Synthesis and Antimicrobial Study of Thiophene Clubbed Thiazolyl Carbohydrazides

Introduction

Heterocyclic compounds containing sulphur¹ are important entities present in various bioactive molecules in the field of medicinal and synthetic organic chemistry. Among the five membered ring containing sulphur heterocycles, thiazole^2-5 and thiophene^6-8 possess promising bioactivity profile. Compounds containing thiophene and thiazole^9-14 moieties exhibited promising bioactivities like antimicrobial and antitumor activities.

Thiosemicarbazide and substituted thiosemicarbazides have been proved not only as efficient precursors for different heterocycles¹⁵ but also as potentially bioactive scaffolds^16,-18. Synthesis of thiosemicarbazides from acid hydrazide derivatives^{18, 19} is one of the effective synthetic routes. Acid hydrazides can be synthesized from esters^{20, 21}. Although thiazole and substituted thiazoles can be synthesized by various routes^22-25, Hantzsch synthesis^26-28 is an efficient and widely preferred route of thiazole synthesis. Phenacyl bromides are widely used in thiazole synthesis²⁹. In our previous work we have reported antibacterial activities of bromine containing compounds³⁰.

Activities associated with thiophene, thiazoles, thienyl-thiazoles, bromine containing compounds, synthetic and biological importance of thiosemicarbazides, phenacyl bromides and efficiency of synthetic routes prompted to club thiophene and thiazoles into carbohydrazides and evaluating them for antimicrobial potential.

Results and Discussion  

Preparation of 4-Methyl-2-(thiophen-2-yl)-1,3-thiazole-5-carbohydrazide 4was carried outby known method^20,21(scheme 1). The reaction of compound 4 and aryl isothiocynates 5a-j in ethanol resulted in substituted thiosemicarbazides 6a-j as shown in scheme 2. The band at 1660 cm^-1in the IR spectrum of 6a was due to C=O stretching.In the¹H NMR spectrum of 6a a singlet at δ 2.69 supports the presence of methyl group on thiazole ring, a triplet at δ 7.05 with J = 8.68 Hz for two protons is for two protons ortho to fluorine.

Scheme 1 Click here to View scheme

Scheme 2 Click here to View figure

The presence of NH protons was confirmed by singlets at δ 9.71, 9.74 for two protons and at δ 10.18 for one proton. Thiosemicarbazides on condensation with 4-bromo-phenacyl bromide in ethanol were transformed into thiazoles 7a-j (Scheme 2).The bands at 3396 and 1666 cm^-1 corresponding to N-H stretching and for highly conjugated C=O group respectively are seen in the IR spectrum of compound 7a. A singlet δ 2.71 was for a deshielded methyl group on thiazole ring, three multiplets at δ 7.14-7.33, 7.43-7.45 and 7.60-7.79 for aromatic protons and a downfield singlet at δ 10.55 for N-H proton are seen in the ¹H NMR spectrum of the compound showed. Mass spectrometric analyses were in support of these compounds.

Antimicrobial Activity

In vitro antimicrobial studies of the compounds 6a-j, 7a-j was determined against three bacterial strains Escherichia coli, Salmonella typhii and Bacillus subtilis and two fungal strains Alternaria and Fusarium oxysorum (Table 1). For this agar well diffusion method was used. Ciprofloxacin and ketoconazole were used as reference antibacterial and antifungal agents while DMSO is used as negative control. The results were recorded as an average of three experimental sets and expressed as zone of inhibition in mm.

The results of antimicrobial study depicted that compounds 6a-jare promisingly active against three bacterial strains while 6a-f are active against Alternaria and 6b, 6i have activity   against F. oxysporum. Among the remaining compounds 7i, 7h-j are active against Bacillus subtilis. Compounds 7c, 7g showed activity against Salmonella typhi. Compounds 7i, 7c exhibited fairly good activity against F. oxysporum. Rest of the compounds are weakly active or inactive at the 1 mg/mL concentration against experimental microbes. All the thiosemicarbazides showed promising antimicrobial activities while on cyclization activities have been diminished. The observed activities are may be due to presence of free C=S group in compounds 6a-f.

Table 1: Antimicrobial Activity (Zone of Inhibition at 1 mg/mL in mm)

	Antibacterial  activity			Antifungal activity
Compounds	Bacillus subtilis	Escherichia coli	Salmonella typhii	Alternaria	Fusarium oxysporum
6a	15	13	14	19	+
6b	13	12	12	21	15
6c	20	16	18	26	+
6d	18	15	17	19	+
6e	20	14	15	20	+
6f	13	15	21	18	+
6g	19	17	17	–	+
6h	15	14	13	+	+
6i	13	13	15	20	16
6j	11	12	15	+	+
7a	12	+		–	14
7b	+	+	–	–	–
7c	–	–	11	–	13
7d	–	–	–	–	–
7e	–	–	–	–	+
7f	–	–	–	–	+
7g	+	–	14	+	–
7h	17	–	+	+	+
7i	15	–	–	–
7j	15	–	+	+	+
Ciprofloxacin	35	40	39	–	–
Ketoconazole	–	–	–	34	38

Experimental Section  

Physical constants were recorded using open glass capillary method. The IR and NMR spectra were recorded using IRAffinity-1S spectrophotometer (Shimadzu) and Bruker Avance II 400 MHz NMR spectrometer respectively.  DMSO-d₆ was used as a solvent and TMS as reference compound in NMR experiment on HP 1100 LC/MSD Mass Spectrometer and Perkin-Elmer analyzer were used for mass spectrometric analyses and elemental analyses respectively.

Table: 2 Physical data of synthesized compounds.

Compounds	Ar	M. P. (°C)	Yield (%)
6a	4-F-C6H4	188	73
6b	4-CH3-C6H4	212	72
6c	2-Cl-C6H4	272	75
6d	3-Cl-C6H4	242	75
6e	4-Cl-C6H4	194	78
6f	2,4-di-Cl-C6H3	291	74
6g	3,4-di-Cl-C6H3	280	77
6h	2-F-C6H4	172	71
6i	3-CH3-C6H4	222	73
6j	2-OCH3-C6H4	182	72
7a	4-F-C6H4	180	66
7b	4-CH3-C6H4	174	67
7c	2-Cl-C6H4	198	65
7d	3-Cl-C6H4	204	60
7e	4-Cl-C6H4	220	62
7f	2,4-di-Cl-C6H3	178	64
7g	3,4-di-Cl-C6H3	158	67
7h	2-F-C6H4	162	65
7i	3-CH3-C6H4	168	68
7j	2-OCH3-C6H4	260	63

N-(Aryl)-2-{[4-methyl-2-(thiophen-2-yl)-1,3-thiazol-5- yl]carbonyl} hydrazinecarbothioamides, 6a-j

Compound 4 and aryl isothiocynates 5ain equimolar quantity were refluxed for 1hin 25 mL ethanol with TLC monitoring. The reaction mixture was left undisturbed for 15 min after completion of reaction. The solid product 6a was filtered and recrystallized from ethanol.Preparation of compounds 6b-j was achieved under same experimental condition.  Physical data of compounds 6a-j is mentioned in Table 2 and analytical data isgiven below.

6a.IR: 3307, 3169 (N-H stretching frequency), 1660 (C=O stretching frequency), 1608 (C=N stretching frequency), 1543 (Ar C=C stretching frequency), 1213 (Ar-F stretching frequency), 827, 734 cm^-1(=C-H bending);¹H NMR: δ 2.69 (3H,s), 7.05 (2H,t,J = 8.68 Hz), 7.13-7.17 (1H,m), 7.36-7.58 (2H,m), 7.60-7.62 (2H,m), 9.71 (1H,s), 9.74 (1H,s), 10.18 (1H,s); MS: (M+1) 393; Analysis: C₁₆H₁₃FN₄OS₃: Cal.: C, 48.96; H, 3.34; N, 14.27; Observed: C, 48.97; H, 3.33; N, 14.24%.          

6b.IR: 3257, 3151 (N-H stretching frequency), 1654 (C=O stretching frequency), 1598 (C=N stretching frequency), 867, 739 cm^-1 (=C-H bending); ¹H NMR: δ 2.31 (3H,s), 2.68 (3H,s), 7.12-7.18 (3H,m), 7.38-7.48 (4H,m), 7.55 (1H,s), 9.48 (1H,s), 9.59 (1H,s), 10.02 (1H,s); MS: (M+1) 389;Analysis: C₁₇H₁₆N₄OS₃: Cal.: C, 52.55; H, 4.15; N, 14.42; Observed: C, 52.54; H, 4.12; N, 14.39%.           

6c.IR: 3317, 3163 (N-H stretching frequency), 1651 (C=O frequency), 1610 (C=C frequency), 835, 725 cm^-1(=C-H bending); ¹H NMR: δ 2.69 (3H,s), 2.77 (3H,s), 7.15-7.25 (4H, m), 7.35-7.50 (3H,m), 9.51 (1H,s) 9.62 (1H,s), 10.09 (1H, s); MS: (M+1) 409;Analysis: C₁₆H₁₃ClN₄OS₃: Cal.: C, 46.99; H, 3.20; N, 13.70; Observed: C, 46.96; H, 3.17; N, 13.68%.

6d.IR: 3319, 3225 (N-H stretching frequency), 1651 (C=O frequency), 1596 (C=C frequency), 834, 743 cm^-1(=C-H bending);¹H NMR: 2.71 (3H,s), 7.13-7.20 (4H,m), 7.32-7.51 (3H, m), 9.47 (1H,s), 9.58 (1H,s), 10.04 (1H,s); MS: (M+1) 409; Analysis: C₁₆H₁₃ClN₄OS₃: Cal.: C, 46.99; H, 3.20; N, 13.70; Observed: C, 46.98; H, 3.18; N, 13.69%.      

6e.IR: 3301, 3192 (N-H stretching frequency), 1652 (C=O stretching frequency), 1547 (Ar C=C stretching frequency), 837 cm^-1; ¹H NMR: δ 2.72 (3H,s), 7.02 (2H,d, J = 8.2 Hz), 7.14-7.21 (3H,m), 7.40-7.47 (2H,m), 9.49 (1H,s), 9.54 (2H,bs), 10.12 (1H,s); MS: (M+1) 409;  Elemental analysis: C₁₆H₁₃ClN₄OS₃: Cal.: C, 46.99; H, 3.20; N, 13.70; Observed: C, 46.96; H, 3.18; N, 13.69%. 

 6f.IR: 3316, 3192 (N-H stretching frequency), 1652 (C=O stretching frequency), 1546 (Ar C=C stretching frequency), 837 cm^-1(=C-H bending); ¹H NMR: δ 2.68 (3H,s), 7.09-7.20 (4H,m), 7.36-7.47 (2H, m), 9.48 (1H,s), 9.57 (1H,s), 10.02 (1H, s); MS: (M+1) 443.Analysis: C₁₆H₁₂Cl₂N₄OS₃: Cal. C, 43.34; H, 2.73; N, 12.64; Observed: C, 43.32; H, 2.71; N, 12.63.          

6g.IR: 3312, 3192 (N-H stretching frequency), 1654 (C=O stretching frequency), 1546 (Ar C=C stretching frequency), 835 cm^-1(=C-H bending); ¹H NMR: δ 2.71 (3H,s), 6.84-6.9 (2H,m), 7.06-7.21 (4H,m), 7.38-7.51 (2H,m), 9.50 (1H,s), 9.59 (1H,s), 10.11 (1H,s); MS: (M+1) 443;Analysis: C₁₆H₁₂Cl₂N₄OS₃: Cal.: C, 43.34; H, 2.73; N, 12.64; Observed: C, 43.33; H, 2.72; N, 12.63%.

 6h. IR: 3304, 3193 (N-H stretching frequency), 1651 (C=O stretching frequency), 1555 (Ar C=C stretching frequency), 831 cm^-1;¹H NMR: δ 2.76 (3H,s), 7.06-7.20 (4H,m), 7.36-7.45 (3H,m), 9.51 (1H,s), 9.59 (1H,s), 10.15 (1H,s); MS: (M+1) 393;Analysis: C₁₆H₁₃FN₄OS₃: Cal.: C, 48.96; H, 3.34; N, 14.27. Observed: C, 48.98; H, 3.32; N, 14.25%.  

6i.IR: 3307, 3169 (N-H stretching frequency), 1660 (C=O stretching frequency), 1608 (C=N stretching frequency), 1504 (Ar C=C stretching frequency), 1213, 827, 707 cm^-1 (=C-H bending); ¹H NMR: δ 2.34 (3H,s), 2.72 (3H, s), 6.96-9.98 (1H,m), 7.15-7.17 (1H, m), 7.19- 7.36 (3H,m), 7.39-7.42 (2H,m), 9.65 (1H,s), 9.68 (1H,s), 10.12 (1H,s); MS: (M+1) 389;Analysis: C₁₇H₁₆N₄OS₃: Cal.: C, 52.55; H, 4.15; N, 14.42; Observed: C, 52.53; H, 4.11; N, 14.38%.

6j. IR: 3321, 3192 (N-H stretching frequency), 1648 (C=O stretching frequency), 1549 (Ar C=C stretching frequency), 827 cm^-1; ¹H NMR: δ 2.76 (3H,s), 3.8 (3H,s), 6.84-6.9 (2H,m), 7.16-7.21 (2H,m), 7.37 (2H, d, J = 7.8Hz), 7.95-8.05(2H, m), 9.53 (2H, bs), 10.01 (1H,s); MS: (M+1) 404; Analysis: C₁₇H₁₆N₄O₂S₃: Cal.:  C, 50.47; H, 3.99; N, 13; Observed: C, 50.45; H, 3.97; N, 13.84%. 

N‘-[(2Z)-4-(4-Bromophenyl)-3-phenyl-1,3-thiazol-2(3H)-ylidene]-4-methyl-2- (thiophen-2-yl)-1,3-thiazole-5-carbohydrazides, 7a-j.   

In a 50 mL RBF, thiosemicarbazide 6a (0.001 mol) and 4-bromophenacyl bromide (0.001 mol) were dissolved in 25 mL ethanol. A TLC monitored reaction completed in 3 h. The reaction mixture was cooled to room temperature and crude compound 7a was filtered, dried and purified by recrystallization from ethanol. Compounds 7b-j were prepared under similar experimental conditions. Physical data of compounds 7a-j is mentioned in Table 2 and analytical data isgiven below.

(2H,m), 7.60-7.79 (2H,m), 10.55 (1H,s); MS: (M+1) 571;Analysis: C₂₄H₁₆N₄S₃OBrF: C, 50.44; H, 2.82; N, 9.80; Observed: C, 50.47; H, 2.84; N, 9.83%.    

7b.IR: 3361, 2921 (N-H stretching frequency), 1614, 1570 (C=C stretching frequency), 841, 759, 701 cm^-1 (=C-H bending); ¹H NMR: δ 2.31 (3H,s), 2.75 (3H,s), 6.57 (1H,s), 7.08-7.18 (4H,m), 7.20-7.36 (5H,m), 7.48 (2H,d,J = 8.5 Hz), 10.56 (1H, s); MS: (M+1) 567; Analysis: C₂₅H₁₉N₄S₃OBr: Cal.: C, 52.91; H, 3.37; N, 9.87; Observed: C, 52.92; H, 3.38; N, 9.86%.     

7c.IR: 3351, 2927 (N-H stretching frequency), 1626, 1581 (C=C stretching frequency), 835, 763, 704 cm^-1(=C-H bending); ¹H NMR: δ 2.70 (3H,s), 6.58 (1H,s), 7.10 (2H,d,J = 8.2 Hz), 7.13-7.35 (7H,m), 7.47 (2H,d,J = 8.2 Hz), 10.70 (1H,s); MS: (M+1) 587;Analysis: C₂₄H₁₆N₄S₃OBrCl: Cal.: C, 49.03; H, 2.74; N, 9.53; Observed: C, 49.06; H, 2.72; N, 9.51%. 

7d.IR: 3361, 2919 (N-H stretching frequency), 1622, 1582 (C=C stretching frequency), 845, 813, 702 cm^-1 (=C-H bending); ¹H NMR: δ 2.69 (3H,s), 6.57 (1H,s), 7.09-7.20 (6H,m), 7.26-7.38 (3H,m), 7.46 (2H,d, J= 8.1 Hz), 10.61 (1H,s); MS: (M+1) 587; Analysis: C₂₄H₁₆N₄S₃OBrCl: Cal.: C, 49.03; H, 2.74; N, 9.53; Observed: C, 49.04; H, 2.72; N, 9.55%.       

7e. IR: 3361, 2908 (N-H stretching frequency), 1619, 1581 (C=C stretching frequency), 843, 813, 702 cm^-1(=C-H bending); ¹H NMR (DMSO-d₆): δ 2.71 (3H,s), 6.62 (1H,s), 7.06-7.16 (4H, m), 7.19-7.35 (5H,m), 7.42 (2H,d, J = 8.4 Hz), 10.58 (1H,s); MS: (M+1) 587;Analysis: C₂₄H₁₆N₄S₃OBrCl: Cal.: C, 49.03; H, 2.74; N, 9.53; Observed: C, 49.05; H, 2.76; N, 9.56%.

7f.IR: 3352, 2933 (N-H stretching frequency), 1631, 1583 (C=C stretching frequency), 855, 803, 702 cm^-1(=C-H bending); ¹H NMR: δ 2.70 (3H,s), 6.59 (1H, s), 7.05-7.20 (5H,m), 7.24-7.36 (3H,m), 7.42 (2H,d, J = 8.2 Hz), 10.52 (1H,s); MS: (M+1) 621;Analysis: C₂₄H₁₅N₄S₃OBrCl₂: Cal.:  C, 46.31; H, 2.43; N, 9.00; Observed: C, 46.33; H, 2.45; N, 9.03%.    

7g.IR: 3361, 2934 (N-H stretching frequency), 1644, 1576 (C=C stretching frequency), 833, 707 cm^-1; ¹H NMR: δ 2.72 (3H,s), 6.54 (1H,s), 7.09 (2H,d, J = 8.4 Hz), 7.21-7.37 (6H,m), 7.48 (2H,d, J = 8.4 Hz), 10.58 (1H,s); MS: (M+1) 621;Analysis: C₂₄H₁₅N₄S₃OBrCl₂: Cal.: C, 46.31; H, 2.43; N, 9.00; Observed: C, 46.30; H, 2.46; N, 9.01%.         

7h.IR: 3354, 2921 (N-H stretching frequency), 1623, 1573 (C=C stretching frequency), 842, 803, 700 cm^-1(=C-H bending); ¹H NMR: δ 2.71 (3H,s), 6.56 (1H,s), 7.08-7.21 (5H, m), 7.24-7.38 (4H,m), 7.46 (2H,d, J = 8.4 Hz), 10.57 (1H,s); MS: (M+1) 571;Analysis: C₂₄H₁₆N₄S₃OBrF: Cal.: C, 50.44; H, 2.82; N, 9.80; Observed: C, 50.46; H, 2.84; N, 9.82%.   

7i.IR: 3351, 2919 (N-H stretching frequency), 1603, 1572 (C=C stretching frequency), 845, 713, 702 cm^-1 (=C-H bending); ¹H NMR: δ 2.32 (3H,s), 2.70 (3H,s), 6.56 (1Hs,), 7.09 (2H,d, J = 8.4 Hz), 7.16-7.35 (7H,m), 7.49 (2H, d,J = 8.4 Hz), 10.54 (1H,s); MS: (M+1) 567;Analysis: C₂₅H₁₉N₄S₃OBr: Cal.:C, 52.91; H, 3.37; N, 9.87; Observed: C, 52.94; H, 3.39; N, 9.85%.   

7j.IR: 3381, 2936 (N-H stretching frequency), 1605, 1575 (C=C stretching frequency), 815, 723, 703 cm^-1 (=C-H bending); δ 2.72 (3H,s), 3.81 (3H,s), 6.52 (2H,s), 6.98-6.16 (4H,m), 7.20-7.34 (5H,m), 7.44 (2H,d, J = 8.4 Hz), 10.57 (1H, s); MS: (M+1) 582; Analysis: C₂₅H₁₉N₄S₃O₂Br: Cal.: C, 51.46; H, 3.28; N, 9.60; Observed: C, 51.48; H, 3.29; N, 9.63%. 

Conclusions

In present study thiophene and thiazole containing carbohydrazides are synthesized quantitatively and spectroscopicdata well support the proposed compounds. Among the N-(Aryl)-2-{[4-methyl-2-(thiophen-2-yl)-1,3-thiazol-5- yl]carbonyl}hydrazinecarbothioamide compounds, 6a-j showed promising bactericidal activity against B. subtilis, E. coli, S. typhi. Most of the compounds from 6a-j series are effective against fungal species Alternaria except 6g. Most of the compounds from this series are weakly active against Fusarium oxysporum. Compounds from 7a-j series are either inactive or showed less activity against all the test organisms. Overall majority of the compounds reported in the present work can be developed into more active agents by performing structural modifications.

Acknowledgement

The author is thankful to Management and Principal of Dadapatil Rajale Arts, Science and Commerce College, Adinathnagar, and also thankful to Guide Hon. Dr. B. K. Karale for providing research facilities and valuable guidance. The author is grateful to the Director, SAIF, Punjab University, Chandigarh, for their support in the form of spectroscopic investigations.

Conflict of Interest

The author declares no conflict of interest.

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