A rapid microwave assisted synthesis of 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3-(aryl)prop-2-en-1-ones and their anti bacterial and anti fungal evaluation

1 Introduction

Quinolines and their derivatives are very important because of their biological activity (Muscia et al., 2006) and their wide occurrence in natural products (Morimoto et al., 1991; Michael, 1997). A large variety of quinolines displayed interesting physiological activities and found to have attractive applications in pharmaceuticals, agrochemicals as well as synthetic building blocks (Markees et al., 1970; Campbell et al., 1988; Maguire et al., 1994; Roma et al., 2000; Chen et al., 2001). They are well-known structural unit in alkaloids, therapeutics and synthetic analogues with interesting biological activities such as antimalarial, antibacterial, antiasthmatic, antihypertensive, anti-inflammatory and tyrokinase PDGF-RTK inhibiting agents (Larsen et al., 1996; Roma et al., 2000; Doube et al., 1998). Among quinolines chloroquine remains a main antimalarial drug but the efficacy of it and other chemotherapeutic agents as mefloquine has been steadily lessened by the spread of resistant parasites. Thus, the development of alternative drugs is a continuing interest (Ayad et al., 2001). Hence some of the derivatives of quinolines such as quinolones have also been synthesised and they were also examined for their biological activities (Siporin et al., 1990). According to the literature information, it is apparent that quinolones are potentiating the antifungal effect. Recently, increased interest in combination therapy has also been developed (Brouillette et al., 2005; Nosanchuk, 2006). The efficacy of the newer quinolones in the treatment of nosocomial pneumonia is currently being assessed in clinical trials. Yet bacterial resistance, relapse of infections and recurrent infections remain critical issues. Complex genitourinary tract infections continue to be a niche for this antibiotic class, these invites the exploration of newer quinoline derivatives. We have reported (Sarveswari and Raja, 2006) the microwave assisted synthesis of some quinolone compounds. There are a few reports on synthesis and biological studies of quinolinyl chalcones compared to quinolones. In view of the above literature survey, herein we report the synthesis, anti fungal and antibacterial activities of newer quinolinyl chalcones.

2 Experimental

All the melting points reported were recorded in open capillaries and uncorrected.

IR spectra of all the compounds were recorded on AVATAR330 FT-IR Spectrometer. ¹H NMR spectra were recorded on Bruker AMX 300. The microwave assisted reactions were carried out in synthetic microwave: CATA R with maximum power of 700 W. The Mass spectra recorded on JEOL GC mate spectrometer. Chemicals for microbial tests like agar and broths were procured from Hi-Media Laboratories Ltd., Mumbai. Chemicals for the synthesis were from Sigma Aldrich Co, St Louis, USA, and SD fine chemicals Pvt. Ltd., Boisar, India. Bacterial and Fungal culture from National Collection of Industrial Microorganisms (NCIM), National Chemical Laboratory Pune 411 008, Maharashtra, India.

2.1

2.1 General procedure for the synthesis of 1-(6-Chloro-2-methyl-4-phenyl quinolin-3-yl)-(aryl) prop-2-en-1-ones (3a–h)

2.1.1

2.1.1 Method I (stirring at room temperature)

A mixture of compound 1 and arylaldehyde in 1:1 molar ratio was added into a 2% solution of KOH in distilled ethanol and stirred at room temperature for 12 h in a round bottom flask. Then the reaction mixture was concentrated and neutralized with acetic acid. The resultant solid was filtered, washed with hot water, dried and purified by 7:1 mixture of petroleum ether–ethyl acetate. Compound 1 was synthesized using literature method (Wang et al., 2006).

2.1.2

2.1.2 Method II (microwave assisted synthesis)

A mixture of compound 1 and pyridine-2-aldehyde in equimolar ratio was added into a 2% solution of KOH in distilled ethanol taken in a beaker and irradiated with microwave at 240 W for 5 min. The reaction mixture was cooled and poured onto ice and acidified with acetic acid. The resultant solid was filtered, washed with sodium bicarbonate and water, dried and purified by column using petroleum ether–ethyl acetate (7:1). The procedure was extended to other arylaldehydes (2b–h) to get the corresponding chalcones (3b–h) and thereby to prove the generality of the reaction. The irradiation time, power levels and the yield of the products are given in Table 1. All the compounds were characterized by IR, ¹H NMR and Mass spectral data. The data are given in results and discussion. The compounds are screened for their anti-microbial activities.

Table 1 Physical data of compounds 3a–h.

S. No	Ar	Mp (°C)	Yield (%)
			MWa (time in min)	Conventional method
3a		220–223	61(5)	68
3b		240–242	78(5)	75
3c		230–233	56(5)	60
3d		210–212	90(5)	87
3e		220–224	84(6)	85
3f		231–232	78(4)	79
3g		215–217	83(5)	80
3h		228–230	83(5)	76

a Power level at 240 W.

3 Results and discussion

3-Acetyl-6-chloro-2-methyl-4-phenyl quinoline (1) has been synthesized using the method (Wang et al., 2006) available in literature which in turn converted into corresponding chalcones (3a–h) (see Scheme 1) by treating it with various aryl aldehydes in the presence of base in ethanol under the micro wave irradiation at 240 W for 4–6 min, whereas conventional method requires 12 h of stirring. Completion of the reaction was monitored by TLC, then the reaction mixture neutralized with acetic acid, filtered and dried. The obtained crude product was purified through column chromatography using petroleum ether–ethyl acetate (7:1).

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Scheme 1

Synthesis of 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3-(aryl)prop-2-en-1-ones.

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The purified compounds 3a–h were characterized through IR, ¹H NMR and mass spectral studies. The stretching frequencies at 1656 cm⁻¹ (due to α,β-unsaturated carbonyl) and 1565 cm⁻¹ (due to conjugated olefinic C⚌C) in IR confirmed the formation of expected products. The observed signal at δ 2.70 (s, 3H, CH₃) ppm integrating for three protons in ¹H NMR spectrum of 3a is due to the methyl group at C-2. The signals at δ 8.45 (d, 1H, 8 Hz), δ 7.70 (d, 1H, 8.5 Hz), δ 7.50 (s, 1H) ppm are due to protons at C-7, C-6 and C-5 of quinoline ring. The protons of phenyl at C-4 observed as a multiplet in the range of δ 7.10–7.20 ppm. The protons of pyridine nucleus appear as a multiplet between δ 7.30–7.45 ppm. The characteristic peaks at δ 8.05 (d, 1H, 15.7 Hz) and δ 7.65 (d, 1H, 15.7 Hz) ppm represents cinnamoyl protons which are trans to each other. The molecular ion peak at 384.3878 in ES-MS also confirmed the product 3a. Similarly the other compounds 3b–h also characterized (spectral data are given in Section 3). The synthesized compounds 3a–h were screened for their anti bacterial, anti-fungal activities through well diffusion method using streptomycin and cephalosporin as respective standard. All the synthesized compounds were found to have moderate anti bacterial activity in comparison with standard streptomycin (Figs. 1–4). The results revealed that the compound 3b, 3f were showed good activity against Escherichia coli (E. coli). Compounds 3e and 3c were active against Bacillus subtilis (B. subtilis) 3a, 3e, 3g and 3b, 3d, 3f and 3h were found to be active against Salmonella typhi (S. typhi) and Staphylococcus aureus (S. aureus), respectively. In anti fungal screening, compounds 3a, 3d–f were found to be active against Aspergillus flavus (A. flavus), among these 3a has equivalent activity as the standard cephalosporin. 3d, 3e and 3g were active against Aspergillus fumigatus (A. fumigatus). The compounds 3b, 3e and 3f were found to be active against candida utilis (C. utilis) among these 3e is very effective (Figs. 5–7) further studies are required on active derivatives.

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Figure 1

Zone of inhibition by compounds (3a–h) on B. subtilis.

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Figure 2

Zone of inhibition by compounds (3a–h) on S. typhi.

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Figure 3

Zone of inhibition by compounds (3a–h) on S. aureus.

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Figure 4

Zone of inhibition by compounds (3a–h) on E. coli.

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Figure 5

Zone of inhibition by compounds (3a–h) on A. flavus.

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Figure 6

Zone of inhibition by compounds (3a–h) on A. fumigatus.

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Figure 7

Zone of inhibition by compounds (3a–h) on C. utilis.

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4 Conclusion

1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)-3-(aryl) prop-2-en-1-ones were synthesised by microwave assisted method as well as conventional method. When the reaction durations were compared among microwave assisted synthesis (4–6 min) and the conventional method (12 h), former method requires much lesser duration with almost equal yield as in the conventional method. Hence the microwave assisted synthesis can be regarded as an efficient method for the synthesis of these compounds. All the synthesized compounds have been screened for their anti microbial activities and are found to be moderately active in comparison with standards. 3e has shown good activity against B. subtilis. Compounds3e and 3h found to be effective against S. typhi. Similarly 3b, 3h acting against S. aerues. In anti fungal screening, compounds 3a, 3d, 3e and 3f were found to be active against A. flavus, among these 3a has equivalent activity as the standard cephalosporin. The compounds 3b, 3e and 3f were found to be active against C. utilis among these 3e is very effective. Further studies are required on active derivatives.