CH₂O/EtOH

N

H

N

COOC₂H₅

S

N

8a-n

R

Molecules 2010, 15

Table 3. Melting points, crystallization solvents, yield percentages, molecular formulae

2530

and molecular weights of compounds 8a–n.

Comp.

No.

Yield

(%)

Molecular Formula

(Mol. Wt.)

R

Mp (°C)

Cryst. Solv.

8a

8b

8c

8d

8e

8f

8g

8h

8i

8j

8k

8l

8m

8n

H

2-F

2-Cl

4-CH₃

2-OH

4-OH

4-OCH₃

2,6-F₂

2-Cl,6-F

2,6-Cl₂

2,4-Cl₂

125-127

134-136

158-160

135-137

127-129

195-197

124-126

148-150

151-153

129-131

186-188

113-115

182-184

EtOH/H₂O

EtOH

EtOH/H₂O

EtOH

82

72

75

92

79

84

88

69

74

75

68

71

76

80

C₂₈H₃₇N₅O₂S (507.69)

C₂₈H₃₆FN₅O₂S (525.68)

C₂₈H₃₆ClN₅O₂S (542.14)

C₂₉H₃₉N₅O₂S (521.72)

C₂₈H₃₇N₅O₃S (523.69)

C₂₉H₃₉N₅O₃S (537.72)

C₂₈H₃₅F₂N₅O₂S (543.67)

C₂₈H₃₅ClFN₅O₂S (560.13)

C₂₈H₃₅Cl₂N₅O₂S (576.58)

C₃₀H₄₁N₅O₄S (567.74)

C₃₀H₄₀N₆O₆S (612.74)

EtOH

3,4-Cl₂

3,4-(CH₃O)₂

2-NO₂,4,5-(CH₃O)₂

EtOH/H₂O

EtOH/CHCl₃

2.2. Antimicrobial Testing

The newly synthesized compounds 6a–v, 7a–p and 8a–n were tested for their in vitro growth

inhibitory activity against the standard strains of the Institute of Fermentation of Osaka (IFO) namely;

Staphylococcus aureus IFO 3060, Bacillus subtilis IFO 3007, Micrococcus luteus IFO 3232 (Gram-

positive bacteria), Escherichia coli IFO 3301, Pseudomonas aeuroginosa IFO 3448 (Gram-negative

bacteria), and the yeast-like pathogenic fungus Candida albicans IFO 0583. The primary screening

was carried out using the agar disc-diffusion method using Müller-Hinton agar medium [30]. The

results of the preliminary antimicrobial testing of compounds 6a–v, 7a–p and 8a–n (200 μg/disc), the

antibacterial antibiotic ampicillin trihydrate (100 μg/disc) and the antifungal drug clotrimazole

(100 μg/disc) are shown in table 4. The antimicrobial activity results of the 4-arylideneaminotriazoles

6a–v revealed that the aryl substituents greatly influenced the antimicrobial activity. The halo and

hydroxyl derivatives were highly active particularly against the tested Gram-positive bacteria, while

the nitro and methoxy derivatives were generally inactive. In addition, the hydroxy derivatives 6g and

6h showed marked activity against the tested Gram-negative bacteria. The 4-fluoro 6c and 4-bromo 6f

derivatives were significantly active against Candida albicans. Based on the antibacterial activity of

the arylideneamino derivatives 6a-v, and the previously reported high chemotherapeutic activity of

several 2,6-dihalophenyl derivatives [31–33], the 2,6-difluoro- and dichlorobenzylideneamino

derivatives 6o and 6q were selected to prepare their 4-substituted-1-piperazinyl Mannich bases 7a–p.

The results of the antimicrobial activity of the 4-substituted-1-piperazinyl Mannich bases 7a–p were

generally lower than those of the arylideneamino derivatives 6a–v but the specificity was almost

similar. On the other hand, the antimicrobial activity of the 4-ethoxycarbonyl-1-piperidyl Mannich

bases 8a–n was higher than the 4-substituted-1-piperazinyl Mannich bases 7a–p. The most potent

member of these derivatives were the 4-hydroxybenzylidene 8f and the 3,4-dimethoxybenzylidene 8m

derivatives which displayed strong broad spectrum activity. The minimal inhibitory concentration

(MIC) for the most active compounds 6h, 6o, 7n, 8a, 8e, 8f and 8m against the same microorganism

used in the primary screening was determined using the microdilution susceptibility method in

Molecules 2010, 15

2531

Müller-Hinton Broth and Sabouraud Liquid Medium [34]. The MIC of the most active compounds, the

antibacterial antibiotic ampicillin trihydrate and the antifungal drug clotrimazole (Table 5) were in

accordance with the results obtained in the primary screening.

Table 4. Antimicrobial activity of compounds 6a–v, 7a–p and 8a–n (200 μg/8 mm disc),

the broad spectrum antibacterial drugs gentamicin (100 μg/8 mm disc), ampicillin

(100 μg/8 mm disc) and the antifungal drug clotrimazole (100 μg/8 mm disc) against

Staphylococcus aureus IFO 3060 (SA), Bacillus subtilis IFO 3007 (BS), Micrococcus

luteus IFO 3232 (ML), Escherichia coli IFO 3301 (EC), Pseudomonas aeuroginosa IFO

3448 (PA), and Candida albicans IFO 0583 (CA).

Diameter of Growth Inhibition Zone (mm)*

Comp. No.

SA

BS

ML

EC

PA

C A

6a

6b

6c

6d

6e

6f

6g

6h

6i

10

14

16

11

14

13

14

19

15

-

13

14

17

14

16

14

16

25

18

-

14

12

13

15

-

17

-

16

-

15

19

-

13

14

-

6j

-

6k

6l

-

14

-

18

-

14

16

17

-

14

-

19

-

16

17

-

6m

6n

6o

6p

6q

6r

6s

-

12

-

6t

6u

6v

7a

7b

7c

7d

7e

7f

7g

7h

7i

7j

7k

7l

-

13

15

11

-

12

-

15

14

15

-

11

-

15

-

18

-

12

11

-

17

-

14

-

12

14

-

11

12

11

-

7m

7n

7o

7p

8a

8b

8c

8d

8e

13

-

12

-

11

17

12

-

19

-

15

22

-

16

-

19

-

15

-

14

-

13

Molecules 2010, 15

2532

Table 4. Cont.

8f

8g

8h

8i

8j

8k

8l

8m

8n

22

15

-

14

12

15

11

20

-

26

11

-

15

16

17

13

24

-

16

-

17

-

19

-

16

-

19

-

14

-

Gentamicin

Ampicillin

Clotrimazole

26

23

NT

25

21

NT

18

19

NT

20

17

NT

19

16

NT

21

* (-): Inactive (inhibition zone <10 mm). (NT): Not tested.

Table 5. The minimal inhibitory concentrations (MIC, μg/mL) of compounds 6h, 6o, 7n,

8a, 8e, 8f, 8m, the broad spectrum antibacterial drugs gentamicin, ampicillin and the

antifungal drug clotrimazole against Staphylococcus aureus IFO 3060 (SA), Bacillus

subtilis IFO 3007 (BS), Micrococcus luteus IFO 3232 (ML), Escherichia coli IFO 3301

(EC), Pseudomonas aeuroginosa IFO 3448 (PA), and Candida albicans IFO 0583 (CA).

Minimal Inhibitory Concentration (MIC, 　g/mL)*

Comp. No.

SA

2

BS

1

ML

ND

2

EC

2

PA

ND

1

C A

ND

8

6h

6o

ND

2

4

ND

2

7n

ND

4

8a

8e

ND

2

8f

1

8m

2

1

ND

2

Gentamicin

Ampicillin

Clotrimazole

2

0.5

2

0.5

ND

2

ND

* ND: Not determined.

2.3. Acute anti-inflammatory activity testing

The acute in vivo anti-inflammatory activity of 21 representative compounds (6b, 6e, 6h, 6j, 6r, 6t,

7b, 7d, 7g, 7j, 7l, 7m, 7p, 8a, 8c, 8e, 8f, 8h, 8k, 8l and 8n) was determined following the carrageenan-

induced paw oedema method in rats [35]. The selection of the representative compounds and dose

levels were made after carrying out pilot experiments which showed the absence of anti-inflammatory

activity for some compounds and that the dose levels 20 and 40 mg/kg showed no signs of acute

toxicity. The results of the anti-inflammatory activity of the tested compounds (20 & 40 mg/kg) and

the potent anti-inflammatory drug Indomethacin (5 mg/kg) are listed in Table 6. The majority of the

tested compounds showed varying degrees of activity. The highest activity was shown by compound

7l, which produced strong dose-dependent inhibition of carrageenan-induced paw oedema (>50%),

while compounds 7d and 8c were moderately active (30–50%) at 20 & 40 mg/kg dose level.

Molecules 2010, 15

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Compounds 7g, 7j, 8e, and 8l were moderately active at 40 mg/kg dose level and weakly active at

20 mg/kg level. The structure-anti-inflammatory activity of the tested derivatives revealed that the

triazole N-2 and N-4 substituents greatly influence the anti-inflammatory activity.

Table 6. Anti-inflammatory effect of intraperitoneal injection of (20 & 40 mg/kg) of

compounds 6b, 6e, 6h, 6j, 6r, 6t, 7b, 7d, 7g, 7j, 7l, 7m, 7p, 8a, 8c, 8e, 8f, 8h, 8k, 8l, 8n

and Indomethacin (5 mg/kg) against carrageenan-induced paw oedema in rats.

Comp. No.

Mean % Reduction of paw oedema from control^a

20 mg/kg

40 mg/kg

Control^b

0 (± 0.04)

6b

6e

6h

6j

6r

6t

7b

7d

7g

7j

7l

7m

7p

8a

8c

8e

-5.50 (± 0.13)^*

3.16 (± 0.11)^*

-2.71 (± 0.12)^*

-8.56 (± 0.07)^*

11.29 (± 0.14)^**

13.91 (± 0.11)^**

10.54 (± 0.11)^**

19.37 (± 0.07)^**

20.01 (± 0.09)^**

39.88 (± 0.89)^**

38.37 (± 0.07)^**

34.76 (± 0.10)^**

50.44 (± 0.06)^**

22.90 (± 0.08)^**

4.99 (± 0.08)^*

13.28 (± 0.15)^**

11.06 (± 0.13)^**

10.32 (± 0.09)^**

21.92 (± 0.08)^**

17.88 (± 0.11)^**

39.16 (± 0.09)^**

25.88 (± 0.07)^**

27.95 (± 0.12)^**

28.86 (± 0.08)^**

13.06 (± 0.08)^**

2.05 (± 0.06)^*

23.23 (± 0.02)^**

33.02 (± 0.11)^**

20.41 (± 0.07)^**

-18.25 (± 0.13)

-20.21 (± 0.11)

9.91 (± 0.133)^*

10.45 (± 0.10)^**

-13.75 (± 0.18)^*

15.27 (± 0.05)^**

37.66 (± 0.14)^**

31.20 (± 0.09)^**

1.36 (± 0.04)

8f

8h

8k

8l

-9.80 (± 0.07)

6.81 (± 0.09)^*

35.01 (± 0.12)^**

-11.61 (± 0.10)^*

8n

Indomethacin (5 mg/kg)

52.79 (± 0.04)

^aResults are expressed as mean % inhibition ± S.E.M. (n = 5) and compared with student “t” test.

^bThe group was injected with 1 ml of 0.5% aqueous carboxymethyl cellulose solution.

^*Inactive: Significantly different from Indomethacin at p < 0.05.

^**Activity comparable to Indomethacin (significantly different from Indomethacin at p < 0.05.

The N-2 unsubstituted adamantyltriazoles 6b, 6e, 6h, 6j, 6r and 6t were weakly active or

completely inactive, while the N-2 piperazinomethyl derivatives 7b, 7d, 7g, 7j, 7l, 7m and 7p were

generally active. The activity was also found to be dependent on the nature of the 4-arylideneamino

and the 4-piperazinyl substituents. The activity of the 2,6-dichlorobenzylidene derivatives were

slightly higher than their 2,6-difluoro-benzylidene analogues. It could be also concluded that the

phenyl substituents are better compared with the ethyl, 4-fluorophenyl, 2-methoxyphenyl and benzyl

substituents. The replacement of the 4-substituted-1-piperazinyl moiety with a 4-carbethoxy-1-

piperidyl moiety resulted in marked decrease in activity, only the chloro derivatives 8c and 8l and the

2-hydroxy derivative 8e exhibited moderate activity. There are in fact a high number of

enzyme/receptors involved in the inflammatory process. Without specific tests it is quite difficult to

hypothesize the mechanism of action of the tested compounds, they may exert their action via

inhibition of the cyclooxygenase enzymes like other nonsteroidal anti-inflammatory agents. In

addition, the recently reported activity of some adamantane derivatives as selective inhibitors of

Molecules 2010, 15

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11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) [36,37] should be taken inconsideration. The

11β-hydroxysteroid dehydrogenase type 1 converts cortisone to the active glucocorticoid cortisol,

which is responsible for various metabolic disorders including water retention, thus the inhibition of

11β-HSD1 would result in increasing the intracellular cortisone level.

3. Experimental

3.1. General

Melting points (ºC) were measured in open glass capillaries using a Branstead 9001 Electrothermal

melting point apparatus and are uncorrected. NMR spectra were obtained on a Bruker AC 500 Ultra

Shield NMR spectrometer (Fällanden, Switzerland) operating at 500.13 MHz for ¹H and 125.76 MHz

for ¹³C; the chemical shifts are expressed in δ (ppm) downfield from tetramethylsilane (TMS) as

internal standard; coupling constants (J) are expressed in Hz. Electrospray ionization mass spectra

(ESI-MS) were recorded on a Waters QuatroMicro triple quadrupole tandem mass spectrometer at

4.0 and 3.5 kV for positive and negative ions, respectively. Elemental analyses (C, H, N, S) were in

full agreement with the proposed structures within ± 0.4% of the theoretical values. Monitoring the

reactions and checking the purity of the final products were carried out by thin layer chromatography

(TLC) using silica gel precoated aluminum sheets (60 F₂₅₄, Merck) and visualization with ultraviolet

light (UV) at 365 and 254 nm. The bacterial strains and Candida albicans fungus were obtained from

the Institute of Fermentation of Osaka (IFO), Osaka, Japan. The reference drugs ampicillin trihydrate

(CAS 7177-48-2), clotrimazole (CAS 23593-75-1) and indomethacin (CAS 53-86-1) were obtained

from Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany. The Sprauge-Dawley rats were purchased

from local animal house (Abu-Rawash, Giza, Egypt). The animal experiments for the determination of

the anti-inflammatory activity were carried out in agreement with the pertinent legal and ethical

standards of the international guidelines.

3.2. 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles 6a–v

Method A: A mixture of the appropriate aromatic aldehyde (2.0 mmol) and 5-(1-adamantyl)-4-

amino-3-mercapto-1,2,4-triazole (5, 0.5 g, 2.0 mmol) in absolute ethanol (10 mL) was heated under

reflux for 5 h. On cooling, the separated solid was filtered, washed with cold ethanol (5 mL), dried and

crystallized (Table 1). Method B (compounds 6l, 6m, 6r, 6s, 6u and 6v): A mixture of the appropriate

aromatic aldehyde (2.0 mmol) and 5-(1-adamantyl)-4-amino-3-mercapto-1,2,4-triazole (5, 0.5 g,

2 mmol) in acetic acid (8 mL) was heated under reflux for 4 h. On cooling, the separated solid was

filtered, washed with cold ethanol (5 mL), dried and crystallized (Table 1).

1

5-(1-Adamantyl)-4-benzylideneamino-3-mercapto-1,2,4-triazole 6a: H-NMR (DMSO-d₆): δ 1.69–

1.73 (m, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.07 (s, 6H, adamantane-H), 7.58–7.65 (m,

13

3H, Ar-H), 7.92 (d, 2H, Ar-H, J = 7.0 Hz), 9.71 (s, 1H, CH=N), 13.82 (s, 1H, SH). C-NMR: 27.72,

35.28, 36.47, 38.61 (adamantane-C), 128.94, 129.78, 132.67, 133.17 (Ar-C), 156.04, 162.50 (triazole

C-5 & CH=N), 165.02 (triazole C-3). MS, m/z (Rel. Int.): 338 (M⁺, 51), 261 (12), 236 (26), 235 (100),

221 (14), 202 (17), 135 (15), 104 (12), 90 (11), 77 (6).

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5-(1-Adamantyl)-4-(2-fluorobenzylideneamino)-3-mercapto-1,2,4-triazole 6b: 1H-NMR (DMSO-d₆): δ

1.71 (s, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.08 (s, 6H, adamantane-H), 7.40–7.45 (m,

2H, Ar-H), 7.67–7.71 (m, 1H, Ar-H), 8.04 (t, 1H, Ar-H, J = 7.0 Hz), 10.18 (s, 1H, CH=N), 13.85 (s,

1H, SH). ¹³C-NMR: 27.77, 35.36, 36.49, 38.37 (adamantane-C), 117.0, 120.45, 125.92, 127.86,

135.25, 156.88 (Ar-C), 156.20, 162.44 (triazole C-5 & CH=N), 163.18 (triazole C-3). MS, m/z (Rel.

Int.): 356 (M⁺, 44), 339 (25), 297 (17), 266(24), 260 (20), 235 (100), 234 (60), 220 (31), 135 (25), 122

(26), 108 (29), 96 (10).

1

5-(1-Adamantyl)-4-(4-fluorobenzylideneamino)-3-mercapto-1,2,4-triazole 6c: H-NMR (DMSO-d₆): δ

1.71 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.07 (s, 6H, adamantane-H), 7.34 (d, 2H, Ar-

13

H, J = 6.5 Hz), 7.94 (d, 2H, Ar-H, J = 6.5 Hz), 9.71 (s, 1H, CH=N), 13.81 (s, 1H, SH). C-NMR:

27.73, 35.28, 36.47, 38.63 (adamantane-C), 116.40, 129.28, 131.09, 163.95 (Ar-C), 156.02, 162.54

(triazole C-5 & CH=N), 165.37 (triazole C-3). MS, m/z (Rel. Int.): 356 (M⁺, 17), 235 (100), 234 (58),

220 (14), 135 (34), 122 (22), 121 (62), 107 (18), 95 (44).

5-(1-Adamantyl)-4-(2-chlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6d: 1H-NMR (DMSO-d₆):

δ 1.73 (s, 6H, adamantane-H), 2.03 (s, 3H, adamantane-H), 2.09 (s, 6H, adamantane-H), 7.58–7.70 (m,

3H, Ar-H), 8.15 (d, 1H, Ar-H, J = 7.5 Hz), 10.48 (s, 1H, CH=N), 13.89 (s, 1H, SH). ¹³C-NMR: 27.76,

35.41, 36.51, 38.70 (adamantane-C), 127.77, 128.64, 130.40, 130.96, 134.46, 135.69 (Ar-C), 156.27,

158.73 (triazole C-5 & CH=N), 162.44 (triazole C-3). MS, m/z (Rel. Int.): 374 (M⁺+2, 25), 372 (M⁺,

100), 337 (34), 261 (25), 249 (26), 235 (58), 234 (48), 221 (20), 140 (32), 135 (21), 125 (26), 110 (12).

1

5-(1-Adamantyl)-4-(4-chlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6e: H-NMR (DMSO-d₆): δ

1.70 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.06 (s, 6H, adamantane-H), 7.66 (d, 2H,

Ar-H, J = 6.5 Hz), 7.93 (d, 2H, Ar-H, J = 6.5 Hz), 9.76 (s, 1H, CH=N), 13.81 (s, 1H, SH). ¹³C-NMR:

27.73, 35.29, 36.46, 38.63 (adamantane-C), 129.98, 130.56, 131.56, 137.89 (Ar-C), 156.04, 162.53

(triazole C-5 & CH=N), 163.66 (triazole C-3). MS, m/z (Rel. Int.): 374 (M⁺+2, 10), 373 (M⁺+1, 40),

372 (M⁺, 23), 371 (100).

1

5-(1-Adamantyl)-4-(2-bromobenzylideneamino)-3-mercapto-1,2,4-triazole 6f: H-NMR (DMSO-d₆): δ

1.71 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.09 (s, 6H, adamantane-H), 7.99 (d, 2H, Ar-

H, J = 8.5), 7.86 (d, 2H, Ar-H, J = 8.5 Hz), 9.75 (s, 1H, CH=N), 13.82 (s, 1H, SH). ¹³C-NMR: 27.80,

35.30, 36.53, 38.64 (adamantane-C), 126.89, 130.71, 131.89, 132.93 (Ar-C), 156.04, 162.51 (triazole

C-5 & CH=N), 162.73 (triazole C-3). MS, m/z (Rel. Int.): 418 (M⁺+2, 20), 417 (M⁺+1, 100), 416 (M⁺,

20), 415 (100).

1

5-(1-Adamantyl)-4-(2-hydroxybenzylideneamino)-3-mercapto-1,2,4-triazole 6g: H-NMR (DMSO-d₆):

δ 1.69–1.73 (m, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.07 (s, 6H, adamantane-H), 6.97–

7.02 (m, 2H, Ar-H), 7.42–7.46 (m, 1H, Ar-H), 7.90–7.92 (m, 1H, Ar-H), 9.91 (s, 1H, CH=N), 10.55 (s,

13

1H, OH), 13.46 (s, 1H, SH). C-NMR: 27.74, 35.29, 36.47, 38.61 (adamantane-C), 117.26, 118.95,

120.26, 127.24, 134.72, 158.97 (Ar-C), 156.01, 161.63 (triazole C-5 & CH=N), 162.49 (triazole C-3).

MS, m/z (Rel. Int.): 355 (M⁺+1, 7), 354 (M⁺, 28), 353 (100).

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1

5-(1-Adamantyl)-4-(4-hydroxybenzylideneamino)-3-mercapto-1,2,4-triazole 6h: H-NMR (DMSO-d₆):

δ 1.67-1.71 (m, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.06 (s, 6H, adamantane-H), 6.94 (d,

2H, Ar-H, J = 8.5 Hz), 7.76 (d, 2H, Ar-H, J = 8.5 Hz), 9.36 (s, 1H, CH=N), 10.38 (s, 1H, OH), 13.70

(s, 1H, SH). ¹³C-NMR: 27.73, 35.21, 36.48, 38.57 (adamantane-C), 116.65, 123.51, 131.18, 162.51

(Ar-C), 155.91, 162.32 (triazole C-5 & CH=N), 165.79 (triazole C-3). MS, m/z (Rel. Int.): 355 (M⁺+1,

6), 354 (M⁺, 26), 353 (100).

1

5-(1-Adamantyl)-4-(4-methylbenzylideneamino)-3-mercapto-1,2,4-triazole 6i: H-NMR (DMSO-d₆): δ

1.69–1.73 (m, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.06 (s, 6H, adamantane-H), 2.40 (s,

3H, CH₃), 7.39 (d, 2H, Ar-H, J = 7.5 Hz), 7.81 (d, 2H, Ar-H, J = 7.5 Hz), 9.61 (s, 1H, CH=N), 13.77

(s, 1H, SH). ¹³C-NMR: 21.72 (CH₃), 27.73, 35.26, 36.47, 38.60 (adamantane-C), 128.96, 129.99,

130.37, 143.57 (Ar-C), 156.0, 162.51 (triazole C-5 & CH=N), 165.19 (triazole C-3). MS, m/z (Rel.

Int.): 351 (M⁺-1, 14), 234 (100), 233 (32).

1

5-(1-Adamantyl)-4-(2-methoxybenzylideneamino)-3-mercapto-1,2,4-triazole 6j: H-NMR (DMSO-d₆):

δ 1.67–1.74 (m, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.07 (s, 6H, adamantane-H), 3.89 (s,

3H, OCH₃), 7.13–7.23 (m, 2H, Ar-H), 7.60–7.63 (m, 1H, Ar-H), 8.01 (d, 1H, Ar-H, J = 8.0 Hz), 10.02

(s, 1H, CH=N), 13.76 (s, 1H, SH). ¹³C-NMR: 27.74, 35.30, 36.49, 38.60 (adamantane-C), 56.54

(OCH₃), 112.99, 120.74, 121.59, 126.69, 134.97, 159.84 (Ar-C), 156.13 (triazole C-5), 159.81

(CH=N), 162.39 (triazole C-3). MS, m/z (Rel. Int.): 369 (M⁺+1, 7), 368 (M⁺, 23), 367 (100).

5-(1-Adamantyl)-4-(4-methoxybenzylideneamino)-3-mercapto-1,2,4-triazole 6k: ¹H-NMR (DMSO-d₆):

δ 1.67–1.73 (m, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.06 (s, 6H, adamantane-H), 3.86 (s,

3H, OCH₃),

7.13

(d,

2H,

Ar-H,

J

=

8.5

Hz),

7.87

(d,

2H,

Ar-H,

J = 8.5 Hz), 9.50 (s, 1H, CH=N), 13.79 (s, 1H, SH). ¹³C-NMR: 27.73, 35.24, 36.48, 38.59

(adamantane-C), 56.04 (OCH₃), 115.32, 125.11, 130.91, 163.43 (Ar-C), 155.95, 162.50 (triazole C-5

& CH=N), 165.12 (triazole C-3). MS, m/z (Rel. Int.): 369 (M⁺+1, 29), 368 (M⁺, 76), 353 (33), 259

(33), 249 (37), 236 (51), 235 (49), 234 (29), 135 (54), 133 (100), 108 (112).

1

5-(1-Adamantyl)-4-(2-nitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6l: H-NMR (DMSO-d₆): δ

1.72 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.07 (s, 6H, adamantane-H), 7.85 (t, 1H, Ar-

H,

J

=

7.5 Hz), 7.94 (t, 1H, Ar-H,

J

=

7.5 Hz), 8.17 (d, 2H, Ar-H,

J = 8.0 Hz), 10.43 (s, 1H, CH=N), 13.90 (s, 1H, SH). ¹³C NMR: 27.76, 35.39, 36.42, 38.63

(adamantane-C), 125.40, 126.87, 129.43, 133.54, 134.53, 149.29 (Ar-C), 156.26, 159.20 (triazole C-5

& CH=N), 162.65 (triazole C-3). MS, m/z (Rel. Int.): 384 (M⁺+1, 7), 383 (M⁺, 24), 382 (100).

1

5-(1-Adamantyl)-4-(4-nitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6m: H-NMR (DMSO-d₆): δ

1.71 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.06 (s, 6H, adamantane-H), 7.89 (d, 2H, Ar-

13

H, J = 8.4 Hz), 8.32(d, 2H, Ar-H, J = 8.4 Hz), 10.21 (s, 1H, CH=N), 13.88 (s, 1H, SH). C NMR:

27.73, 35.21, 36.40, 38.61 (adamantane-C), 124.12, 128.83, 136.55, 150.22 (Ar-C), 155.66, 161.26

(triazole C-5 & CH=N), 162.85 (triazole C-3).

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5-(1-Adamantyl)-4-(4-dimethylaminobenzylideneamino)-3-mercapto-1,2,4-triazole

6n:

¹H-NMR

(DMSO-d₆): δ 1.66–1.71 (m, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.06 (s, 6H,

adamantane-H), 3.04 (s, 6H, CH₃), 6.83 (d, 2H, Ar-H, J = 8.5 Hz), 7.71 (d, 2H, Ar-H,

J = 9.0 Hz), 9.21 (s, 1H, CH=N), 13.74 (s, 1H, SH). ¹³C NMR: 27.74, 35.18, 36.50, 38.55

(adamantane-C), 39.89 (CH₃), 112.20, 119.31, 130.66, 153.72 (Ar-C), 155.88, 162.51 (triazole C-5 &

CH=N), 165.99 (triazole C-3). MS, m/z (Rel. Int.): 382 (M⁺+1, 8), 381 (M⁺, 36), 379 (100).

1

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-3-mercapto-1,2,4-triazole 6o: H-NMR (DMSO-

d₆): δ 1.71 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.09 (s, 6H, adamantane-H), 7.30–7.34

13

(m, 2H, Ar-H), 7.67-7.72 (m, 1H, Ar-H), 10.37 (s, 1H, CH=N), 13.87 (s, 1H, SH). C NMR: 27.30,

34.89, 35.87, 37.67 (adamantane-C), 109.74, 112.67, 134.86, 160.06 (Ar-C), 155.87, 160.06 (triazole

C-5 & CH=N), 162.11 (triazole C-3). MS, m/z (Rel. Int.): 375 (M⁺+1, 10), 374 (M⁺, 33), 343 (14), 236

(37), 235 (100), 234 (43), 220 (17), 139 (40), 135 (18), 126 (18), 113 (13).

5-(1-Adamantyl)-4-(2-chloro-6-fluorobenzylideneamino)-3-mercapto-1,2,4-triazole 6p: ¹H-NMR

(DMSO-d₆): δ 1.71 (s, 6H, adamantane-H), 2.01 (s, 3H, adamantane-H), 2.09 (s, 6H, adamantane-H),

7.44–7.48 (m, 1H, Ar-H), 7.52 (d, 1H, Ar-H, J = 8.0 Hz), 7.63–7.67 (m, 1H, Ar-H), 10.54 (s, 1H,

CH=N), 13.89 (s, 1H, SH). ¹³C NMR: 27.79, 35.41, 36.36, 38.23 (adamantane-C), 116.52, 119.14,

127.17, 134.57, 135.99, 162.59 (Ar-C), 156.41, 160.51 (triazole C-5 & CH=N), 162.21 (triazole C-3).

MS, m/z (Rel. Int.): 392 (M⁺+2, 8), 390 (M⁺, 20), 371 (12), 355 (22), 336 (9), 236 (56), 235 (100), 234

(18), 220 (26), 156 (33), 135 (14), 129 (7), 127 (22).

1

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6q: H-NMR (DMSO-

d₆): δ 1.68 (s, 6H, adamantane-H), 1.99 (s, 3H, adamantane-H), 2.09 (s, 6H, adamantane-H), 7.53–7.68

(m, 3H, Ar-H), 10.63 (s, 1H, CH=N), 13.93 (s, 1H, SH). ¹³C NMR: 27.77, 35.48, 36.38, 38.38

(adamantane-C), 128.33, 130.42, 133.60, 135.32 (Ar-C), 156.43, 158.38 (triazole C-5 & CH=N),

162.46 (triazole C-3). MS, m/z (Rel. Int.): 410 (M⁺+4, 4), 409 (M⁺+3, 16), 408 (M⁺+2, 18), 407 (M⁺

+1, 74), 406 (M⁺, 22), 405 (100).

1

5-(1-Adamantyl)-4-(2,4-dichlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6r: H-NMR (DMSO-

d₆): δ 1.72 (s, 6H, adamantane-H), 2.03 (s, 3H, adamantane-H), 2.08 (s, 6H, adamantane-H), 7.67–7.69

(m, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 8.12 (d, 1H, Ar-H, J = 8.0 Hz), 10.50 (s, 1H, CH=N), 13.89 (s, 1H,

13

SH). C NMR: 27.76, 35.41, 36.49, 38.71 (adamantane-C), 128.91, 129.12, 129.49, 130.48, 136.44,

138.29 (Ar-C), 156.26, 157.41 (triazole C-5 & CH=N), 162.44 (triazole C-3). MS, m/z (Rel. Int.): 410

(M⁺+4, 3), 409 (M⁺+3, 15), 408 (M⁺+2, 17), 407 (M⁺+1, 69), 406 (M⁺, 22), 405 (100).

1

5-(1-Adamantyl)-4-(3,4-dichlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6s: H-NMR (DMSO-

d₆): δ 1.70–1.72 (m, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.06 (s, 6H, adamantane-H),

7.85–7.93 (m, 2H, Ar-H), 8.13 (s, 1H, Ar-H), 9.88 (s, 1H, CH=N), 13.86 (s, 1H, SH). ¹³C NMR: 27.74,

35.33, 36.47, 38.67 (adamantane-C), 128.34, 130.61, 132.19, 132.74, 133.40, 135.64 (Ar-C), 156.09,

161.65 (triazole C-5 & CH=N), 162.56 (triazole C-3). MS, m/z (Rel. Int.): 410 (M⁺+4, 3), 409 (M⁺+3,

15), 408 (M⁺+2, 17), 407 (M⁺+1, 73), 406 (M⁺, 23), 405 (100).

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1

5-(1-Adamantyl)-4-(3,4-dimethoxybenzylideneamino)-3-mercapto-1,2,4-triazole 6t: H-NMR (DMSO-

d₆): δ 1.67–1.74 (m, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.08 (s, 6H, adamantane-H),

3.84 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 7.15 (d, 1H, Ar-H, J = 8.5 Hz), 7.47 (d, 1H, Ar-H, J = 8.5

Hz), 7.50 (s, 1H, Ar-H), 9.56 (s, 1H, CH=N), 13.74 (s, 1H, SH). ¹³C NMR: 27.76, 35.28, 36.52, 38.64

(adamantane-C), 56.0 (OCH₃), 56.28 (OCH₃), 110.09, 112.34, 124.20, 125.25, 149.74, 153.35 (Ar-C),

156.01, 162.46 (triazole C-5 & CH=N), 164.54 (triazole C-3). MS, m/z (Rel. Int.): 399 (M⁺+1, 7), 398

(M⁺, 24), 397 (100).

1

5-(1-Adamantyl)-4-(2,4-dinitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6u: H-NMR (DMSO-

d₆): δ 1.72 (s, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.08 (s, 6H, adamantane-H), 8.41 (d,

1H, Ar-H, J = 8.5 Hz), 8.65 (d, 1H, Ar-H, J = 8.5 Hz), 9.03 (s, 1H, Ar-H), 11.51 (s, 1H, CH=N), 13.46

13

(s, 1H, SH). C NMR: 27.80, 34.80, 36.52, 38.36 (adamantane-C), 120.79, 128.01, 129.52, 131.72,

135.05, 147.74 (Ar-C), 157.09, 157.86 (triazole C-5 & CH=N), 167.73 (triazole C-3). MS, m/z (Rel.

Int.): 451 (M⁺+Na, 4), 450 (11), 451 (48), 436 (100), 428 (M⁺, 3), 427 (10).

1

5-(1-Adamantyl)-4-(4,5-dimethoxy-2-nitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6v: H-NMR

(DMSO-d₆): δ 1.70–1.74 (m, 6H, adamantane-H), 2.02 (s, 3H, adamantane-H), 2.10 (s, 6H,

adamantane-H), 3.96 (s, 3H, OCH₃), 3.97 (s, 3H, OCH₃), 7.64 (s, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 10.56

(s, 1H, CH=N), 13.86 (s, 1H, SH). ¹³C NMR: 27.77, 35.44, 36.49, 38.76 (adamantane-C), 56.67

(OCH₃), 57.05 (OCH₃), 108.73, 109.16, 120.95, 143.12, 151.89, 153.10 (Ar-C), 156.28, 157.92

(triazole C-5 & CH=N), 162.56 (triazole C-3). MS, m/z (Rel. Int.): 444 (M⁺+1, 7), 443 (M⁺, 24),

442 (100).

5-(1-Adamantyl)-4-arylideneamino-2-(4-substituted-1-piperazinylmethyl)-1,2,4-triazoline-3-thiones

7a-p

A mixture of the 5-(1-adamantyl)-4-(2,6-dihalobenzylideneamino)-3-mercapto-1,2,4-triazoles 6o or

6q (1.0 mmol), the appropriate N-substituted piperazine (1.0 mmol) and 37% formaldehyde solution

(1 mL), in ethanol (8 mL), was heated under reflux for 15 min when a clear solution was obtained.

Stirring was continued for 12 h at room temperature and the mixture was allowed to stand overnight.

Cold water (5 mL) was added and the reaction mixture was stirred for 20 min. The precipitated crude

products were filtered, washed with water, dried, and crystallized (Table 2).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-(4-methyl-1-piperazinylmethyl)-1,2,4-triazoline-

1

3-thione 7a: H-NMR (CDCl₃): 1.78 (s, 6H, adamantane-H), 2.08 (s, 3H, adamantane-H), 2.16 (s, 6H,

adamantane-H), 2.30 (s, 3H, CH₃), 2.47 (s, 4H, piperazine-H), 2.92 (s, 4H, piperazine-H), 5.18 (s, 2H,

CH₂), 7.02–7.07 (m, 2H, Ar-H), 7.46–7.48 (m. 1H, Ar-H), 10.64 (s, 1H, CH=N). ¹³C NMR: 27.95,

35.51, 36.45, 38.32 (adamantane-C), 46.05 (CH₃), 55.05, 58.36 (piperazine-C), 68.68 (CH₂), 110.87,

112.16, 133.21, 152.24 (Ar-C), 155.52, 160.99 (triazole C-5 & CH=N), 163.05 (C=S). MS, m/z (Rel.

Int.): 488 (M⁺+2, 30), 487 (M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-(4-ethyl-1-piperazinylmethyl)-1,2,4-triazoline-3-

thione 7b: ¹H-NMR (CDCl₃): δ 1.07 (t, 3H, CH₃, J = 7.0 Hz), 1.78 (s, 6H, adamantane-H), 2.08 (s, 3H,

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adamantane-H), 2.16 (s, 6H, adamantane-H), 2.40 (q, 2H, CH₂CH₃, J = 7.0 Hz), 2.48–2.49 (m, 4H,

piperazine-H), 2.92 (s, 4H, piperazine-H), 5.18 (s, 2H, CH₂), 7.02 (t, 2H, Ar-H, J = 8.5 Hz), 7.44–7.48

(m. 1H, Ar-H), 10.62 (s, 1H, CH=N). ¹³C NMR: 11.91 (CH₃), 28.0, 35.50, 36.46, 38.33 (adamantane-

C), 52.32 (CH₂CH₃), 50.42, 52.80 (piperazine-C), 68.79 (CH₂), 110.89, 112.16, 133.20, 152.22 (Ar-C),

155.45, 161.0 (triazole C-5 & CH=N), 163.14 (C=S). MS, m/z (Rel. Int.): 502 (M⁺+2, 32), 501

(M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperazinylmethyl)-1,2,4-

triazoline-3-thione 7c: ¹H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃, J = 7.0 Hz), 1.79 (s, 6H, adamantane-H),

2.09 (s, 3H, adamantane-H), 2.17 (s, 6H, adamantane-H), 2.81 (s, 4H, piperazine-H), 3.50 (s, 4H,

piperazine-H), 4.10 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.16 (s, 2H, CH₂), 7.02 (t, 2H, Ar-H, J = 7.0 Hz),

13

7.46–7.50 (m. 1H, Ar-H), 10.64 (s, 1H, CH=N). C NMR: 14.62 (CH₃), 27.98, 35.55, 36.43, 38.35

(adamantane-C), 50.37, 52.39 (piperazine-C), 61.32 (CH₂CH₃), 68.97 (CH₂), 110.81, 112.22, 133.29,

152.23 (Ar-C), 155.46, 155.70, 161.04 (C=O, triazole C-5 & CH=N), 163.20 (C=S). MS, m/z (Rel.

Int.): 546 (M⁺+2, 6), 445 (M⁺+1, 20).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-(4-phenyl-1-piperazinylmethyl)-1,2,4-triazoline-

1

3-thione 7d: H-NMR (CDCl₃): δ 1.80 (s, 6H, adamantane-H), 2.10 (s, 3H, adamantane-H), 2.19 (s,

6H, adamantane-H), 3.04 (s, 4H, piperazine-H), 3.23 (s, 4H, piperazine-H), 5.24 (s, 2H, CH₂), 6.89 (t,

1H, Ar-H, J = 7.0 Hz), 6.94 (d, 2H, Ar-H, J = 8.0 Hz), 7.03 (t. 2H, Ar-H, J = 8.5 Hz), 7.26–7.28 (m,

2H, Ar-H), 7.47–7.50 (m. 1H, Ar-H), 10.67 (s, 1H, CH=N). ¹³C NMR: 28.0, 35.56, 36.46, 38.37

(adamantane-C), 49.41, 50.55 (piperazine-C), 68.82 (CH₂), 110.76, 112.19, 116.31, 119.88, 129.10,

133.27, 151.38, 152.24 (Ar-C), 155.64, 161.06 (triazole C-5 & CH=N), 163.22 (C=S). MS, m/z (Rel.

Int.): 550 (M⁺+2, 36), 549 (M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-[4-(4-fluorophenyl)-1-piperazinylmethyl]-1,2,4-

1

triazoline-3-thione 7e: H-NMR (CDCl₃): δ 1.80 (s, 6H, adamantane-H), 2.10 (s, 3H, adamantane-H),

2.19 (s, 6H, adamantane-H), 3.04 (s, 4H, piperazine-H), 3.14 (s, 4H, piperazine-H), 5.23 (s, 2H, CH₂),

6.89–6.99 (m, 4H, Ar-H), 7.03 (t. 2H, Ar-H, J = 8.5 Hz), 7.48–7.49 (m, 1H, Ar-H), 10.66 (s, 1H,

CH=N). ¹³C NMR: 28.0, 35.57, 36.46, 38.38 (adamantane-C), 50.40, 50.54 (piperazine-C), 68.78

(CH₂), 110.85, 112.39, 115.41, 118.10, 133.28, 148.04, 152.24, 158.24 (Ar-C), 155.65 (CH=N),

161.06 (triazole C-5), 163.23 (C=S). MS, m/z (Rel. Int.): 568 (M⁺+2, 33), 567 (M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-[4-(3-trifluoromethylphenyl)-1-

piperazinylmethyl]-1,2,4-triazoline-3-thione 7f: ¹H-NMR (CDCl₃): δ 1.80 (s, 6H, adamantane-H), 2.10

(s, 3H, adamantane-H), 2.19 (s, 6H, adamantane-H), 3.03-3.04 (m, 4H, piperazine-H), 3.21-3.27 (m,

4H, piperazine-H), 5.24 (s, 2H, CH₂), 7.04–7.13 (m, 5H, Ar-H), 7.34 (t. 1H, Ar-H, J = 8.0 Hz), 7.46–

7.50 (m, 1H, Ar-H), 10.67 (s, 1H, CH=N). ¹³C NMR: 27.99, 35.57, 36.44, 38.38 (adamantane-C),

48.87, 50.36 (piperazine-C), 68.73 (CH₂), 118.86 (CF₃), 110.83, 112.36, 115.09, 123.22, 125.39,

129.53, 131.58, 133.31, 151.44, 152.27 (Ar-C), 155.71, 161.01 (triazole C-5 & CH=N), 163.25 (C=S).

MS, m/z (Rel. Int.): 618 (M⁺+2, 35), 617 (M⁺+1, 100).

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5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-[4-(2-methoxylphenyl)-1-piperazinylmethyl]-

1,2,4-triazoline-3-thione 7g: ¹H-NMR (CDCl₃): δ 1.80 (s, 6H, adamantane-H), 2.10 (s, 3H,

adamantane-H), 2.20 (s, 6H, adamantane-H), 3.10 (s, 8H, piperazine-H), 3.87 (s, 3H, OCH₃), 5.25 (s,

2H, CH₂), 6.86 (d, 1H, Ar-H, J = 7.5 Hz), 6.92–6.98 (m, 2H, Ar-H), 7.0–7.07 (m, 3H, Ar-H), 7.47–

7.49 (m, 1H, Ar-H), 10.63 (s, 1H, CH=N). ¹³C NMR: 28.02, 35.55, 36.48, 38.34 (adamantane-C),

50.72, 50.83 (piperazine-C), 55.27 (OCH₃), 69.04 (CH₂), 110.03, 112.18, 112.38, 118.28, 120.94,

123.02, 133.23, 141.34, 152.26, 152.33 (Ar-C), 155.55, 161.02 (triazole C-5 & CH=N), 163.21 (C=S).

MS, m/z (Rel. Int.): 580 (M⁺+2, 33), 579 (M⁺+1, 92).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-(4-benzyl-1-piperazinylmethyl)-1,2,4-triazoline-

1

3-thione 7h: H-NMR (CDCl₃): δ 1.80 (s, 6H, adamantane-H), 2.09 (s, 3H, adamantane-H), 2.18 (s,

6H, adamantane-H), 2.41–2.52 (m, 4H, piperazine-H), 2.95 (s, 4H, piperazine-H), 3.52 (s, 2H,

PhCH₂), 5.17 (s, 2H, CH₂), 7.03 (t, 2H, Ar-H, J = 8.5 Hz), 7.25–7.32 (m, 5H, Ar-H), 7.45–7.49 (m,

13

1H, Ar-H), 10.65 (s, 1H, CH=N). C NMR: 28.0, 35.52, 36.47, 38.36 (adamantane-C), 50.51, 53.12

(piperazine-C), 63.18 (PhCH₂), 68.96 (CH₂), 110.89, 112.17, 127.04, 128.18, 129.29, 133.11, 137.96,

152.11 (Ar-C), 155.47, 161.05 (triazole C-5 & CH=N), 163.19 (C=S). MS, m/z (Rel. Int.): 564 (M⁺+2,

34), 563 (M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-(4-methyl-1-piperazinylmethyl)-1,2,4-triazoline-

3-thione 7i: ¹H-NMR (CDCl₃): δ 1.76 (s, 6H, adamantane-H), 2.07 (s, 3H, adamantane-H), 2.16 (s, 6H,

adamantane-H), 2.33 (s, 3H, CH₃), 2.50–2.54 (m, 4H, piperazine-H), 2.92–2.96 (m, 4H, piperazine-H),

5.17 (s, 2H, CH₂), 7.22-7.48 (m, 3H, Ar-H), 10.80 (s, 1H, CH=N). ¹³C-NMR: 27.91, 35.54, 36.43,

38.44 (adamantane-C), 43.85 (CH₃), 54.36, 56.42 (piperazine-C), 68.71 (CH₂), 128.62, 129.43, 131.75,

136.18 (Ar-C), 155.42, 158.18 (triazole C-5 & CH=N), 163.44 (C=S). MS, m/z (Rel. Int.): 522 (M⁺+4,

6), 520 (M⁺+2, 55), 518 (M⁺, 100).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-(4-ethyl-1-piperazinylmethyl)-1,2,4-triazoline-3-

thione 7j: ¹H-NMR (CDCl₃): δ 1.08 (t, 3H, CH₃, J = 7.0 Hz), 1.75 (s, 6H, adamantane-H), 2.06 (s, 3H,

adamantane-H), 2.16–2.17 (m, 6H, adamantane-H), 2.42 (q, 2H, CH₂CH₃, J = 7.0 Hz), 2.52–2.53 (m,

4H, piperazine-H), 2.95 (s, 4H, piperazine-H), 5.19 (s, 2H, CH₂), 7.32-7.37 (m, 1H, Ar-H), 7.42–7.47

(m. 2H, Ar-H), 10.74 (s, 1H, CH=N). ¹³C-NMR: 11.87 (CH₃), 27.96, 35.55, 36.47, 38.51 (adamantane-

C), 50.41 (CH₂CH₃), 52.31, 52.76 (piperazine-C), 68.93 (CH₂), 129.32, 129.40, 131.53, 136.10 (Ar-C),

155.41, 157.82 (triazole C-5 & CH=N), 163.42 (C=S). MS, m/z (Rel. Int.): 536 (M⁺+4, 5), 534 (M⁺

+2, 43), 532 (M⁺, 100).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperazinylmethyl)-1,2,4-

triazoline-3-thione 7k: ¹H-NMR (CDCl₃): δ 1.25 (t, 3H, CH₃, J = 7.0 Hz), 1.76 (s, 6H, adamantane-H),

2.07 (s, 3H, adamantane-H), 2.16 (s, 6H, adamantane-H), 2.83 (s, 4H, piperazine-H), 3.51 (s, 4H,

piperazine-H), 4.11 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.17 (s, 2H, CH₂), 7.30–7.36 (m, 1H, Ar-H), 7.41–

7.46 (m. 2H, Ar-H), 10.79 (s, 1H, CH=N). ¹³C-NMR: 14.64 (CH₃), 27.94, 35.61, 36.44, 38.52

(adamantane-C), 50.30, 52.50 (piperazine-C), 61.33 (CH₂CH₃), 69.15 (CH₂), 128.94, 129.37, 131.61,

136.09 (Ar-C), 155.30, 155.46, 157.76 (C=O, triazole C-5 & CH=N), 163.46 (C=S). MS, m/z (Rel.

Int.): 599 (M⁺+Na, 100), 577 (M⁺+1, 7).

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5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-(4-phenyl-1-piperazinylmethyl)-1,2,4-triazoline-

3-thione 7l: ¹H-NMR (CDCl₃): δ 1.77 (s, 6H, adamantane-H), 2.08 (s, 3H, adamantane-H), 2.18 (s, 6H,

adamantane-H), 3.06 (s, 4H, piperazine-H), 3.23 (s, 4H, piperazine-H), 5.25 (s, 2H, CH₂), 6.87 (t, 1H,

Ar-H, J = 7.5 Hz), 6.95 (d, 2H, Ar-H, J = 8.0 Hz), 7.27–7.37 (m, 4H, Ar-H), 7.46–7.47 (m, 1H, Ar-H),

10.80 (s, 1H, CH=N). ¹³C-NMR: 27.96, 35.61, 36.46, 38.54 (adamantane-C), 49.45, 50.60 (piperazine-

C), 69.0 (CH₂), 116.35, 119.92, 129.06, 129.11, 129.37, 131.60, 136.12, 151.39 (Ar-C), 155.61,

156.09, 157.83 (triazole C-5 & CH=N), 163.48 (C=S). MS, m/z (Rel. Int.): 585 (M⁺+4, 16), 583 (M⁺

+2, 77), 581 (M⁺, 100).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-[4-(4-fluorophenyl)-1-piperazinylmethyl]-1,2,4-

triazoline-3-thione 7m: ¹H-NMR (CDCl₃): δ 1.76 (s, 6H, adamantane-H), 2.08 (s, 3H, adamantane-H),

2.18 (s, 6H, adamantane-H), 3.05–3.06 (m, 4H, piperazine-H), 3.15 (s, 4H, piperazine-H), 5.24 (s, 2H,

CH₂), 6.88–6.91 (m, 2H, Ar-H), 6.96–6.99 (m, 2H, Ar-H), 7.33–7.36 (m, 1H, Ar-H), 7.45 (d, 2H, Ar-

13

H, J = 7.0 Hz), 10.79 (s, 1H, CH=N). C-NMR: 27.96, 35.61, 36.46, 38.55 (adamantane-C), 50.44,

50.59 (piperazine-C), 68.95 (CH₂), 115.43, 115.60, 118.08, 118.14, 129.37, 131.60, 136.11, 148.06

(Ar-C), 155.62, 157.83 (triazole C-5 & CH=N), 163.49 (C=S). MS, m/z (Rel. Int.): 602 (M⁺+4, 23),

601 (M⁺+3, 78), 600 (M⁺+2, 32), 599 (M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-[4-(3-trifluoromethylphenyl)-1-

1

piperazinylmethyl]-1,2,4-triazoline-3-thione 7n: H-NMR (CDCl₃): δ 1.77 (s, 6H, adamantane-H),

2.08 (s, 3H, adamantane-H), 2.18 (s, 6H, adamantane-H), 3.05–3.06 (m, 4H, piperazine-H), 3.27–3.28

(m, 4H, piperazine-H), 5.24 (s, 2H, CH₂), 7.07 (t, 2H, Ar-H, J = 8.5 Hz), 7.14 (s, 1H, Ar-H), 7.34–7.37

13

(m, 2H, Ar-H), 7.46 (d, 2H, Ar-H, J = 8.0 Hz), 10.80 (s, 1H, CH=N). C-NMR: 27.94, 35.62, 36.44,

38.55 (adamantane-C), 48.89, 50.40 (piperazine-C), 68.91 (CH₂), 118.89 (CF₃), 112.43, 115.98,

123.22, 125.39, 129.02, 129.39, 129.55, 131.78, 136.12, 151.44 (Ar-C), 155.68, 157.86 (triazole C-5 &

CH=N), 163.50 (C=S). MS, m/z (Rel. Int.): 652 (M⁺+4, 16), 651 (M⁺+3, 76), 650 (M⁺+2, 32), 649

(M⁺+1, 100).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-[4-(2-methoxyphenyl)-1-piperazinylmethyl]-

1,2,4-triazoline-3-thione 7o: ¹H-NMR (CDCl₃): δ 1.77 (s, 6H, adamantane-H), 2.08 (s, 3H,

adamantane-H), 2.19 (s, 6H, adamantane-H), 3.11 (s, 8H, piperazine-H), 3.87 (s, 3H, OCH₃), 5.26 (s,

2H, CH₂), 6.86 (d, 1H, Ar-H, J = 7.5 Hz), 6.93–7.04 (m, 3H, Ar-H), 7.33–7.36 (m, 1H, Ar-H) 7.45 (d,

13

2H, Ar-H, J = 8.0 Hz), 10.76 (s, 1H, CH=N). C-NMR: 27.98, 35.59, 36.49, 38.51 (adamantane-C),

50.76, 50.84 (piperazine-C), 55.28 (OCH₃), 69.22 (CH₂), 110.98, 118.29, 120.93, 123.04, 129.12,

129.34, 131.55, 136.12, 141.32, 152.27 (Ar-C), 155.50 (triazole C-5), 157.89 (CH=N), 163.49 (C=S).

MS, m/z (Rel. Int.): 614 (M⁺+4, 9), 613 (M⁺+3, 35), 612 (M⁺+2, 14), 611 (M⁺+1, 46).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-(4-benzyl-1-piperazinylmethyl)-1,2,4-triazoline-

1

3-thione 7p: H-NMR (CDCl₃): δ 1.76 (s, 6H, adamantane-H), 2.07 (s, 3H, adamantane-H), 2.17 (s,

6H, adamantane-H), 2.51 (s, 4H, piperazine-H), 2.92 (s, 4H, piperazine-H), 3.52 (s, 2H, PhCH₂), 5.17

13

(s, 2H, CH₂), 7.26–7.36 (m, 6H, Ar-H), 7.45 (d, 2H, Ar-H , J = 8.0 Hz), 10.78 (s, 1H, CH=N). C-

NMR: 27.96, 35.56, 36.47, 38.53 (adamantane-C), 50.53, 53.14 (piperazine-C), 63.24 (PhCH₂), 69.11

(CH₂), 127.07, 128.20, 129.12, 129.33, 129.42, 131.54, 136.10, 137.90 (Ar-C), 155.45, 157.68

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(triazole C-5 & CH=N), 163.45 (C=S). MS, m/z (Rel. Int.): 598 (M⁺+4, 13), 597 (M⁺+3, 76), 596 (M⁺

+2, 35), 595 (M⁺+1, 100).

5-(1-Adamantyl)-4-arylideneamino-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-triazoline-3-thiones

8a–n

A mixture of the 5-(1-adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazole 6 (1.0 mmol), ethyl

4-piperidinecarboxylate (0.16 g, 1.0 mmol) and 37% formaldehyde solution (1 mL), in ethanol (8 mL),

was heated under reflux for 20 min when a clear solution was obtained. Stirring was continued for 12 h

at room temperature and the mixture was allowed to stand overnight. Cold water

(5 mL) was added and the reaction mixture was stirred for 20 min. The precipitated crude products

were filtered, washed with water, dried, and crystallized (Table 3).

5-(1-Adamantyl)-4-benzylideneamino-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-triazoline-3-

1

thione 8a: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃, J = 7.0 Hz), 1.72–1.83 (m, 8H, 6 adamantane-H & 2

piperidine-H), 1.92–1.94 (m, 2H, piperidine-H), 2.10 (s, 3H, adamantane-H), 2.17 (s, 6H, adamantane-

H), 2.20–2.25 (m, 1H, piperidine-4 H), 2.46–2.50 (m, 2H, piperidine-H), 3.20–3.22 (m, 2H, piperidine-

H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.51–7.58 (m, 3H, Ar-H), 7.91 (d, 2H, Ar-H,

J = 7.0 Hz), 10.08 (s, 1H, CH=N). ¹³C-NMR: 14.20 (CH₃), 27.93, 35.44, 36.58, 38.77 (adamantane-C),

28.35 (piperidine C-3), 40.42 (piperidine C-4), 50.42 (piperidine C-2), 60.25 (CH₂CH₃), 69.63 (CH₂),

128.72, 129.02, 132.28, 132.84 (Ar-C), 155.28, 162.26 (triazole C-5 & CH=N), 163.21 (C=S), 174.99

(C=O). MS, m/z (Rel. Int.): 509 (M⁺+2, 21), 508 (M⁺+1, 72).

5-(1-Adamantyl)-4-(2-fluorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8b: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.72–1.82 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.92–1.94 (m, 2H, piperidine-H), 2.10 (s, 3H, adamantane-H), 2.16

(s, 6H, adamantane-H), 2.20–2.25 (m, 1H, piperidine-4 H), 2.50–2.54 (m, 2H, piperidine-H), 3.19–

3.22 (m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.18 (t, 1H, Ar-H,

J = 8.0 Hz), 7.30 (d, 1H, Ar-H, J = 7.5 Hz), 7.53–7.56 (m, 1H, Ar-H), 8.08-8.11 (m, 1H, Ar-H), 10.42

(s, 1H, CH=N). ¹³C-NMR: 14.20 (CH₃), 27.93, 35.46, 36.56, 38.76 (adamantane-C), 28.35 (piperidine

C-3), 40.77 (piperidine C-4), 50.42 (piperidine C-2), 60.25 (CH₂CH₃), 69.64 (CH₂), 116.31, 120.89,

124.66, 127.57, 133.90, 155.82 (Ar-C), 155.28, 161.54 (triazole C-5 & CH=N), 163.31 (C=S), 174.99

(C=O). MS, m/z (Rel. Int.): (M⁺+2, 33), 526 (M⁺+1, 100).

5-(1-Adamantyl)-4-(2-chlorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8c: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.72–1.79 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.92–1.94 (m, 2H, piperidine-H), 2.11 (s, 3H, adamantane-H), 2.17

(s, 6H, adamantane-H), 2.21–2.25 (m, 1H, piperidine-4 H), 2.51-2.55 (m, 2H, piperidine-H), 3.20–3.22

(m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.40 (t, 1H, Ar-H,

J = 7.5 Hz), 7.46–7.51 (m, 2H, Ar-H), 8.19 (d, 1H, Ar-H, J = 7.5 Hz), 10.69 (s, 1H, CH=N). ¹³C-

NMR: 14.20 (CH₃), 27.93, 35.49, 36.58, 38.83 (adamantane-C), 28.35 (piperidine C-3), 40.78

(piperidine C-4), 50.43 (piperidine C-2), 60.25 (CH₂CH₃), 69.65 (CH₂), 127.20, 127.60, 130.34,

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130.85, 132.97, 136.68 (Ar-C), 155.28, 158.27 (triazole C-5 & CH=N), 163.37 (C=S), 174.99 (C=O).

MS, m/z (Rel. Int.): 564 (M⁺+Na, 100), 544 (23), 542 (54).

5-(1-Adamantyl)-4-(4-methylbenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8d: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.72–1.78 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.91–1.94 (m, 2H, piperidine-H), 2.09 (s, 3H, adamantane-H), 2.16

(s, 6H, adamantane-H), 2.20–2.25 (m, 1H, piperidine-4 H), 2.45 (s, 3H, PhCH₃), 2.50–2.54 (m, 2H,

piperidine-H), 3.19–3.22 (m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂),

7.31 (d, 2H, Ar-H, J = 8.0 Hz), 7.80 (d, 2H, Ar-H, J = 8.0 Hz), 9.94 (s, 1H, CH=N). ¹³C-NMR: 14.20

(CH₃), 21.71 (PhCH₃), 27.93, 35.40, 36.58, 38.75 (adamantane-C), 28.35 (piperidine C-3), 40.78

(piperidine C-4), 50.41 (piperidine C-2), 60.24 (CH₂CH₃), 69.62 (CH₂), 128.75, 129.76, 130.10,

143.05 (Ar-C), 155.24, 162.69 (triazole C-5 & CH=N), 163.21 (C=S), 174.99 (C=O). MS, m/z (Rel.

Int.): 544 (M⁺+Na, 100), 523 (M⁺+2, 43), 522 (M⁺+1, 76).

5-(1-Adamantyl)-4-(2-hydroxybenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8e: H-NMR (CDCl₃): δ 1.25 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.73–1.79 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.92–1.95 (m, 2H, piperidine-H), 2.10 (s, 9H, adamantane-H), 2.22–

2.24 (m, 1H, piperidine-4 H), 2.51–2.55 (m, 2H, piperidine-H), 3.19–3.21 (m, 2H, piperidine-H), 4.12

(q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.03–7.06 (m, 1H, Ar-H), 7.08 (d, 1H, Ar-H, J = 8.5

Hz), 7.44–7.51 (m, 2H, Ar-H), 9.69 (s, 1H, CH=N), 10.45 (s, 1H, OH). ¹³C-NMR: 14.20 (CH₃), 27.80,

35.35, 36.29, 38.97 (adamantane-C), 28.32 (piperidine C-3), 40.73 (piperidine C-4), 50.42 (piperidine

C-2), 60.28 (CH₂CH₃), 70.22 (CH₂), 116.09, 117.56, 120.09, 133.60, 134.69, 169.08 (Ar-C), 154.28,

160.08 (triazole C-5 & CH=N), 164.01 (C=S), 174.94 (C=O). MS, m/z (Rel. Int.): 546 (M⁺+Na, 100),

525 (M⁺+2, 26), 524 (M⁺+1, 84).

5-(1-Adamantyl)-4-(4-hydroxybenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8f: H-NMR (CDCl₃): δ 1.25 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.75–1.78 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.94–1.96 (m, 2H, piperidine-H), 2.07 (s, 3H, adamantane-H), 2.12

(s, 6H, adamantane-H), 2.24–2.28 (m, 1H, piperidine-4 H), 2.52–2.56 (m, 2H, piperidine-H), 3.21–

3.23 (m, 2H, piperidine-H), 4.13 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.14 (s, 2H, CH₂), 6.92 (d, 2H, Ar-H,

J = 8.5 Hz), 7.72 (d, 2H, Ar-H, J = 8.5 Hz), 9.55 (s, 1H, CH=N). ¹³C-NMR: 14.17 (CH₃), 27.88, 35.37,

36.52, 38.66 (adamantane-C), 28.15 (piperidine C-3), 40.72 (piperidine C-4), 50.43 (piperidine C-2),

58.53 (CH₂CH₃), 69.64 (CH₂), 116.24, 124.64, 130.91, 163.01 (Ar-C), 155.38, 160.42 (triazole C-5 &

CH=N), 164.17 (C=S), 175.32 (C=O). MS, m/z (Rel. Int.): 525 (M⁺+2, 33), 524 (M⁺+1, 100).

5-(1-Adamantyl)-4-(4-methoxybenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8g: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.72–1.79 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.91–1.93 (m, 2H, piperidine-H), 2.09 (s, 3H, adamantane-H), 2.16

(s, 6H, adamantane-H), 2.20–2.24 (m, 1H, piperidine-4 H), 2.50-2.53 (m, 2H, piperidine-H), 3.19–3.21

(m, 2H, piperidine-H), 3.90 (s, 3H, OCH₃), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.02

13

(d, 2H, Ar-H, J = 8.5 Hz), 7.86 (d, 2H, Ar-H , J = 8.5 Hz), 9.81 (s, 1H, CH=N). C-NMR: 14.20

(CH₃), 27.93, 35.37, 36.58, 38.74 (adamantane-C), 28.35 (piperidine C-3), 40.79 (piperidine C-4),

55.48 (piperidine C-2), 60.23 (CH₂CH₃), 69.64 (CH₂), 114.54, 125.35, 130.59, 162.76 (Ar-C), 155.18,

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162.69 (triazole C-5 & CH=N), 163.21 (C=S), 174.99 (C=O). MS, m/z (Rel. Int.): 560 (M⁺+Na, 100),

539 (M⁺+2, 38), 538 (M⁺+1, 86).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8h: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.71–1.80 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.92–1.94 (m, 2H, piperidine-H), 2.09 (s, 3H, adamantane-H), 2.18

(s, 6H, adamantane-H), 2.21–2.25 (m, 1H, piperidine-4 H), 2.50–2.54 (m, 2H, piperidine-H), 3.19–

3.21 (m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.14 (s, 2H, CH₂), 7.03 (t, 2H, Ar-H,

J = 8.5 Hz), 7.45–7.49 (m, 1H, Ar-H), 10.70 (s, 1H, CH=N). ¹³C-NMR: 14.19 (CH₃), 28.0, 35.53,

36.46, 38.41 (adamantane-C), 28.35 (piperidine C-3), 40.77 (piperidine C-4), 50.42 (piperidine C-2),

60.25 (CH₂CH₃), 69.43 (CH₂), 110.89, 112.37, 133.21, 161.04 (Ar-C), 155.53, 160.99 (triazole C-5 &

CH=N), 163.21 (C=S), 174.98 (C=O). MS, m/z (Rel. Int.): 566 (M⁺+Na, 100), 545 (M⁺+2, 18), 544

(M⁺+1, 61).

5-(1-Adamantyl)-4-(2-chloro-6-fluorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-

1,2,4-triazoline-3-thione 8i: ¹H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.71–1.79 (m, 8H,

6 adamantane-H & 2 piperidine-H), 1.92–1.94 (m, 2H, piperidine-H), 2.09 (s, 3H, adamantane-H),

2.18 (s, 6H, adamantane-H), 2.21–2.25 (m, 1H, piperidine-4 H), 2.51–2.55 (m, 2H, piperidine-H),

3.20–3.22 (m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.14–7.17 (m,

2H, Ar-H), 7.33 (d, 1H, Ar-H, J = 7.5 Hz), 10.87 (s, 1H, CH=N). ¹³C-NMR: 14.19 (CH₃), 28.0, 35.55,

36.46, 38.40 (adamantane-C), 28.36 (piperidine C-3), 40.77 (piperidine C-4), 50.43 (piperidine C-2),

60.24 (CH₂CH₃), 69.46 (CH₂), 115.35, 119.81, 126.25, 132.52, 137.10, 162.85 (Ar-C), 155.11

(CH=N), 160.76 (triazole C-5), 163.05 (C=S), 174.99 (C=O). MS, m/z (Rel. Int.): 582 (M⁺+Na, 100),

562 (29), 561 (M⁺+2, 21), 560 (M⁺+1, 63).

5-(1-Adamantyl)-4-(2,6-dichlorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8j: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.72–1.81 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.92–1.95 (m, 2H, piperidine-H), 2.07 (s, 3H, adamantane-H), 2.17

(s, 6H, adamantane-H), 2.21–2.26 (m, 1H, piperidine-4 H), 2.53–2.57 (m, 2H, piperidine-H), 3.20–

3.22 (m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.15 (s, 2H, CH₂), 7.33–7.36 (m, 1H,

13

Ar-H), 7.45 (d, 2H, Ar-H, J = 8.0 Hz), 10.84 (s, 1H, CH=N). C-NMR: 14.20 (CH₃), 27.96, 35.59,

36.46, 38.58 (adamantane-C), 28.36 (piperidine C-3), 40.77 (piperidine C-4), 50.44 (piperidine C-2),

60.24 (CH₂CH₃), 69.62 (CH₂), 128.77, 129.36, 131.54, 136.08 (Ar-C), 155.52, 157.56 (triazole C-5 &

CH=N), 163.22 (C=S), 174.99 (C=O). MS, m/z (Rel. Int.): 598 (M⁺+Na, 100), 578 (52), 577 (M⁺+2,

23), 576 (M⁺+1, 73).

5-(1-Adamantyl)-4-(2,4-dichlorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8k: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.72–1.83 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.91–1.94 (m, 2H, piperidine-H), 2.11 (s, 3H, adamantane-H), 2.16

(s, 6H, adamantane-H), 2.20–2.25 (m, 1H, piperidine-4 H), 2.50–2.54 (m, 2H, piperidine-H), 3.19–

3.21 (m, 2H, piperidine-H), 4.12 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.14 (s, 2H, CH₂), 7.40 (d, 1H, Ar-H, J

= 8.5 Hz), 7.53 (s, 1H, Ar-H), 8.11 (d, 1H, Ar-H, J = 8.5 Hz), 10.73 (s, 1H, CH=N). ¹³C-NMR: 14.20

(CH₃), 27.91, 35.50, 36.57, 38.86 (adamantane-C), 28.34 (piperidine C-3), 40.76 (piperidine C-4),

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50.42 (piperidine C-2), 60.26 (CH₂CH₃), 69.62 (CH₂), 127.88, 128.28, 129.55, 130.16, 137.15, 138.58

(Ar-C), 155.23, 156.68 (triazole C-5 & CH=N), 163.33 (C=S), 174.96 (C=O). MS, m/z (Rel. Int.): 598

(M⁺+Na, 100), 578 (56), 577 (M⁺+2, 24), 576 (M⁺+1, 78).

5-(1-Adamantyl)-4-(3,4-dichlorobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8l: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.71–1.84 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.91–1.93 (m, 2H, piperidine-H), 2.12 (s, 3H, adamantane-H), 2.15

(s, 6H, adamantane-H), 2.20–2.24 (m, 1H, piperidine-4 H), 2.49–2.53 (m, 2H, piperidine-H), 3.18–

3.20 (m, 2H, piperidine-H), 4.11 (q, 2H, CH₂CH₃, J = 7.0 Hz), 5.13 (s, 2H, CH₂), 7.59 (d, 1H, Ar-H,

J = 8.0 Hz), 7.72 (d, 1H, Ar-H, J = 8.0 Hz), 7.98 (s, 1H, Ar-H), 10.29 (s, 1H, CH=N). ¹³C-NMR: 14.20

(CH₃), 27.90, 35.50, 36.57, 38.86 (adamantane-C), 28.33 (piperidine C-3), 40.74 (piperidine C-4),

50.41 (piperidine C-2), 60.27 (CH₂CH₃), 69.63 (CH₂), 127.44, 130.03, 131.16, 133.01, 133.67, 136.40

(Ar-C), 155.25, 158.17 (triazole C-5 & CH=N), 163.20 (C=S), 174.94 (C=O). MS, m/z (Rel. Int.): 598

(M⁺+Na, 100), 577 (M⁺+2, 20), 576 (M⁺+1, 67).

5-(1-Adamantyl)-4-(3,4-dimethoxybenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-

1

triazoline-3-thione 8m: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.76–1.82 (m, 8H, 6

adamantane-H & 2 piperidine-H), 1.91–1.93 (m, 2H, piperidine-H), 2.09 (s, 3H, adamantane-H), 2.17

(s, 6H, adamantane-H), 2.20–2.24 (m, 1H, piperidine-4 H), 2.49–2.54 (m, 2H, piperidine-H), 3.19–

3.21 (m, 2H, piperidine-H), 3.96 (s, 3H, OCH₃), 3.98 (s, 3H, OCH₃), 4.11 (q, 2H, CH₂CH₃, J = 7.0

Hz), 5.15 (s, 2H, CH₂), 6.79 (d, 1H, Ar-H, J = 8.0 Hz), 7.40 (d, 1H, Ar-H, J = 8.0 Hz), 7.54 (s, 1H, Ar-

13

H), 9.85 (s, 1H, CH=N). C-NMR: 14.19 (CH₃), 27.94, 35.39, 36.61, 38.80 (adamantane-C), 28.35

(piperidine C-3), 40.78 (piperidine C-4), 50.41 (piperidine C-2), 55.92 (OCH₃), 56.08 (OCH₃), 60.24

(CH₂CH₃), 69.63 (CH₂), 109.19, 110.96, 124.42, 125.61, 149.60, 152.98 (Ar-C), 155.13, 162.48

(triazole C-5 & CH=N), 163.18 (C=S), 174.98 (C=O). MS, m/z (Rel. Int.): 590 (M⁺+Na, 100), 569

(M⁺+2, 26), 568 (M⁺+1, 84).

5-(1-Adamantyl)-4-(4,5-dimethoxy-2-nitrobenzylideneamino)-2-(4-ethoxycarbonyl-1-piperidylmethyl)-

1

1,2,4-triazoline-3-thione 8n: H-NMR (CDCl₃): δ 1.24 (t, 3H, CH₃CH₂, J = 7.0 Hz), 1.73–1.80 (m,

8H, 6 adamantane-H & 2 piperidine-H), 1.92–1.94 (m, 2H, piperidine-H), 2.08 (s, 3H, adamantane-H),

2.15 (s, 6H, adamantane-H), 2.21–2.23 (m, 1H, piperidine-4 H), 2.51–2.55 (m, 2H, piperidine-H),

3.18–3.21 (m, 2H, piperidine-H), 4.04 (s, 3H, OCH₃), 4.05 (s, 3H, OCH₃), 4.11 (q, 2H, CH₂CH₃, J =

13

7.0 Hz), 5.14 (s, 2H, CH₂), 7.65 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 10.54 (s, 1H, CH=N). C-NMR:

14.20 (CH₃), 27.89, 35.42, 36.51, 38.81 (adamantane-C), 28.34 (piperidine C-3), 40.75 (piperidine C-

4), 50.41 (piperidine C-2), 56.60 (OCH₃), 56.68 (OCH₃), 60.25 (CH₂CH₃), 69.85 (CH₂), 107.82, 110.0,

122.50, 142.33, 151.45, 153.30 (Ar-C), 155.03, 160.57 (triazole C-5 & CH=N), 163.57 (C=S), 174.99

(C=O). MS, m/z (Rel. Int.): 635 (M⁺+Na, 100), 614 (M⁺+2, 23), 613 (M⁺+1, 68).

Determination of the antimicrobial activity by the agar disc-diffusion method. Sterile filter paper discs

(8 mm diameter) were moistened with the compound solution in dimethylsulphoxide of specific

concentration (200 μg/disc), the antibacterial antibiotics Gentamicin and Ampicillin trihydrate

(100 μg/disc) and the antifungal drug Clotrimazole (100 μg/disc) were carefully placed on the agar

culture plates that had been previously inoculated separately with the microorganisms. The plates were

Molecules 2010, 15

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incubated at 37 ºC, and the diameter of the growth inhibition zones were measured after 24 h in case of

bacteria and 48 h in case of Candida albicans.

Determination of minimal inhibitory concentration (MIC). Compounds 6h, 6o, 7n, 8a, 8e, 8f and 8m,

Gentamicin, Ampicillin trihydrate and Clotrimazole were dissolved in dimethylsulphoxide at

concentration of 128 μg/mL. The twofold dilutions of the solution were prepared (128, 64, 32, …, 0.5

μg/mL). The microorganism suspensions at 106 CFU/mL (colony forming unit/ml) concentrations

were inoculated to the corresponding wells. The plates were incubated at 36 ºC for 24 and 48 h for the

bacteria and Candida albicans, respectively. The MIC values were determined as the lowest

concentration that completely inhibited visible growth of the microorganism as detected by unaided eye.

Determination of the anti-inflammatory activity. Male Sprague-Dawley rats weighing 140–190 g were

maintained at room temperature (20–23 ºC). The animals were randomly divided into 42 groups each

of 5 animals. The animals were housed with food and water ad libitum and allowed to be accustomed

to their environment for two days before testing. Each group was injected with the specific dose of the

test compound (20 and 40 mg/kg), or Indomethacin (5 mg/kg) intraperitoneally as a uniform

suspension in 1 ml of 0.5% (w/v) aqueous carboxymethyl cellulose solution, one hour before injection

of 0.1 mL of carrageenan (1% solution in normal saline) into the plantar tissue of the right hind paw.

The left hind paw was injected with 0.1 mL of normal saline solution. Four hours after carrageenan

injection, the volume of paw oedema (mL) was determined using water plethysmometer. The

percentage protection against inflammation was calculated as follows:

V_c- V_d

______

X 100

V_c

Where V_cis the mean percentage increase in paw volume in the absence of the test compound

(control) and V_dis the mean percentage increase in paw volume after injection of the test compound.

The values are expressed as the mean percentage reduction ± S.E.M. Statistical significance between

the control and treated groups was performed using the Student “t” test.

4. Conclusions

In this study, new series of 5-(1-adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles 6a-v , the

N-Mannich bases 5-(1-adamantyl)-4-arylideneamino-2-(4-substituted-1-piperazinylmethyl)-1,2,4-

triazoline-3-thiones 7a–p and 5-(1-adamantyl)-4-arylideneamino-2-(4-ethoxycarbonyl-1-piperidyl-

methyl)-1,2,4-triazoline-3-thiones 8a-n, were synthesized and their antimicrobial and anti-

inflammatory activity was determined. Several of the newly synthesized derivatives displayed

promising antimicrobial and anti-inflammatory activities compared to known antibacterial, antifungal

and anti-inflammatory drugs. Though, the mechanism of the biological activity needs further

investigations, which are in progress.

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2547

Acknowledgements

The financial support of the Research Center of the College of Pharmacy, King Saud University is

greatly appreciated.

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Synthesis, antimicrobial, and anti-inflammatory activities of novel 5-(1-adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles and related derivatives

DOI: 10.3390/molecules15042526

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