WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Abdelhamid et al. World Journal of Pharmacy and Pharmaceutical Sciences

S JIF Impact Factor 6.041

Volume 5, Issue 9, 299-307 Research Article ISSN 2278 4357

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW 1,3,4-

THIADIAZOLES AND THIAZOLES FROM 1-(5-METHYL-1-(P-
TOLYL)-1H-1,2,3-TRIAZOL-4-YL)ETHANONE

Abdou O. Abdelhamid*, Nadia A. Abdelriheem and Ali M. M. Mohamed

Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613 Egypt.

Article Received on
10 July 2016,
Revised on 01 Aug. 2016,
Accepted on 22 Aug. 2016
DOI: 10.20959/wjpps20169-7658
*Corresponding Author
Abdou O. Abdelhamid
Department of Chemistry,
Faculty of Science, Cairo
University, Giza, 12613
Egypt.
ABSTRACT
A novel 1,3,4-thiadiazoles and 1,3-thiazoles containing 1,2,3-triazole
moiety were synthesized via reaction of hydrazonoyl halides with alkyl
carbothioate and thiosemicarbazone derivatives. The structures of the
newly synthesized compounds were established based on their spectral
data and elemental analyses. Also, the newly synthesized compounds
were screened for their antimicrobial activity against various
microorganisms.
KEYWORDS: 1,3,4-Thiadiazoles; 1,3-thiazoles; Hydrazonoyl
halides; Antimicrobial.

INTRODUCTION
1,3,4-Thiadiazoles are among the most common heterocyclic pharmacophores. They display
a broad spectrum of biological activities including antimicrobial[1] anticancer[2,3],
antioxidant[4], antidepressant[5], anticonvulsant[6,7], and antihypertensive activity[8] as well as
acetylcholinesterase inhibitors for the treatment of Alzheimer disease.[9, 10] Also, thiazole can
found in drug development for the treatment of allergies[11], hypertension[12],
inflammation[13], schizophrenia[14], bacterial[15], HIV infections[16], hypnotics[17] and more
recently for the treatment of pain[18], as fibrinogen receptor antagonists with
antithromboticactivity[19] and as new inhibitors of bacterial DNA gyrase B.[20]

RESULTS AND DISCUSSION

Treatment of 1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethan-1-one[21] (1) with
methyl(benzyl) carbodithioates[22, 23], gave the corresponding methyl(benzyl) 2-(1-(5-methyl-
1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene)hydrazine-1-carbodithioate 2a and 2b,

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Abdelhamid et al. World Journal of Pharmacy and Pharmaceutical Sciences

respectively in a good yield (Scheme 1). Structures 2 were elucidated on the bases of
elemental analyses, spectral data and chemical transformation. Thus, treatment of 2a with 2-
oxo-N,2-diphenylacetohydrazonoyl bromide (3a) in ethanolic triethylamine at room
temperature gave one isolated product formulated as gave one isolated product formulated as
(5-((1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene)hydrazono)-4-phenyl-4,5-
dihydro-1,3,4-thiadiazol-2-yl)(phenyl)methanone (7a) (Scheme 1). Structure 7a was
confirmed by elemental analysis, spectral data and alternative synthetic route. Thus, treatment
of 3a with 2b in ethanolic triethylamune gave a product identical in all aspects (mp., mixed
mp. and spectra) with 7a.

In the light of these results, the mechanism outlined in Scheme 1 seems to be the most
plausible pathway for the formation of 7a from the reaction of the 2a or (2b) with 3a. The
reaction involves initial formation of thiohydrazonate 5, which undergoes intermolecular
cyclization as soon as it is formed to yield the intermediate 6 or via 1,3-dipolar cycloaddition
of nitrileimine 4a [generated in situ from 3a with triethylamine] to the C=S double bond of 2.
The formation of 5 and 6 are similar to the reactions of hydrazonoyl halides with 1-phenyl-

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Abdelhamid et al. World Journal of Pharmacy and Pharmaceutical Sciences

1,4-dihydrotetrazole-5-thione[24] and 5-phenyl-1,3,4-thiadiazole-2(3H)-thione.[25] Intermidate

6 was converted to 7 by elimination of methanthiol (or benzylthiol). Analogously, treatment
of the appropriate 2a or 2b with 2-oxo-N-phenyl-2-(phenylamino)acetohydrazonoyl chloride
(3b) gave 5-((1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene)hydrazono)-N,4-
diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (7b) yield (Scheme 1).

Next, 2-(1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene)hydrazine-1-
[26]
carbothioamide (8), was reacted with 2-oxo-N-(p-tolyl)propanehydrazonoyl chloride (3c)
in ethanolic triethylamine under reflux gave the corresponding 4-methyl-2-(2-(1-(5-methyl-1-
(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene)hydrazinyl)-5-(p-tolyldiazenyl)-thiazole (10a) in
quantitative yield (Scheme 2).

Antimicrobial Activity: The antimicrobial activity of samples was determined using agar
well diffusion method.[27] Seven of the newly synthesized target compounds were evaluated
for their in vitro antibacterial activity against Staphylococcus aureus and Bacillis subtilis as
examples of Gram-positive bacteria and Pseudomonas aeruginosa and Escherichia coli as
examples of Gram-negative bacteria. They were also evaluated for their in vitro antifungal
activity against a representative panel of fungal strains i.e. Aspergillus fumigatus, and
Candida albicans. Ampicillin and Gentamicin are used as reference drugs for in vitro
antibacterial activity while Amphotericin B is used as reference drug for in vitro antifungal
activity in The Regional Center for Mycology and Biotechnology at Al-Azhar University,

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Nasr City, Cairo, Egypt. DMSO was used as solvent control. The compounds were tested at
a concentration of 10 mg/mL against both bacterial and fungal strains. The results of testing
for antimicrobial effects are summarized in Table 1.

Table 1
Bacillus Streptococcus Pseudomonas Escherichia Candida Aspergillus
subtilis pneumoniae aeruginosa coli albicans fumigates
Compound no
(RCMB (RCMB (RCMB (RCMB (RCMB (RCMB
010067) 010010) 010043) 010053) 05036) 02568)
2a 13.4 0.58 11.3 0.44 NA 12.3 0.63 9.2 0.44 11.1 2.1
2b 18.3 1.5 16.2 1.2 NA 16.3 0.46 16.4 2.1 18.2 1.5
7a 21.2 0.53 19.3 0.43 NA 19.3 0.25 19.3 0.58 20.3 0.58
7b 21.4 0.53 18.7 2.1 NA 18.6 1.5 20.3 1.2 21.4 0.58
8 20.2 0.44 17.3 0.63 NA 15.9 0.37 12.6 0.58 16.3 2.1
11a 20.1 0.67 20.3 0.44 NA 19.7 1.5 20.9 2.1 22.1 1.5
11b 23.2 0.58 21.4 0.63 NA 20.9 0.58 21.4 0.63 22.3 1.2
St.
Ampicillin 32.4 0.63 23.8 1.2
Gentamicin 17.3 0.58 22.4 1.2
Amphoteric-in B 25.4 1.5 23.7 0.58
The entire newly synthesized compound had no activity against Pseudomonas aeruginosa
Compounds 2a, 2b, 7a, 7b, 11a, 11b are middle activity towards Bacillus subtilis,
Streptococcus pneumonia, Escherichia coli, Candida albicans and Aspergillus fumigates
Candida albicans, and Aspergillus fumigates were excellent resistant to compounds 7b and
11b

Experimental: All meting points were determined on an electrothermal Gallen Kamp

melting point apparatus and are uncorrected. IR (cm-1) spectra were recorded on KBr disk on
a FTIR-8201 PC Shimadzu spectrophotometer. 1HNMR spectra were recorded in CDCl3 or
(CD3)2SO on Gemini 200 MHz and Varian 300 MHz spectrometers, using TMS as internal
reference. And chemical shifts are express as ppm unit. Element analysis was performed at
the Microanalytical Center in Cairo University.

Alkyl 2-(1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-ethylidene)hydrazine-1-
carbodithioate 2a and 2b.
A mixture of 1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4yl)ethanone[21] (1) (1 g, 5 mmol) and
alkyl carbodithioate[22, 23] (5 mmol) in 2-propanol (20 mL) was refluxed 30 min. The reaction
mixture was cooled and resulting solid was collected and crystallized from the proper solvent
to give 2a, b.

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Methyl 2-(1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-ethylidene)hydrazine-1-
carbodithioate (2a).
Buff crystals from ethanol: yield: 75% ,mp.: 186 oC, FT-IR (KBr, cm-1) : 3522 (NH), 3064
(CH), 1603 (C=N), 1561 (C=C); 1HNMR (300MHz , DMSO- d6) : = 2.36 (s, 3H, CH3),
2.45 (s, 3H, CH3), 2.50 (s, 3H, CH3), 3.20 (s, 3H, CH3), 7.38-7.51 (m, 4H, ArHs) and 12.4 (s,
br., 1H, NH). Anal. Calcd. For C14H17N5S2 (319.46) C, 52.64; H, 5.36; N, 21.92; S, 20.08
Found C, 52.70; H, 5.40; N, 21.90; S, 20.18

Benzyl 2-(1-(5-methy-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-ethylidene)hydrazine-1-
carbodithioate ( 2b).
Buff crystals from DMF : yield 75% , mp.: 324 oC , FT- IR (KBr , cm-1) : 3421 (NH), 3052
(CH), 1611 (C=N), 1553 (C= C); 1HNMR (300MHz, DMSO-d6): = 2.41 (s, 3H, CH3),
2.50 (s, 3H, CH3), 2.73 (s, 3H, CH3), 3.28 (s, 2H, CH2), 7.39-7.47 (m, 9H, ArHs) and 12.35
(s, br., 1H, NH). Anal. Calcd. For C20H21N5S2 (419.58) C, 62.98; H, 5.05; N, 16.69; S, 5.28
Found C, 62.90; H, 5.15; N, 16.70; S,15.30.

5-((1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene-4-phenyl-4,5-dihydro-1,3,4-
thiadiazole derivatives 7 a and 7b.
Method A: Triethylamine (0.75 ml, 0.5 g, 5mmol) was added dropwise with stirring to a
mixture of the appropriate alkyl carbodithioate 2a or 2b (5 mmol) and the appropriate
hydrazonoyl halides[28-30] 3a and 3b (5 mmol) in ethanol (20 mL). The resulting solid which
formed after 30 min., was collected and crystallized from the proper solvent to give the
corresponding thiadiazoles derivatives 7a and 7b, respectively.

5-(1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene-4-phenyl-4,5-dihydro-1,3,4-
thiadiazole-2-Benzoyl. (7a)
Orange crystals from acetic acid; Yield: 80% , mp.:203-205 oC; FT-IR( KBr, cm-1): 2924
(CH), 1637 (CO), 1616 (C= N); 1HNMR (300 MHz, CDCl3): = 2.48 (s, 3H, CH3), 2.65 (s,
3H, CH3), 2.74 (s, 3H, CH3) and 7.26-8.34 (m, 14H, ArHs); MS(El, m/z(%)) : 493 (M+, 90),
465 (10), 432 (10), 360 (15), 243 (20), 184 (30), 135 (40), 105 (100), 91 (40), 77 (50),
65(20); Anal. Calcd. For C27H23N7OS (493.60), C, 65.70; H, 4.70; N, 19.86 S, 6.50 Found C,
65.75; H, 4.69; N, 19.89, S, 6.60.

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5-(1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene-4-phenyl-4,5-dihydro-1,3,4-
thiadiazole-2-phenylcarbamyl (7b).
Yellow crystals from acetic acid; Yield: 75% , mp.: 250-253 oC ; FT-IR( KBr, cm-1): 3248 (
NH ), 2924(CH),1705 ( CO ), 1616 ( C = N ); 1HNMR (300 MHz, CDCl3): = 2.48 (s, 3H,
CH3), 2.64 (s, 3H, CH3), 2.72 (s, 3H, CH3), 7.20-8.11 (m, 14H, ArHs) and 8.50 (s,br., 1H,
NH); MS (El, m/z(%)) : 508 (M+, 40), 447 (10), 360 (15), 336 (20), 243 (25), 184 (50), 156
(45), 90 (100), 77 (50), 65 (30) Anal. Calcd. For C27H24N8OS (508.61), C, 63.76; H, 4.76; N,
22.03; S, 6.30 Found C, 63.80; H, 4.79; N, 22.13; S, 6.39

2-(2-(1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidene-hydrazinylthiazole derivatives
11a and 11b.
A mixture of 8 ( 1.4 g, 5 mmol), the appropriate hydrazonoyl halides 3c, 3d (5 mmol) and
triethylamine (0.5 g, 0.7 mL, 5 mmol) in ethanol was heated under reflux for 3 h .The
resulting solid was collected and recrystallized gave thiazoles derivatives 11a and 11b,
respectively.

2-(2-(1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidenehydrazinyl)-4-methyl-5-(p-
tolyl diazenyl)thiazole (11a).
Gray crystals from acetic acid, Yield: 70% , mp.: 250 oC; FT-IR (KBr, cm-1): 3421 (NH ),
3020 (CH), 1593 (C=C) ; 1HNMR (300 MHz, DMSO-d6): = 2.30 (s, 3H, CH3), 2.44 (s,
3H, CH3), 2.58 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.15-7.53 (m, 8H, ArHs)
, 10.54 (s, br., 1H, NH). Anal. Calcd. For C33H24N8S (444.57), C, 62.14; H, 5.44; N, 25.21 S,
7.21 Found C, 62.15; H, 5.55; N, 25.25; S, 7.30

2-(2-(1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethylidenehydrazinyl)-4-methyl-5-(p-
chlorophenyl diazenyl)thiazole (11b).
Red crystals from ethanol, Yield: 70%, mp.: 240 oC; FT-IR( KBr, cm-1) : 3387 (NH ), 3089,
3028 (CH), 1585 (C=C) ; 1HNMR (300 MHz, DMSO-d6): = 2.49 (s, 3H, CH3), 2.58 (s,
3H, CH3), 2.65 (s, 3H, CH3), 3.30 (s, 3H, CH3), 7.34-7.54 (m, 8H, ArHs) and 10.65 (s, br.,
1H, NH). Anal. Calcd. For C22H21N8S C l (464.99), C, 56.83; H, 4.55; N, 24.10; S, 6.90; Cl,
7.62 Found C, 56.89; H, 4.60; N, 24.15; S, 6.85,Cl,7.65.

ANTIMICROBIAL ACTIVITY ASSAY

Chemical compounds under investigation were individually tested against a panel of Gram-
positive and Gram-negative bacteria pathogens, and fungi.

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Antimicrobial tests were carried out using the agar well-diffusion method.[24] After the media
had cooled and solidified, wells (6 mm in diameter) were made in the solidified agar, after
that microbial inoculum was uniformly spread using sterile cotton swab on a sterile Petri dish
containing nutrient agar (NA) medium or Sabouraud dextrose agar (SDA) media for bacteria
and fungi, respectively. 100 L of the tested compound solution prepared by dissolving 1 mg
of the compound in 1 mL of dimethylsulfoxide (DMSO). The inoculated plates were then
incubated for 24 h at 37C for bacteria and yeast, 48 h at 28 C for fungi. Negative controls
were prepared using DMSO employed for dissolving the tested compound. Amphotericin B
(1 mg/mL), Ampicillin (1 mg/mL), and Gentamicin (1 mg/mL) were used as standards for
bacteria and fungi, respectively. After incubation, antimicrobial activity was evaluated by
measuring the zone of inhibition against tested microorganisms. Antimicrobial activity was
expressed as inhibition diameter zones in millimeters (mm). The experiment was carried out
in triplicate and the average zones of inhibition S.D were calculated.

RCMB: Regional Center for Mycology and Biotechnology Antimicrobial unit test organisms.
* NA: No activity, data are expressed in the form of mean SD.

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