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Article

Synthesis and Antibacterial Activities of Novel Imidazo[2,1-b]-1,3,4-thiadiazoles

by
Kamal F. M. Atta
*,
Omaima O.M. Farahat
,
Alaa Z. A. Ahmed
and
Mohamed G. Marei
Chemistry Department, Faculty of Science, Alexandria University, Ibrahimia P.O. Box 426, Alexandria 21321, Egypt
*
Author to whom correspondence should be addressed.
Molecules 2011, 16(7), 5496-5506; https://doi.org/10.3390/molecules16075496
Submission received: 18 March 2011 / Revised: 2 June 2011 / Accepted: 7 June 2011 / Published: 28 June 2011
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
2-Amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 have been synthesized by the reaction of 2-aryl-2H-1,2,3-triazole-4-carboxylic acids 1 with thiosemicarbazide. Their reaction with phenacyl (p-substituted phenacyl) bromides led to formation of the respective 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazoles 5. Reactivity of the latter fused ring towards reaction with different electrophilic reagents afforded the corresponding 5-substituted derivatives 6-8. The structure of the above compounds was confirmed from their spectral characteristics. Some of these compounds were found to possess slight to moderate activity against the microorganisms Staphylococcus aureus, Candida albicans, Pseudomonas aeruginosa, and Escherichia coli.

1. Introduction

2-Amino-1,3,4-thiadiazole derivatives are well known as compounds of a wide range of anticancer activity [1,2,3,4] that have been prepared from their respective aldehydes [5] or carboxylic acids [6]. They appeared to be the most feasible route to fused imidazo[2,1-b]-1,3,4-thiadiazole rings [6,7,8,9,10,11,12,13,14] of interesting potential applications [15,16]. Some of these compounds show anticancer [17], antitubercular [18], antibacterial [19], antifungal [20], anticonvulsant analgesic [21], antisercetory [22] and antiapoptotic [23] properties. Also, certain compounds incorporating the imidazo[2,1-b]-1,3,4-thiadiazole moiety are used as anti-inflammatory [24], cardiotonic [25], diuretic [26] and herbicidal [27] agents and are used in the manufacture of dyes [28,29,30]. With all this in mind, the present paper focused on the synthesis of some new fused imidazo[2,1-b]-1,3,4-thiadiazole rings and testing their reactivity towards electrophilic substitution reactions and against Staphylococcus aureus, Candida albicans, Pseudomonas aeruginosa and Escherichia coli.

2. Results and Discussion

2-Aryl-2H-1,2,3-triazole-4-carboxylic acids 1 [31] were chosen as starting materials for these studies. They were converted with thiosemicarbazide in the presence of POCl3 to the corresponding 2-amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 in good yields (Scheme 1).
Molecules 16 05496 g002 550
Scheme 1. Synthesis and electrophilic substitution reactions of imidazo[2,1-b]-1,3,4-thiadiazoles.
Scheme 1. Synthesis and electrophilic substitution reactions of imidazo[2,1-b]-1,3,4-thiadiazoles.
Molecules 16 05496 g002
The structures of the above compounds were confirmed from their spectral data. Their IR spectra showed two medium intensity bands at range 3282–3485 and 3165–3300 cm−1 due to the asymmetric and symmetric NH stretching frequencies of the primary amino group [32,33].
Table
Table 1. Infrared and 1H NMR spectral data of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Table 1. Infrared and 1H NMR spectral data of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Cpd. No.IR (cm−1)1H-NMR Chemical Shift (δ/ppm) *
C=NC=NC=NC=CC-S-CArHImidazole protonTriazole proton
(thiadiazole ring)(imidazole ring)(triazole ring)(imidazole ring)(thiadiazole ring)(m)(s, 1H) (s, 1H)
5a16381594153414906907.33–8.14 (10H)8.078.33
5b16351595153214906697.61–8.84 (9H)7.508.46
5c1634159415361490669
5d1629152715401844690
5e1631155515281488669
5f16261600152914886697.42–8.11 (8H)8.068.50
5g1651160115381486690
5h1649156515331487671
5i1652159915331485670
6a16401597154514896627.25–8.14 (10H) 8.41
6b16411594152214876697.44–8.15 (9H) 8.42
6c16371595152414886697.42–8.14 (9H) 8.41
6d16321549152614366867.35–8.06 (9H) 8.42
6e16321552152214866697.57–8.03 (8H) 8.42
6f16281545152116866697.42–8.04 (8H) 8.42
6g16451550151014886867.36–8.10 (9H) 8.42
6h16421568151914876727.49–8.09 (8H) 8.41
6i16411585152214886727.42–8.09 (8H) 8.41
7a16341595153214886637.37–8.15 (10H) 8.43
7b16401594152714896687.42–8.14 (9H) 8.41
7c16361596153014896697.43–8.14 (9H) 8.41
7d1642154715221486685
7e16331565153514856717.58–8.03 (8H) 8.41
7f16331565152114876717.43–8.03 (8H) 8.42
7g16391545150914886857.39–8.11 (9H) 8.42
7h16401595155514876697.49–8.09 (8H) 8.41
7i16391598156514866707.43–8.10 (8H) 8.41
*s = Singlet, m = multiplet.
Also, the 1H-NMR spectra revealed a singlet at δ 7.60–7.61 (2H) for exchangeable NH2 protons and a singlet at δ 8.51–8.52 for the H-5 triazole proton. The structures were further confirmed from mass spectral data (cf. Experimental). The reaction of 2-amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 with phenacyl(p-substituted phenacyl) bromides in boiling dry ethanol led to the formation of the new series of 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazoles 5a-i. The reaction proceeds via the formation of the iminothiadiazole intermediate, followed by dehydrative cyclization to form the desired fused heterocycle [19]. The disappearance of the NH2 absorption bands in the IR spectra of 5 as well as the absence of the exchangeable singlets of this group in their 1H-NMR spectra, in addition to the presence of singlets at δ 8.33–8.50 for triazole protons, and a singlet at δ 7.50–8.07 for imidazole protons confirmed the structures (Table 1). It was reported that [27,28,29] the electrophilic substitution reactions of imidazo[2,1-b]-1,3,4-thiadiazole take place at position 5. Thus, in the present work, bromination of 5 with bromine as well as iodination with iodine monochloride gave the respective 5-bromo (6a-i) and 5-iodo derivatives 7a-i. The 1H-NMR spectra of both derivatives revealed the disappearance of H-5 singlet of imidazole ring and presence of triazole proton as singlets at δ 8.41–8.43 (Table 1). The structure of the imidazothiadiazoles 5-7 was further confirmed by studying their mass spectral data, where the possible fragmentation pathways for all compounds gave rise to the bicyclic (I), 2-aryl-4-cyano-1,2,3-triazole (II). In addition to 2-acetylenic imidazo-thiadiazoles (III) (Figure 1). The relative intensity of the molecular ion peaks and the most prominent peaks are listed in (Table 2).
Molecules 16 05496 g001 550
Figure 1. The most prominent fragments of the mass spectra of imidazo[2,1-b]-1,3,4-thiadiazoles.
Figure 1. The most prominent fragments of the mass spectra of imidazo[2,1-b]-1,3,4-thiadiazoles.
Molecules 16 05496 g001
Table
Table 2. Relative intensity of the molecular ion peaks and the most prominent peaks in the mass spectra of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Table 2. Relative intensity of the molecular ion peaks and the most prominent peaks in the mass spectra of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Cpd. No.MIIIIII
5a332118
5b100,7810705
5g215364
5i2924404
6a691003418
6d75710012
6f84087
6g221002919
6i535341
7a100732218
7e3916,1544,462
7g461001857
7i1436181
Formylation of 5a with dimethylformamide in the presence of phosphorus oxychloride (Vilsmeier-Haack reagent) gave the 5-formyl derivative 8 in excellent yield. Its IR spectrum showed a strong absorption band at 1676 cm−1 characteristic of the entered carbonyl group and two weak absorption bands at 2921 and 2885 cm−1 of formyl hydrogen. Also, the 1H-NMR spectrum revealed the absence of the H-5 singlet of the imidazole ring and exhibited two singlets at δ 8.53 and 10.10 for the triazole and formyl protons respectively.

Biological screening: antimicrobial activity tests

The antibacterial activities of compounds 2-8 were tested against the micro-organisms Staphylococcus aureus (ATCC6538p), Candida albicans (ATCC2091), Pseudomonas aeruginosa (ATCC9027) and Escherichia coli (ATCC8739). After incubation, the diameters of inhibition zones around the wells were measured, to the nearest mm, in three different directions using a ruler and the average diameter was recorded and compared to that of the control. From the data presented in Table 3 it is clear that compounds 5d and 6h were moderately active against Escherischia coli, while 7b was also moderately active but against Pseudomonas aeruginosa microorganisms. Generally, other derivatives were slightly too moderately active against Candida albicans, Pseudomonas aeruginosa and Escherischia coli. Finally, compounds 2–8 were found to be inactive against Staphylococcus aureus.
Table
Table 3. Result of antimicrobial activity tests (agar diffusion method) of compounds (2–8).
Table 3. Result of antimicrobial activity tests (agar diffusion method) of compounds (2–8).
Test microorganismsSCPsE
Test compoundsAverage inhibition zone diameter in mms
Imepenam30-3026
Ampicillin30---
Clotrimazole -40--
2-182217
3-182216
4-182216
5a-182217
5b-182218
5c-182216
5d-182220
5e-182216
5f-182218
5g-182216
5h-192218
5i-182316
6a-192217
6b-182316
6c-182217
6d-182317
6e-182216
6f-182217
6g-182217
6h-182220
6i-182216
7a-182219
7b-182619
7c-182216
7d-182216
7e-192217
7f-192217
7g-192216
7h-182217
7i-182216
8-182219
DMF -182216
S: Staphylococcus aureus; C: Candida albicans; Ps: Pseudomonas aeruginosa; E: Escherichia coli.

3. Experimental

3.1. General

Melting points were determined on a Kofler Block and are uncorrected. TLC was done on Merck Kiesel gel 60-f 254 precoated plastic plates. Infrared spectra (IR) were measured with a Fourier Transform Infrared 8400 spectrophotometer (BRUKER TENSOR 37) using potassium bromide pellets. The 1H-NMR spectra were recorded on a JEOL JNM ECA 500 MHZ with tetramethylsilane as internal standard. Mass spectra (MS) were recorded at 70 ev using GCMS-QP 1000EX mass spectrometer. Microanalyses were performed by the Microanalytical Unit, Cairo University, Cairo. 2-Aryl-2H-1,2,3-triazole-4-carboxylic acids 1 were prepared from the respective D-glucose arylosotriazoles as described earlier [31].

3.2.1. 2-Amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles (2-4)

2-Aryl-2H-1,2,3-triazole-4carboxylic acids (1, 0.1 mol) and thiosemicarbazide (9.1 g, 0.1 mol) were refluxed gently in the presence of phosphorus oxychloride (30 mL) for 45 min. The reaction mixture was cooled and quenched with cold water (90 mL). The resulting solution was refluxed for an additional 6 hours. The separated solid was filtered and suspended in water and basified with potassium hydroxide. The solid was filtered, washed with water, dried and crystallized from a suitable solvent.
2-Amino-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazole (2). Yield (75%); m.p. 251–252 °C (crystallization from ethanol); IR (cm−1): 3282, 3165 (NH2), 1637 (thiadiazole ring C=N), 1555 (triazole ring C=N) and 690 (thiadiazole ring C-S-C); 1H-NMR (DMSO-d6, δ, ppm): 7.42 (t, 1H, aromatic-H), 7.55 (t, 2H, aromatic-H), 7.60 (s, 2H, exchangeable NH2), 7.98 (d, 2H, aromatic-H) and 8.51 (s, 1H, triazole-H); MS, m/z (%): 244 (100, M+), 188 (23, M+-C2H2N3), 161 (3, M+-C2H3N4), 145 (2, M+-C2HN3S), 105 (3, M+-C4H3N4S) and 91 (21, M+-C2H3N5S); Anal. Calc. for C10H8N6S (244.28): C, 49.17; H, 3.30; N, 34.40%, found: C, 49.00; H, 3.45; N, 34.25%.
2-Amino-5-[2-(4-bromophenyl)-2H-1,2,3-triazol-4-yl]-1,3,4-thiadiazole (3). Yield (77%); m.p. 259–260 °C (crystallization from dioxane); IR (cm−1): 3485, 3300 (NH2), 1639 (thiadiazole ring C=N), 1597 (triazole ring C=N) and 660 (thiadiazole ring C-S-C); 1H-NMR (DMSO-d6δ, ppm): 7.55 (d, 2H, aromatic-H), 7.61 (s,2H, exchangeable NH2), 7.98 (d, 2H, aromatic-H) and 8.52 (s, 1H, triazole-H); MS, m/z (%): 324 (8, M+ +2), 322 (5, M+), 266 (3, M+-CH2N3), 239 (1, M+-C2H3N4), 244 (100, M+-Br+H), 188 (54, M+-CHBrN3), 184 (3, M+-C4H2N4S), 169 (4, M+-C4H3N5S),161 (1, M+-C2H2BrN4), 145 (1, M+-C2BrN3S), 133 (2, M+-C3BrN3S), 105 (4, M+-C4H2BrN4S) and 91 (9, M+-C2HBrN5S); Anal. Calc. for C10H7BrN6S (323.17): C, 37.17; H, 2.18; N, 26.00%, found. C, 37.00; H, 2.60; N, 25.70%.
2-Amino-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl]-1,3,4-thiadiazole (4). Yield (65%); m.p. 269–270 °C (crystallization from dioxane); IR (cm−1): 3465, 3290 (NH2), 1626 (thiadiazole C=N), 1532 (triazole C=N) and 694 (thiadiazole C-S-C); Anal. Calc. for C10H7ClN6S (278.72): C, 43.09; H, 2.53; N, 30.15%, found. C, 43.12; H, 2.51; N, 30.17%.

3.2.2. 6-Aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazoles 5a-i

A mixture of equimolar quantities of thiadiazoles 2-4 (0.01 mol) and phenacyl (p-substituted phenacyl) bromides (0.01 mol) was refluxed in dry ethanol (50 mL) for 24 hours. The excess of solvent was distilled off and the solid hydrobromide salt that separated out was collected by filtration, suspended in water and neutralized by sodium carbonate to get free base 5a-i. The product was filtered, washed with water, dried and crystallized from carbon tetrachloride. Their IR, 1H-NMR spectra and analytical data are listed in Table 1 and Table 4.

3.2.3. 6-Aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl)-5-haloimidazo[2,1-b]-1,3,4-thiadiazoles 6a-i and 7a-i

A solution of bromine (iodine monochloride) (0.01 mol) in acetic acid (10 mL) was gradually added to a suspension of 5a-i (0.01 mol) in acetic acid (10 mL) with stirring for one to eight days at room temperature. The reaction mixture was poured onto ice cold water. The separated solid was collected, washed with water, dried and crystallized from either chloroform or benzene in methanol mixture. Their IR, 1H-NMR spectra and analytical data are listed in Table 1 and Table 4.
Table
Table 4. Analytical data of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Table 4. Analytical data of imidazo[2,1-b]-1,3,4-thiadiazoles (5-7).
Cpd. No.Mp (°C)Yield (%)FormulaCalcd. %Found %
CHNCHN
5a225-22660C18H12N6S62.773.5124.4062.503.4224.43
5b253-25462C18H11BrN6S51.072.6219.8551.002.3219.92
5c257-25861C18H11ClN6S57.072.9322.1857.112.8622.20
5d285-28661C18H11BrN6S51.072.6219.8551.152.4020.06
5e281-28260C18H10 Br2N6S43.052.0116.7343.072.0016.81
5f276-27766C18H10BrClN6S47.232.2018.3647.312.1218.02
5g279-28058C18H11ClN6S57.072.9322.1857.102.9222.21
5h267-26855C18H10BrClN6S47.232.2018.3647.192.2618.41
5i271-27258C18H10 Cl2N6S52.312.4420.3352.402.4020.21
6a221-22280C18H11BrN6S51.072.6219.8551.122.4220.03
6b261-26280C18H10 Br2N6S43.052.0116.7343.122.0016.92
6c255-25680C18H10BrClN6S47.232.2018.3647.212.1518.38
6d265-26682C18H10 Br2N6S43.052.0116.7343.052.0116.73
6e246-24776C18H9 Br3N6S37.211.5614.4637.221.8114.51
6f248-24980C18H9Br2ClN6S40.291.6915.6640.011.8115.62
6g257-25880C18H10BrClN6S47.232.2018.3647.122.2518.39
6h259-26080C18H9Br2ClN6S 0.291.6915.6640.421.7215.52
6i237-23880C18H9 BrCl2N6S43.931.8417.0843.901.8716.90
7a270-27185C18H11IN6S45.972.3617.8745.822.3917.85
7b251-25283C18H10BrIN6S39.371.8415.3039.401.9015.21
7c251-25282C18H10ClIN6S42.832.0016.6542.902.0316.82
7d273-27485C18H10BrIN6S39.371.8415.3039.211.6115.42
7e251-25280C18H9Br2IN6S34.421.4413.3834.501.4913.42
7f243-24485C18H9BrClIN6S37.041.5514.4037.241.5214.43
7g285-28682C18H10ClIN6S42.832.0016.6542.721.9516.62
7h255-25684C18H9BrClIN6S37.041.5514.4036.921.6114.41
7i253-25480C18H9Cl2IN6S40.101.6815.5940.201.7215.51

3.2.4. 5-Formyl-6-phenyl-2-(2-phenyl-2H-1,2,3-triazol-4-yl)imidazo[2,1-b]-1,3,4-thiadiazole (8)

The Vilsmeir-Haack reagent was prepared by adding phosphorus oxychloride (3 mL) to dimethyl-formamide (20 mL) at 0 °C with stirring. Then, compound 5a (3.44 g, 0.01 mol) was added to the reagent and stirred at 0 °C for 30 min. The mixture was further stirred at room temperature for 2 hours and then at 60 °C for an additional 2 hours. The reaction mixture was then poured onto sodium carbonate solution and stirred at 90 °C for 2 hours. After cooling, the mixture was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and the residue obtained after removal of the solvent was crystallized from chloroform/ methanol. Yield (80%); m.p. 184–185 °C; IR (cm−1): 2921, 2885 (formyl hydrogen), 1676 (CO), 1629 (thiadiazole C=N), 1589 (imidazole C=N), 1492 (triazole C=N), 1444 (imidazole C=C) and 664 (thiadiazole C-S-C); 1H-NMR (CDCl3,δ, ppm): 7.44 (t, 1H, aromatic-H), 7.54 (m, 5H, aromatic-H), 7.89 (d, 2H, aromatic-H), 8.15 (d, 2H, aromatic-H), 8.53 (s, 1H, triazole-H) and 10.1 (s, 1H, formyl-H); Anal. Calc. for C19H12N6OS (372.40): C, 61.28; H, 3.25; N, 22.57%, found. C, 61.30; H, 3.30; N, 22.57%.

3.3. Antibacterial Activity Tests

The antibacterial activity tests were performed according to agar diffusion method [34] using ampicillin, imepenam and clotrimazole as the reference compounds. The Sterile cotton swabs were separately dipped into each of the adjusted organism cultures and excess inoculum was removed by pressing and rotating the swab firmly several times against the wall of the tube above the level of the liquid. The swab was streaked all over the surface of the nutrient agar in three dimensions at an angle of 60° to obtain an even distribution of the inoculum. The plates were then left to dry at room temperature for few minutes. A sterile cork porer (8 mm in diameter) is used to make wells in the solid nutrient agar plates, so that the distance between the edges of each two wells is not less than 24 mm. Fill each well with 75 μL of the test compound and another well with same volume of DMF as a vehicle control. Allow a period of free diffusion for 2 h, then incubated at 37 °C for 18–24 h.

4. Conclusions

In conclusion, formation of diverse 2-amino-5-substituted-1,3,4-thiadiazoles using carbohydrates as precursors was successfully achieved, followed by their conversion into the novel target imidazo[2,1-b]-1,3,4-thiadiazole fused heterocyles. The antibacterial activities of the synthesized compounds were also examined.

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  • Sample Availability: Samples of the compounds (1-8) are available from the authors.

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MDPI and ACS Style

Atta, K.F.M.; Farahat, O.O.M.; Ahmed, A.Z.A.; Marei, M.G. Synthesis and Antibacterial Activities of Novel Imidazo[2,1-b]-1,3,4-thiadiazoles. Molecules 2011, 16, 5496-5506. https://doi.org/10.3390/molecules16075496

AMA Style

Atta KFM, Farahat OOM, Ahmed AZA, Marei MG. Synthesis and Antibacterial Activities of Novel Imidazo[2,1-b]-1,3,4-thiadiazoles. Molecules. 2011; 16(7):5496-5506. https://doi.org/10.3390/molecules16075496

Chicago/Turabian Style

Atta, Kamal F. M., Omaima O.M. Farahat, Alaa Z. A. Ahmed, and Mohamed G. Marei. 2011. "Synthesis and Antibacterial Activities of Novel Imidazo[2,1-b]-1,3,4-thiadiazoles" Molecules 16, no. 7: 5496-5506. https://doi.org/10.3390/molecules16075496

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