Microwave assisted synthesis and biological activity of 3-aryl-furo[3,2-c]coumarins

2.1 Method A

A solution of appropriate 4-hydroxy coumarin 1a–d (0.002 mol) and 2-aryl-1-nitro-ethenes 2a–c (0.002 mol) in methanol (5 ml) containing piperidine in catalytic amount was stirred at room temperature for 10 min and then irradiated for 5–7 min in microwave at 240 W (40%) power. The residue was treated with water (50 ml) and then extracted with chloroform (3 × 25 ml). The chloroform extract was washed with 50% HCl (25 ml), water and dried over anhydrous sodium sulphate. The removal of chloroform under vacuum resulted in gummy residue, which was subjected to column chromatography using silica gel and hexane–ethyl acetate (9:1) as an eluent to afford the compounds 4a–l. The compounds thus obtained were recrystallized from chloroform–hexane.

2.2 Method B

To a solution of appropriate 4-hydroxy coumarin 1a–d (0.002 mol) and aroylmethyl bromide 3a–c (0.002 mol) in acetic acid (4 ml) ammonium acetate (0.01 mol) was added at room temperature. The reaction mixture was stirred at room temperature for 10 min and then irradiated for 2–3 min in microwave at 240 W (40%) power. The residue was treated with water (50 ml) and then extracted with chloroform (3 × 25 ml). The chloroform extract was washed with 5% NaHCO₃, water and dried over anhydrous sodium sulphate. The removal of chloroform under vacuum resulted in gummy residue, which was subjected to column chromatography using silica gel and hexane–ethyl acetate (9:1) as an eluent to afford the compounds 4a–l. The compounds thus obtained were recrystallized from chloroform–hexane Table 1.

3.1 Analytical results

A series of 3-aryl-furo[3,2-c]coumarins 4a–l has been synthesized using two methodologies as exemplified in scheme 1. The structures of all the newly synthesized compounds were confirmed by elemental analysis and FT-IR, ¹H NMR, ¹³C NMR, DEPT-90 spectral analysis. Mass spectrum for one representative compound 4a was also recorded.

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Scheme 1

Synthetic scheme for 3-aryl-furo[3,2-c]coumarins 4a–l. (a) Piperidine, Methanol, mw (b) NH₄OAc, AcOH, mw.

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The IR spectra of compounds 4a–l exhibited a strong δ-lactone carbonyl (C⚌O) stretching band between 1725 and 1751 cm⁻¹. C⚌C and C–H aromatic stretching band was observed between 1590 and 1640 and 3035 and 3120 cm⁻¹, respectively. The C–O–C stretching of furan moiety was observed between 1100 and 1125 cm⁻¹. The ¹H NMR spectrum of compounds 4a–l showed a multiplet between 6.99 and 7.59 δ for aromatic protons. The C₂–H of the furan ring appeared as a singlet at 7.77 δ. The C₂′–H and C₆′–H were observed in downfield region due to close proximity of the carbonyl group. The C₉–H appeared in the most downfield region due to peri effect of furan ring oxygen. Compounds 4a, 4e, and 4i showed C₉′–H signal as a doublet of doublet around 7.94 δ (J = 8 and 1.2 Hz) while compounds 4d, 4h, and 4l showed C₉–H signal as a doublet around 7.91 δ (J = 2.4 Hz). The ¹³C NMR spectrum is in good agreement with the structure assigned. The carbonyl carbon of δ-lactone ring of coumarin appeared as the most deshielded signal around 158.5 δ. The signals appearing between 108 and 157 δ attributed to aromatic carbons. The DEPT 90 spectra gave the expected non equivalent tertiary carbon signals. The mass spectrum of selected compound 4a showed M⁺ peak at m/z 262 (100%) which is also the base peak. The appearance of a molecular ion peak at 262 mass unit supports the structure of compound 4a. The peaks corresponding to the fragments [M-CO]⁺, [M-2(CO)]⁺, [M-2(CO)-H]⁺ and [M-3(CO)]⁺ were observed at m/z 234 (5%), 206 (30%), 205 (12%) and 176 (35%), respectively. The other fragments [C₇H₄]⁺, [C₆H₅]⁺ and [C₄H₃]⁺ showed peaks at 88 (27%), 77 (8%) and 51 (10%), respectively.

3.2 Antimicrobial activity

All the synthesized compounds 3a–l were screened for their antimicrobial activities using Streptomycin and Cotrimazole as standard drugs. Compounds 3a–l were screened against Escherichia coli (MTCC 443) (Gram-negative bacteria) and Bacillus subtilis (MTCC 441) (Gram-positive bacteria) and antifungal activity against Candida albican (MTCC 227) (Fungi). The evaluation of antimicrobial activity was carried out using the agar cup diffusion method. The results are summarized in Table 2.

The antimicrobial activity data revealed that almost all the compounds 4a–l exhibited promising antibacterial activity against gram negative bacteria E. coli compared to streptomycin. Compound 4h showed the highest antibacterial effectiveness against gram negative bacteria E. coli. Compounds 4b, 4c, 4e–g, 4i, 4j and 4l were found to exhibit better activity compared to streptomycin against E. coli. Compounds 4a, 4d and 4k showed comparable activity to streptomycin against gram negative bacterial strain. None of the compounds showed better activity against gram positive bacterial strain Bacillus subtilis and fungi Candida albicans.

A close look at the SAR (structure activity relationship) of these compounds clearly bares the inherent antimicrobial activity associated with the basic skeleton consisting of furo fused coumarin and the phenyl ring as seen in the case of the unsubstituted compound 4a with zone of inhibition similar to that of standard streptomycin, which in some cases was enhanced by the influence of some substituents and decreased by some other substituents. Compounds 4a–d having unsubstituted phenyl ring do not affect the antimicrobial activity to a larger extent. An increase in antibacterial activity was observed when the phenyl ring was substituted at para positions by the electron releasing group such as CH₃ and OCH₃ as seen in the case of 4e and 4i. Introduction of another electron releasing group does not affect the activity as seen in the case of compounds 4f, 4g, 4j and 4k. Among the compounds 4a–l, the compounds 4h and 4l (R = Cl) showed excellent antibacterial activity against gram negative bacteria E. coli. None of the compounds showed promising activity against Bacillus subtilis and Candida albicans.