Synthesis, Characterization and Antimicrobial Activity of Novel Benzimidazole Containing Ligand and Its Metal Complexes

Introduction

Benzimidazole is fused heterocyclic compound, which are associated with various pharmaceutical activities such as antimicrobial, anti-cancer, antiproliferative, anti-diabetic and  antibacterial, etc^1-5. Due to various biological properties, Thiosemicarbazides became significant functional group. The numbers of researches on Thiosemicarbazides were done for and they show excellent pharmaceutical activities ^6-9. In the treatment of cancer thiosemicarbazides compounds exhibit some significant activities. Thiosemicarbazides compounds are exceptionally discriminated in antitumor activity.  The metal chelates of thiosemicarbazides compounds elevated the biological properties ^7,8. Among them nitrogen and sulfur -containing compounds, thiosemicarbazides show importantance in the field of medicinal chemistry ¹⁰. Many scientists have developed a variety of bioactive and pharmacological activities heterocyclic molecules, which contains thiosemicarbazides and thiosemicarbazides moiety ¹¹. Thiosemicarbazides generally act as chelating ligands containing which react with transition metal giving complexes, which shows biological activities rather than ligands^12,13.

Looking to systematic literature study of benzimidazole and Thiosemicarbazides derivatives, and in continuous of our previous work the present paper comprise the metal complexation study of benzimidazole-thiosemicarbazides clubbed compound The reaction steps is shown in scheme 1.

Experimental

Laboratory mark chemicals were utilized. Elemental analysis of synthesised compounds were find out by volumetrically by reported process¹⁴. Nicolet-FT-IRspectrometer-760,NMR spectrophotometer-60MHz and LC-MSD-Trap-SL_01046 were utilized for spectral data studies of synthesized BITS (Ligand) and complexes. Magnetic properties find out by Gouy Balance. The antibacterial activities of the synthesized BITS (Ligand) and complexes were detetmined for selected bacteria. Evaluation of antimicrobial activity has been carried out using Broth Dilution method for antimicrobial study^15-17. Similar conditions using Amoxillin and Nystatin were used standard for comparison.

Synthesis of 5-methyl-1-(1H-Benzimidazol-1-yl) -2-propanone(MBIP) :

In round bottom flask take a mixture of 5-methyl-1H-benzimidazole (0.01 mole), chloroacetone (0.01 mole) and 150 mL of dry acetone and 35 g of anhydrous potassium carbonate and refluxed this reaction mixture for 7 hrs. The product separated out was filter and recrystallized from ethanol^8,9. Yield: 74 %, m.p:138°C.Elemental Analysis for C₁₁H₁₂N₂O (188 gm/mole): Clac. %C, 70.19;  H, 6.43; N, 14.88; Found. % C, 70.1; H, 6.4; N, 14.8. IR Spectral data of IR(cm^-1) at 2900,2852,1513,1400(Carbon-H Stra.), 1686 (Carbonyl), 3005 (Ar.Carbon-H Stra.),1595(-C=N) and 1595,1452(Aromatic C-C Str.). NMR Signals (δ ppm) at 2.08-2.40 (s, 6H, -CH3), 7.40-8.20 (m, 4H, benzoimidazole C-H) and 4.90-4.92 (s, 2H, -CH2-).

 Synthesis of 2-(1-(5-methyl-1H-benzimidazol-1-yl)propan-2-ylidene)hydrazine carbothioamide (MBITS) :

Thiosemicarbazides was synthesized by refluxing the solution of thiosemicarbazide (0.03mol) in ethanol and the alcoholic solution of 5-methyl-1-(1H-Benzimidazol-1-yl) -2-propanone (0.03mol) at 60°C for 5-6 hrs with continuous stirring. After cooling the compounds were filtered and recrystallized from ethanol^8,9. Yield: 76%; m.p. 154°C; Elemental Analysis for C₁₂H₁₅N₅S (261gm/mole): Clac. % C, 55.15; H, 5.79; N, 26.80; S, 12.27; Found.% C, 55.1; H, 5.7; N, 26.7; S, 12.2. IR Spectral Features (cm^-1) shows at 3376-3274 (N-H Str.) ,2905,2852,1479,1400(Carbon-H Stra.),1686(C=N) ,3050(Ar. Carbon-H Stra.)  in addition, 741(C=S). NMR Signals (δ ppm) at 1.99-1.77 (s,3H,C-CH3), 2.37-2.39 (s,3H,C-CH3),7.20-8.25(m,4H,Ar C-H), 4.90 – 4.95(s, 2H,-CH2-),8.60(s, 1H,-NH-) and 3.75-3.72(s, 2H,-NH2). LC-MS: M/z at 261.2(M+).

Scheme 1: Reaction scheme Click here to View Figure

Table 1: Analysis of BITS Ligand and Complexes

Ligand and Metal Complex	Elemental analysis (%)
	Mol.Wt.	Color	Yield %	C%	H%	N%	S%	M%
				Cald. Found	Cald. Found	Cald. Found	Cald. Found	Cald. Found
C12H15N5S	261	Pale Yellow	72	55.15 55.1	5.79 5.7	26.80 26.7	12.27 12.2	– –
C24H30N10S2Cu2+.2H2O	622.54	yellow	70	46.32 46.3	5.51 5.5	22.51 22.5	10.31 10.2	10.21 10.2
C24H30N10S2Ni2+.2H2O	617.71	light green	68	46.69 46.6	5.55 5.5	22.69 22.6	10.39 10.3	9.51 9.5
C24H30N10S2Co2+.2H2O	617.94	red	72	46.67 46.6	5.55 5.5	22.68 22.6	10.38 10.3	9.54 9.5
C24H30N10S2Zn2+.2H2O	624.38	yellowish white	73	46.19 46.1	5.49 5.4	22.44 22.4	10.28 10.2	10.48 10.4
C24H30N10S2Mn2+.2H2O	613.94	white	70	46.97 46.9	5.58 5.5	22.82 22.8	10.45 10.4	8.95 8.9

Synthesis of Metal complex of 2-1-(5-methyl-1H-benzimidazol-1-yl)propan-2-ylidene)hydrazine carbothioamide (MBITS):

The metal chelates of  MBITS (i.e. of  Cu²⁺, Mn²⁺, Zn²⁺, Co²⁺, Ni²⁺ ions) were prepared in similar manner. The general method for it is as follow.

Add the appropriate metal ion salts (0.001 mol) in 15 ml alcohol/H2O (50:50) volume into hot 2-(1-(5-methyl-1H-benzimidazol-1-yl)propan-2-ylidene)hydrazine carbothioamide (MBITS)  ligand (0.02 mol) in 30 ml alcohol with continuous stirring than refluxed for one hr in water bath. Next day later, solid colored complexes formed, it were filtered,washed with alcohol.

Results And Discuss

2-(1-(5-methyl-1H-benzimidazol-1-yl) propan-2-ylidene) hydrazine carbothioamide (MBITS) was prepared by condensation of 5- methyl -1-(1H-Benzo [d] imidazol-1-yl) -2-propanone with thiosemicarbazide. The important IR bands of MBITS contains because of  thiosemicarbazide.

Figure 1: IR of MBITS Click here to View Figure

MBITS shows thiosemicarbazide NH at 3.75-3.72 and 8.60. The methylene proton shows singlet at 1.77-1.99 and 2.37-2.39.

Figure 2: NMR of MBITS Click here to View Figure

The presence of IR- band characteristic of metal-nitrogen and metal-Sulpher of indicate making of cyclicmetallic complexes^18,19.

Figure 3: IR of MBITS-Cu+2 Click here to View Figure

Table-I confirms the synthesised compounds and divalnt complexes^18,19. The magnetic and reflectance properties of complexes suggest octa-hedral shape^18,19(Table-2).

Table 2: Magnetic And Reflectance Properties MBITS- Metal Complexes

Metal Chelates	µeff (BM)	Electronic spectral    data(cm-1)	Transition
MBITS-Cu2+	2.35	23989 15762	CT 2B1gà 2A1g
MBITS-Ni2+	3.42	22240 15793	3A2gà 3T 1g ( P) 3A2gà 3T 1g  ( F)
MBITS-Co2+	4.50	23954 18117 8739	4T1g(F) à6 T 2g(u1) 4 T 1g (F) à4 A 2g( u2) 4 T 1g( F) à 4  T 1g ( P)
MBITS-Mn2+	5.53	23885 18344 16851	6A1gà6A1g( 4Eg) 6A1gà4 T 2g( 4G) 6A1gà4 T 1g(4G)
MBITS-Zn2+	D	–	–

D*=Diamagnetic

The antibacterial and antifungal properties of MBITS ligand and complexes shows MBITS ligand less effective than complexes, every complexes shows notable toxicity(Table-3 and 4).

Table 3: Antibacterial study of MBITS ligand and complexes

Compound	Minimum Inhibitory Concentration (MIC, μgmL-1)
	Gram +ve		Gram -ve
	B. megaterium	S.Aureus	E.Coli	Ps.Aeruginosa
MBITS	125.5	120	150	150
MBITS-Cu2+	30	25	20	22.5
MBITS-Ni2+	75	105	110	67.5
MBITS-Co2+	55	40	52.5	45
MBITS-Zn2+	35.5	42.5	93.5	100
MBITS-Mn2+	72.5	75	62	140
Amoxillin	250	150	250	200

 

Figure 4: Antibacterial study of MBITS ligand and complexes Click here to View Figure

Table 4: Antifungal study of MBITS ligand and complexes

Compound	Minimum Inhibitory Concentration (MIC, μgmL-1)
	Penicillium Expansum	Botrydepladia Thiobromine	Nigrospora Sp.	Fusarium oxyporium
MBITS	100	80.5	65.5	75
MBITS-Cu2+	22.5	20	30	22.5
MBITS-Ni2+	75.5	70	75	50
MBITS-Co2+	75	65.5	82	50.5
MBITS-Zn2+	40	25	42.5	35
MBITS-Mn2+	65	50.5	75	50
Nystatin	300	200	250	200

 

Figure 5: Antifungal study of MBITS ligand and complexes Click here to View Figure

Conclusion

5- methyl-1-(1H-Benzimidazol-1-yl) -2-propanone (MBIP) react with Thio- semicarbazone afforded novel ligand, 2-(1-(5-methyl-1H-benzimidazol-1-yl)propan-2-ylidene)hydrazine carbothioamide (MBITS). Elemental analysis, IR-NMR spectral analysis, M : L and magnetic properties of MBITS and complexes were characterized. The MBITS and complexes also were displays good antimicrobial activity.

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