J. Indian Chem. Soc., NOTE Vol. 85, November 2008, pp. 1163-1168 Halogenated 4-aryloxymethylcoumarins as potent antimicrobial agents K. Shivashankar 0 , Lokesh A. Shastri 0 , Manohar V. Kulkarni 0 *, Vijaykumar P. Rasalb and Deepak M. Saindaneb 0 Department of Chemistry, Karnatak University, Dharwad-580 003, Karnataka, India E-mail : profmvk@rediffmail.com Fax : 91-836-2747884 bDepartment of Pharmacology and Toxicology, Karnataka Liberal Education Society's College of Pharmacy, Belgaum-590 010, Karnataka, India Manuscript received 30 March 2007, revised 23 July 2008, accepted 25 August 2008 Abstract : Halogenated phenols reacted with various 4-bromomethylcoumarins to furnish the corresponding 4- aryloxymethylcoumarins. Introduction of chloro and methoxy groups in the coumarin ring elicited considerable antimi- crobial activity against B. subtilis, E. coli, A. niger and C. albicans. In the aryloxy moiety, the chloro group as a substituent were found to be more active than the corresponding bromo compounds. The growth inhibition was ob- served even at concentrations of less than 10 11g ml- 1 in some cases. Keywords : 4-Chloro/bromo phenoxymethylcoumarins, synthesis, antimicrobial. Introduction Natural products containing chloro and bromo subs- tituents have been found to exhibit insecticidal and fungi- cidal activities 1 . Poly halogenated marine natural prod- ucts have recently been reported to exhibit selective toxi- city towards cancer cells 2 . Chlorinated aromatic hydro- carbons and phenols are well known antibacterial agents3.4. The wide ranging biological properties exhibited by both naturally occurring and synthetic coumarins5-7 have prompted us to investigate various 4-aryloxy- methylcoumarins containing bio-compatible fragments like paracetamol 8 and vanillin 9 as potential antiinflammatory and antimicrobial agents. In view of this, it was contem- plated to generate various 4-aryloxymethylcoumarins with polyhalogenated groups and to study their antimicrobial properties. Results and discussion The required 4-bromomethylcoumarins 10 1 was syn- thesized by the Pechmann cyclisation of various phenols with ethyl 4-bromoacetoacetate using sulphuric acid as the condensing agent. 4-Bromo, 2,4-dichloro, 2,4,5- trichloro and 2,4,6-tribromophenols were employed as nucleophiles under standard acetone-potassium carbonate conditions. The reactions'were complete in 24 hat room temperature. The time required for the completion of the reactions was almost independent of the number of halo- gen atoms present in the phenolic moiety (Scheme 1). In the IR spectrum of compound 6-methyl-4-(2' ,4' ,6'- tribromophenoxymethyl)chromen-2-one Sa, the lactone carbonyl stretching frequency was observed at 1721 cm- 1 . In the 1 H NMR (300 MHz) (DMSO-d 6 ) spectrum of compound Sa, a singlet each at 8 2.50 (3H), 5.29 (2H) and 6.67 (lH) was observed due to C 6 -CH 3 , C 4 -CH 2 and CrH protons, respectively. The C 5 -H of coumarin ap- peared as a doublet at 8 7.63, ]meta 3.3 Hz. The CTH of coumarin was observed as a doublet of doublet at 8 7. 35, Jortho 8.4 Hz and ]meta 3.3 Hz. The C 8 -H of coumarin was observed as a doublet at 8 7.47, lonho 8.4 Hz. The protons H-3' and H-5' in the aryloxy moiety appeared as a singlet at 8 8.03 (2H). The mass spectra of the 6-methyl products 2a, 3a, 4a, 4g and Sa have shown that the molecular ion-peaks and the relative intensities observed were in agreement with the number of halogens present 11 . A brief generalized mass spectral fragmentation for ethers 2a, 3a, 4a and Sa is given in Scheme 2, which shows that the base peak is observed at mlz 145 in all the cases by the initial ho- molytic cleavage of the CHrO bond and subsequent loss of carbon monoxide. This is in accordance with the es- tablished fragmentation pattern for coumarins 12 . 1163