Synthesis and Biological Evaluation of Novel Imidazolinone Derivatives

 

B. C. Revanasiddappa*, M. Vijay Kumar, Prashanth Nayak,  Ajmal Roshan Ali, Jasmine Kalsi

Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences of Nitte University, Paneer, Deralakatte, Mangalore-575 018 Karnataka, India

 

ABSTRACT:

A new series of Oxazolones (2a-j) were prepared by reacting substituted aromatic aldehydes with N-acetylglycine in presence of anhydrous sodium acetate and acetic anhydride as the solvent medium. The respective Oxazolones (2a-j) were then treated with 4-Amino-1,2,4-triazole (1) in glacial acetic acid medium to yield the title compounds Imidazolinones (3a-j). All the newly synthesized compounds were evaluated for their In –Vitro antibacterial and antifungal activities. The new compounds were assigned on the basis of ¹H-NMR, IR, Mass spectral data and elemental analysis.

 

 

 

 

 

INTRODUCTION:

In heterocyclic chemistry, the five membered compounds are known to be an important class of compounds because of their wide variety of pharmacological and biological activities. Nitrogen containing heterocycles play an important role, not only for life science industry but also in many other industrial fields related to synthetic chemistry. In the present work, we have planned to synthesize, Imidazolinones, a five membered heterocyclic compound, and a derivative derived from Imidazole. It belongs to five membered Nitrogen heterocycles.

 

Imidazole is a planer five-membered heterocyclic ring system with three carbon and two nitrogen atoms in 1 and 3 positions. Imidazolones are keto dihydro imidazoles. Imidazolone that is known as oxoimidazoline is a five- membered heterocyclic ring system having nitrogen atoms in 1 and 3 positions and carbonyl group in 5 positions.

 

During the past decade a large number of Imidazole/Imidazolines have been found to be associated with various therapeutic activities. Naphazoline hydrochloride, Xylometazoline hydrochloride etc. are various Imidazolinone derivatives which have been used as adrenergic stimulants and Tolazoline, Phenotolamine are used as adrenergic blocking agents, Cimetidine as antiulcer, Dacarbazine as anticancer agents. Recently some new Imidazolinone derivatives have been reported as antimicrobial¹, MAO inhibitors², CNS depressants³, analgesic⁴, antiparkinsonian⁵, antihelmintics⁶,  anticonvusalnt⁷  and  enzyme inhibitory agents⁸.

 

Prompted by these observations and in continuation of our research on the synthesis of biologically active nitrogen heterocycles^9-11, we herein report the synthesis of antibacterial and antifungal activity of novel series of Imidazolinone derivatives.

 

MATERIALS  AND METHODS:

The homogeneity of the compounds was checked by TLC using silica gel plates (Merck) using ethyl acetate: methanol as mobile phase. Melting points were determined by open capillary method and are uncorrected. The IR spectra are recorded by using Alpha Bruker IR Spectrometer using a thin film on KBr pellet technique and frequencies are expressed in cm^-1. The ¹H-NMR spectra were recorded on Bruker Avance II 400 MHz NMR Spectrometer. All the spectra were obtained in CDCl₃ and DMSO. Chemical shift values are reported as values in ppm relative to TMS (δ=0) as internal standard. Mass spectra were recorded on ESI. Elemental analysis was carried out on Vario-El elemental-III model analyzer.

 

All the chemicals such as aromatic aldehydes, N-acetyl glycine, 4-amino-1,2,4-triazole were procured from Himedia labs, Mumbai and were used without further purification. The key intermediates Oxazolones (2a-j) were prepared as per the reported procedure¹³.

General procedure for the synthesis of substituted Imidazolinones (3a-j)

A solution of Oxazolones (2a-j) (0.01 mol) and 4-Amino-1,2,4-triazole (1) (0.01 mol) in glacial acetic acid (25 ml) was refluxed for about 21-26 hr. Excess of solvent was removed under reduced pressure and the reaction mixture was poured  into ice cold water. The precipitated compound is filtered, washed with water and recrystallized from ethanol. The physical data of compounds (3a-j) is given in table-1.

 

 

Table-1: Physical data of Imidazolinones (3a-j)

 

 

 

(Z)-4-benzylidene-2-methyl-1-(4H-1,2,4-triazol-4-yl)-1H-imidazol-5(4H)-one 3a

Yield: 62%,

M.P.:90-92^OC, 

IR (V_max, KBr): 1449(C=C), 1643(C=N), 1711(C=O), 3060(C-H),

¹H-NMR (CDCl_3, 400 MHz, δ): 2.19 (s, CH_3, 3H), 7.10-7.73 (m, Ar-H, 2H of 1,2,4-triazole, 7H),12.06(s, C=CH, 1H), 

MS(m/z): 253(M⁺)

 

(Z)-4-(4-fluorobenzylidene)-2-methyl-1-(4H-1,2,4-triazol-4-yl)-1H-imidazol-5(4H)-one 3b

Yield: 63%,

M.P.: 135-137^OC,

IR(V_max,KBr):837(C-F), 1509(C=C), 1599(C=N), 1721(C=O),  3073(C-H),

¹H-NMR (CDCl_3, 400 MHz, δ): 2.18 (s, CH_{3 ,}3H) ,7.17-7.75 (m, Ar-H, 2H of 1,2,4-triazole, 6H),12.10(s, C=CH, 1H), 

MS(m/z): 271(M⁺)

 

(Z)-2-methyl-4-(4-nitrobenzylidene)-1-(4H-1,2,4-triazol-4-yl)-1H-imidazol-5(4H)-one 3c

Yield: 65%,

M.P.:80-82^OC, IR(V_max,KBr):1513,1345(NO₂),1600(C=N),1710(C=O), 2932(C-H),

¹H-NMR (CDCl_3, 400 MHz, δ):2.18 (s, CH_3, 3H), 7.17-7.74 (m, Ar-H, 2H of 1,2,4-triazole, 6H) ,12.07(s, C=CH, 1H).

 

 

 

(Z)-4-(2-chlorobenzylidene)-2-methyl-1-(4H-1,2,4-triazol-4-yl)-1H-imidazol-5(4H)-one 3d

Yield: 67%,

M.P.:120-1222^OC,

IR(V_max,KBr): 753(C-Cl), 1519(C=C), 1641(C=O), 3062(C-H);

¹H-NMR (CDCl_3, 400 MHz, δ):2.21 (s, CH_3, 3H), 7.11-7.83 (m, Ar-H, C=CH, 2H of 1,2,4-triazole, 7H).

 

Antibacterial activity

The compounds (3a-j) were screened for their antibacterial potential against four pathogenic organisms viz. S.aureus, P.aeruginosa, E.coli and B.subtilis by Cup-Plate method¹² at 100 µgm/ml. Ciprofloxacin was used as standard. All the tested compounds showed weak to moderate activity against all the four pathogenic micro-organisms. None of the compounds showed significant activity when compared to the standard drug Ciprofloxacin. The antimicrobial data of the compounds (3a-j) is given in table-2.

 

Antifungal activity

The compounds (3a-j) were screened for their antifungal activity against A.flavus and A.fumigatus. The technique used was Cup-Plate method¹² at 100 µgm/ml.. Flucanazole was used as standard. The tested compounds showed moderate activity against A.fumigatus and compounds with electron withdrawing groups like NO₂, Cl showed good activity upon comparison with standard Flucanazole. All the tested compounds showed very weak activity against A.flavus. The antifungal data of the compounds (3a-j) is given in table-2.

 

 

 

Table 2: Antimicrobial activity of Compounds (3a-j)

Comp.	Diameter of zone of inhibition (mm)
	S.aureus	B.subtilis	E.coli	P.aeruginosa	A.flavus	A.fumigatus
3a	08	12	13	08	12	08
3b	07	12	12	07	08	08
3c	08	08	08	08	12	21
3d	13	12	12	13	07	21
3e	12	08	08	12	13	21
3f	11	11	11	09	12	13
3g	10	10	10	10	10	12
3h	11	11	10	11	10	09
3i	12	10	11	12	11	11
3j	10	12	12	10	11	10
Ciprofloxacin	24	24	24	23	-	-
Fluconazole	-	-	-	-	24	24

 

 

 

 

 

 

 

 

 

 

 

 

 

RESULTS AND DISCUSSION:

Oxazolones  (2a-j)were prepared based on the special type of Perkin condensation reaction, in which the reaction between substituted aromatic aldehydes with N-acetylglycine proceeds first, followed by ring closer reaction. It is observed that aldehyde condenses under the influence of  a base with active methylene group in the azalactone, which is formed by the dehydration of N-acetylglycine, when the later reacts with Ac₂O in presence of sodium acetate.

 

The title compounds substituted Imidazolinones (3a-j) were prepared by reacting Oxazolones (2a-j) and 4-Amino-1,2,4-triazole (1) in glacial acetic acid medium. The target compounds were prepared by the method outlined in Scheme-01. All the new compounds were characterized by spectral data and also evaluated for biological evaluation. The structures of the novel compounds were elucidated by spectral methods.

In compound 3a, the CH stretching was observed at 3060. The Imidazolinone C=O and C=N stretching was observed at 1710 and 1643 respectively. The ¹H-NMR of this compound 3a showed the methyl protons resonated as singlet at 2.19 integrating for three protons. The signals due to aromatic protons resonated as multiplets in the region 7.10-7.30 integrating for seven protons of Imidazolinone and triazole. The C=CH proton came into resonance as a singlet at 12.06 Further evidence for the proposed structure was obtained by recording mass spectra of the synthesized compounds. The mass spectrum of the compound 3a showed the M+ peak at 253 which is consistence with its molecular formula.

 

CONCLUSION:

A novel series of imidazolinones were synthesized and evaluated for antibacterial and antifungal activities. All the new compounds were assigned on the basis of spectral data. Some of the tested compounds showed weak antibacterial activity and good antifungal activity.

 

ACKNOWLEDGEMENTS:

Authors are thankful to the authorities of NGSM Institute of Pharmaceutical Sciences, Nitte University, Mangalore for providing all the necessary facilities. The authors are thankful to SAIF, Punjab University, Chandigarh and Oxygen Health Care Research Pvt. Ltd, Ahmadabad for providing spectral data.

 

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