Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles and Related Derivatives

Al-Omar, Mohamed A.; Al-Abdullah, Ebtehal S.; Shehata, Ihsan A.; Habib, Elsayed E.; Ibrahim, Tarek M.; El-Emam, Ali A.

doi:10.3390/molecules15042526

Open AccessArticle

Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles and Related Derivatives

by

Mohamed A. Al-Omar

¹,

Ebtehal S. Al-Abdullah

¹,

Ihsan A. Shehata

¹,

Elsayed E. Habib

²,

Tarek M. Ibrahim

³ and

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.

Molecules 2010, 15(4), 2526-2550; https://doi.org/10.3390/molecules15042526

Submission received: 8 March 2010 / Revised: 29 March 2010 / Accepted: 2 April 2010 / Published: 9 April 2010

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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-induced paw oedema method in rats. Compounds 7d, 7g, 7i, 7j, 7l, 8c, 8e and 8l showed 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 [1,2,3] and HIV viruses [4,5,6,7], were also associated with central nervous [8,9,10], antimicrobial [11,12,13,14,15] and anti-inflammatory activities [14,15,16,17,18]. 1,2,4-Triazole derivatives were reported to possess diverse biological activities, such as antibacterial [19,20,21] and anti-inflammatory [22,23,24,25] 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 [26,27,28]. In continuation to our interest in the chemical and pharmacological properties of adamantane derivatives [6,11,14,15,16], 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 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, Table 2 and Table 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.

Table 1. Melting points, crystallization solvents, yields, molecular formulae and molecular weights of compounds 6a–v.

**Table 1.** Melting points, crystallization solvents, yields, molecular formulae and molecular weights of compounds **6a–v**.
Comp. No.	R	Mp (ºC)	Cryst. Solv.	Yield (%)	Molecular Formula (Mol. Wt.)
6a	H	222-224	EtOH/H₂O	81	C₁₉H₂₂N₄S (338.47)
6b	2-F	226-228	EtOH	74	C₁₉H₂₁FN₄S (356.46)
6c	4-F	255-257	EtOH	71	C₁₉H₂₁FN₄S (356.46)
6d	2-Cl	223-225	EtOH	75	C₁₉H₂₁ClN₄S (372.91)
6e	4-Cl	207-209	AcOH	68	C₁₉H₂₁ClN₄S (372.91)
6f	4-Br	228-230	EtOH/H₂O	59	C₁₉H₂₁BrN₄S (417.37)
6g	2-OH	238-240	EtOH	79	C₁₉H₂₂N₄OS (354.47)
6h	4-OH	264-266	EtOH	82	C₁₉H₂₂N₄OS (354.47)
6i	4-CH₃	208-210	EtOH/H₂O	80	C₂₀H₂₄N₄S (352.50)
6j	2-OCH₃	226-228	EtOH	77	C₂₀H₂₄N₄OS (368.50)
6k	4-OCH₃	214-216	EtOH	81	C₂₀H₂₄N₄OS (368.50)
6l*	2-NO₂	226-228	EtOH	52	C₁₉H₂₁N₅O₂S (383.47)
6m*	4-NO₂	242-244	AcOH	50	C₁₉H₂₁N₅O₂S (383.47)
6n	4-(CH₃)₂N	223-225	EtOH	66	C₂₁H₂₇N₅S (381.54)
6o	2,6-F₂	241-243	EtOH	68	C₁₉H₂₀F₂N₄S (374.45)
6p	2-Cl,6-F	219-221	EtOH	62	C₁₉H₂₀ClFN₄S (390.91)
6q	2,6-Cl₂	207-209	DMF	49	C₁₉H₂₀Cl₂N₄S (407.36)
6r*	2,4-Cl₂	233-235	AcOH	62	C₁₉H₂₀Cl₂N₄S (407.36)
6s*	3,4-Cl₂	237-239	AcOH	69	C₁₉H₂₀Cl₂N₄S (407.36)
6t	3,4-(CH₃O)₂	191-193	EtOH	86	C₂₁H₂₆N₄O₂S (398.52)
6u*	2,4-(NO₂)₂	245-247	AcOH	49	C₁₉H₂₀N₆O₄S (428.46)
6v*	2-NO₂,4,5-(CH₃O)₂	145-147	AcOH	68	C₂₁H₂₅N₅O₄S (443.52)

* Prepared by method B.

Table 2. Melting points, crystallization solvents, yields, molecular formulae and molecular weights of compounds 7a–p.

**Table 2.** Melting points, crystallization solvents, yields, molecular formulae and molecular weights of compounds **7a–p**.
Comp. No.	X	R	Mp (°C)	Cryst. Solv.	Yield (%)	Molecular Formula (Mol. Wt.)
7a	F	CH₃	102-104	EtOH/H₂O	54	C₂₅H₃₂F₂N₆S (486.62)
7b	F	C₂H₅	169-171	EtOH/H₂O	89	C₂₆H₃₄F₂N₆S (500.65)
7c	F	COOC₂H₅	156-158	EtOH/H₂O	82	C₂₇H₃₄F₂N₆O₂S (544.66)
7d	F	C₆H₅	151-153	EtOH	79	C₃₀H₃₄F₂N₆S (548.69)
7e	F	4-FC₆H₄	140-142	EtOH/H₂O	80	C₃₀H₃₃F₃N₆S (566.68)
7f	F	3-CF₃C₆H₄	132-134	EtOH/H₂O	88	C₃₁H₃₃F₅N₆S (616.69)
7g	F	2-CH₃OC₆H₄	184-186	EtOH/CHCl₃	85	C₃₁H₃₆F₂N₆OS (578.72)
7h	F	C₆H₅CH₂	148-150	EtOH	80	C₃₁H₃₆F₂N₆S (562.72)
7i	Cl	CH₃	109-111	EtOH/H₂O	68	C₂₅H₃₂Cl₂N₆S (519.53)
7j	Cl	C₂H₅	117-119	EtOH/H₂O	75	C₂₆H₃₄Cl₂N₆S (533.56)
7k	Cl	COOC₂H₅	136-138	EtOH/H₂O	72	C₂₇H₃₄Cl₂N₆O₂S (577.57)
7l	Cl	C₆H₅	170-172	EtOH	83	C₃₀H₃₄Cl₂N₆S (581.60)
7m	Cl	4-FC₆H₄	184-186	EtOH	85	C₃₀H₃₃Cl₂FN₆S (599.59)
7n	Cl	3-CF₃C₆H₄	159-161	EtOH	86	C₃₁H₃₃Cl₂F₃N₆S (649.60)
7o	Cl	2-CH₃OC₆H₄	139-141	EtOH	67	C₃₁H₃₆Cl₂N₆OS (611.63)
7p	Cl	C₆H₅CH₂	178-180	EtOH	80	C₃₁H₃₆Cl₂N₆S (595.63)

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

Table 3. Melting points, crystallization solvents, yield percentages, molecular formulae and molecular weights of compounds 8a–n.

**Table 3.** Melting points, crystallization solvents, yield percentages, molecular formulae and molecular weights of compounds **8a–n**.
Comp. No.	R	Mp (°C)	Cryst. Solv.	Yield (%)	Molecular Formula (Mol. Wt.)
8a	H	125-127	EtOH/H₂O	82	C₂₈H₃₇N₅O₂S (507.69)
8b	2-F	134-136	EtOH/H₂O	72	C₂₈H₃₆FN₅O₂S (525.68)
8c	2-Cl	158-160	EtOH	75	C₂₈H₃₆ClN₅O₂S (542.14)
8d	4-CH₃	135-137	EtOH/H₂O	92	C₂₉H₃₉N₅O₂S (521.72)
8e	2-OH	127-129	EtOH/H₂O	79	C₂₈H₃₇N₅O₃S (523.69)
8f	4-OH	195-197	EtOH/H₂O	84	C₂₈H₃₇N₅O₃S (523.69)
8g	4-OCH₃	124-126	EtOH/H₂O	88	C₂₉H₃₉N₅O₃S (537.72)
8h	2,6-F₂	148-150	EtOH/H₂O	69	C₂₈H₃₅F₂N₅O₂S (543.67)
8i	2-Cl,6-F	148-150	EtOH	74	C₂₈H₃₅ClFN₅O₂S (560.13)
8j	2,6-Cl₂	151-153	EtOH	75	C₂₈H₃₅Cl₂N₅O₂S (576.58)
8k	2,4-Cl₂	129-131	EtOH	68	C₂₈H₃₅Cl₂N₅O₂S (576.58)
8l	3,4-Cl₂	186-188	EtOH	71	C₂₈H₃₅Cl₂N₅O₂S (576.58)
8m	3,4-(CH₃O)₂	113-115	EtOH/H₂O	76	C₃₀H₄₁N₅O₄S (567.74)
8n	2-NO₂,4,5-(CH₃O)₂	182-184	EtOH/CHCl₃	80	C₃₀H₄₀N₆O₆S (612.74)

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 [31,32,33], 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 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).

**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).
Comp. No.	Diameter of Growth Inhibition Zone (mm)*
Comp. No.	SA	BS	ML	EC	PA	C A
6a	10	13	-	-	-	-
6b	14	14	-	-	-	-
6c	16	17	-	-	-	17
6d	11	14	-	-	-	-
6e	14	16	-	-	-	-
6f	13	14	14	-	-	16
6g	14	16	12	15	13	-
6h	19	25	13	19	14	-
6i	15	18	15	-	-	-
6j	-	-	-	-	-	-
6k	-	-	-	-	-	-
6l	14	14	-	-	-	-
6m	-	-	-	-	-	-
6n	-	-	-	-	-	-
6o	18	19	-	-	-	-
6p	-	-	-	-	-	-
6q	14	16	-	-	-	-
6r	16	17	-	-	-	-
6s	17	17	-	-	-	12
6t	-	-	-	-	-	-
6u	-	-	-	-	-	-
6v	-	-	-	-	-	-
7a	13	15	-	-	-	-
7b	15	14	-	15	-	-
7c	11	15		-	-	-
7d	-	-	14	-	-	-
7e	-	-	-	-	12	-
7f	12	11	-	18	11	-
7g	-	-	-	-	-	-
7h	-	-	-	-	-	17
7i	12	11	-	-	-	-
7j	14	12	-	-	-	-
7k	-	11	-	-	-	-
7l	-	-	-	-	-	-
7m	13	12	-	-	-	-
7n	-	-	-	19	14	-
7o	-	-	-	-	-	-
7p	-	-	-	-	-	-
8a	12	19	16	-	-	-
8b	-	-	-	-	-	-
8c	-	-	-	15	-	-
8d	11	15	-	-	-	-
8e	17	22	-	-	-	13
8f	22	26	-	-	-	19
8g	15	11	-	-	-	-
8h	-	-	-	-	-	14
8i	14	15	-	-	-	-
8j	12	16	16	-	-	-
8k	15	17	-	-	-	-
8l	11	13	-	-	-	-
8m	20	24	17	19	16	-
8n	-	-	-	-	-	-
Gentamicin	26	25	18	20	19	NT
Ampicillin	23	21	19	17	16	NT
Clotrimazole	NT	NT	NT	NT	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).

**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).
Comp. No.	Minimal Inhibitory Concentration (MIC, g/mL)*
Comp. No.	SA	BS	ML	EC	PA	C A
6h	2	1	ND	2	ND	ND
6o	ND	4	ND	ND	ND	ND
7n	ND	ND	ND	2	ND	ND
8a	ND	4	ND	ND	ND	ND
8e	ND	2	ND	ND	ND	ND
8f	2	1	ND	ND	ND	8
8m	2	1	ND	2	ND	ND
Gentamicin	2	2	2	0.5	1	ND
Ampicillin	2	0.5	2	2	2	ND
Clotrimazole	ND	ND	ND	ND	ND	2

* 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. 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.

**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
Comp. No.	20 mg/kg	40 mg/kg
Control^b	0 (± 0.04)
6b	-5.50 (± 0.13)^*	-2.71 (± 0.12)^*
6e	3.16 (± 0.11)^*	-8.56 (± 0.07)^*
6h	13.28 (± 0.15)^**	11.29 (± 0.14)^**
6j	11.06 (± 0.13)^**	13.91 (± 0.11)^**
6r	10.32 (± 0.09)^**	10.54 (± 0.11)^**
6t	21.92 (± 0.08)^**	19.37 (± 0.07)^**
7b	17.88 (± 0.11)^**	20.01 (± 0.09)^**
7d	39.16 (± 0.09)^**	39.88 (± 0.89)^**
7g	25.88 (± 0.07)^**	38.37 (± 0.07)^**
7j	27.95 (± 0.12)^**	34.76 (± 0.10)^**
7l	28.86 (± 0.08)^**	50.44 (± 0.06)^**
7m	13.06 (± 0.08)^**	22.90 (± 0.08)^**
7p	2.05 (± 0.06)^*	4.99 (± 0.08)^*
8a	23.23 (± 0.02)^**	15.27 (± 0.05)^**
8c	33.02 (± 0.11)^**	37.66 (± 0.14)^**
8e	20.41 (± 0.07)^**	31.20 (± 0.09)^**
8f	-18.25 (± 0.13)	1.36 (± 0.04)
8h	-20.21 (± 0.11)	-9.80 (± 0.07)
8k	9.91 (± 0.133)^*	6.81 (± 0.09)^*
8l	10.45 (± 0.10)^**	35.01 (± 0.12)^**
8n	-13.75 (± 0.18)^*	-11.61 (± 0.10)^*
Indomethacin (5 mg/kg)	52.79 (± 0.04)

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

5-(1-Adamantyl)-4-benzylideneamino-3-mercapto-1,2,4-triazole 6a: ¹H-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, 3H, Ar-H), 7.92 (d, 2H, Ar-H, J = 7.0 Hz), 9.71 (s, 1H, CH=N), 13.82 (s, 1H, SH). ¹³C-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).

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).

5-(1-Adamantyl)-4-(4-fluorobenzylideneamino)-3-mercapto-1,2,4-triazole 6c: ¹H-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-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). ¹³C-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).

5-(1-Adamantyl)-4-(4-chlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6e: ¹H-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).

5-(1-Adamantyl)-4-(2-bromobenzylideneamino)-3-mercapto-1,2,4-triazole 6f: ¹H-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).

5-(1-Adamantyl)-4-(2-hydroxybenzylideneamino)-3-mercapto-1,2,4-triazole 6g: ¹H-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, 1H, OH), 13.46 (s, 1H, SH). ¹³C-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).

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

5-(1-Adamantyl)-4-(4-methylbenzylideneamino)-3-mercapto-1,2,4-triazole 6i: ¹H-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).

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

5-(1-Adamantyl)-4-(2-nitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6l: ¹H-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).

5-(1-Adamantyl)-4-(4-nitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6m: ¹H-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-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). ¹³C 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).

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).

5-(1-Adamantyl)-4-(2,6-difluorobenzylideneamino)-3-mercapto-1,2,4-triazole 6o: ¹H-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 (m, 2H, Ar-H), 7.67-7.72 (m, 1H, Ar-H), 10.37 (s, 1H, CH=N), 13.87 (s, 1H, SH). ¹³C 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).

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

5-(1-Adamantyl)-4-(2,4-dichlorobenzylideneamino)-3-mercapto-1,2,4-triazole 6r: ¹H-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, SH). ¹³C 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).

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

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

5-(1-Adamantyl)-4-(2,4-dinitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6u: ¹H-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 (s, 1H, SH). ¹³C 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).

5-(1-Adamantyl)-4-(4,5-dimethoxy-2-nitrobenzylideneamino)-3-mercapto-1,2,4-triazole 6v: ¹H-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-3-thione 7a: ¹H-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, 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), 7.46–7.50 (m. 1H, Ar-H), 10.64 (s, 1H, CH=N). ¹³C 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-3-thione 7d: ¹H-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-triazoline-3-thione 7e: ¹H-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).

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-3-thione 7h: ¹H-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, 1H, Ar-H), 10.65 (s, 1H, CH=N). ¹³C 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).

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-H, J = 7.0 Hz), 10.79 (s, 1H, CH=N). ¹³C-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-piperazinylmethyl]-1,2,4-triazoline-3-thione 7n: ¹H-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 (m, 2H, Ar-H), 7.46 (d, 2H, Ar-H, J = 8.0 Hz), 10.80 (s, 1H, CH=N). ¹³C-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, 2H, Ar-H, J = 8.0 Hz), 10.76 (s, 1H, CH=N). ¹³C-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-3-thione 7p: ¹H-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 (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). ¹³C-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 (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-thione 8a: ¹H-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-triazoline-3-thione 8b: ¹H-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-triazoline-3-thione 8c: ¹H-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, 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-triazoline-3-thione 8d: ¹H-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-triazoline-3-thione 8e: ¹H-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-triazoline-3-thione 8f: ¹H-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-triazoline-3-thione 8g: ¹H-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 (d, 2H, Ar-H, J = 8.5 Hz), 7.86 (d, 2H, Ar-H , J = 8.5 Hz), 9.81 (s, 1H, CH=N). ¹³C-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, 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-triazoline-3-thione 8h: ¹H-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-triazoline-3-thione 8j: ¹H-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, Ar-H), 7.45 (d, 2H, Ar-H, J = 8.0 Hz), 10.84 (s, 1H, CH=N). ¹³C-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-triazoline-3-thione 8k: ¹H-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), 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-triazoline-3-thione 8l: ¹H-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-triazoline-3-thione 8m: ¹H-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-H), 9.85 (s, 1H, CH=N). ¹³C-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)-1,2,4-triazoline-3-thione 8n: ¹H-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 = 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). ¹³C-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 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:

Where V_c is the mean percentage increase in paw volume in the absence of the test compound (control) and V_d is 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.

Acknowledgements

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

Sample Availability: Contact the corresponding author.

References

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Al-Omar, M.A.; Al-Abdullah, E.S.; Shehata, I.A.; Habib, E.E.; Ibrahim, T.M.; El-Emam, A.A. 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. https://doi.org/10.3390/molecules15042526

AMA Style

Al-Omar MA, Al-Abdullah ES, Shehata IA, Habib EE, Ibrahim TM, El-Emam AA. 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(4):2526-2550. https://doi.org/10.3390/molecules15042526

Chicago/Turabian Style

Al-Omar, Mohamed A., Ebtehal S. Al-Abdullah, Ihsan A. Shehata, Elsayed E. Habib, Tarek M. Ibrahim, and Ali A. El-Emam. 2010. "Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles and Related Derivatives" Molecules 15, no. 4: 2526-2550. https://doi.org/10.3390/molecules15042526

APA Style

Al-Omar, M. A., Al-Abdullah, E. S., Shehata, I. A., Habib, E. E., Ibrahim, T. M., & El-Emam, A. A. (2010). Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4-triazoles and Related Derivatives. Molecules, 15(4), 2526-2550. https://doi.org/10.3390/molecules15042526

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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

Abstract

1. Introduction

2. Results and Discussion

2.1. Chemistry

2.2. Antimicrobial Testing

2.3. Acute anti-inflammatory activity testing

3. Experimental

3.1. General

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

5-(1-Adamantyl)-4-arylideneamino-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

4. Conclusions

Acknowledgements

References

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