Synthesis and Reactions of Some New Diiodocoumarin Derivatives Bearing Side Chains and Some of Their Biological Activities

The synthesis of 6,8-diiodocoumarin derivatives (2-6) by condensation of 3,5-diiodosalicylaldehyde (1) with active methylene compounds is described. Reaction of 6 with malononitrile afforded two products pyridine and ethylidine malononitrile derivatives (7, 8), while treatment of 6 with p-methoxybenzylidenemalononitrile in absolute ethanol/piperdine provided pyrane and bis coumarin derivatives (9,10). Reaction of 6 with DMF/POCl3 afforded three products coumarin derivatives (11,12,13), while bromination of 6 with Br2/AcOH gave 3-bromo-6,8-diiodocoumarin (14). Treatment 6 with aromatic aldehydes gave the corresponding 3-(3-arylacryloyl)-6,8-diiodocoumarin derivatives (16a,b) while reaction of 6 with aniline or phenylhydrazine gave coumarin derivatives 17 and 18. Reaction of 18 with DMF/POCl3 gave pyrazole-4-aldehyde derivative (19). Condensation of 19 with active methylene compounds afforded pyrazole and pyrimidine derivatives (20a-c) and 21). Reaction of 8 with sulphur via the Gewald reaction afforded thiophene derivative (22), while the reaction of 8 with p-methoxybenzylidenemalononitrile gave biphenyl derivative (23). Treatment of 8 with chloroacetyl chloride afforded the furan derivative (24). The structures of the newly synthesized compounds were confirmed by IR, 1 H NMR and 13 C NMR and mass spectral data. The newly synthesized compounds were also screened for their antimicrobial activity.


Introduction
Coumarins and its derivatives have been used as additives in food, perfumes, cosmetics, pharmaceuticals, platelet aggregation, agrochemicals [1,2]. Coumarins have also been reported to exhibit several biological activities such as antimicrobial and anticancer, antifungal, anti-HIV, and anti-clotting [3][4][5][6], but also served as versatile precursors of many organic transformations in the synthesis of a number of drug-like molecules [7,8]. Moreover, coumarin-based dyes and pigments are organic fluorescent materials exhibiting unique photochemical and photophysical properties, which render them useful in a variety of applications such as dye lasers, anion sensors, organic light emitting diodes, and solar cells [9,10].
The structures of all the newly synthesized compounds were confirmed by IR, 1 H NMR, 13 C NMR and mass spectroscopy.

Antibacterial Activities
Preliminary antimicrobial screening is illustrated in Table  1. It was found that compounds 19-24 possess a pronounced antimicrobial activity against all tested microorganisms. Markedly stronger antimicrobial activity was observed against both Gram-positive and Gram-negative bacteria compared to ampicillin. Compounds 2-18 showed moderate inhibition of antimicrobial activity against both Gram-positive and Gram-negative bacteria relative to ampicillin.
Compounds 5-8 and 14-16 showed moderate inhibition towards Aspergillus fumigatus and Candida albicans relative to Claforan. Compounds 2-4 and 9-13 exhibited inactive inhibition compared to Claforan towards Aspergillus fumigatus and Candida albicans. Inhibition zone diameter shows a dependence on their chemical structure (Table 1).

Conclusions
The results from this screening demonstrated that replacing hydrogen atom attached to coumarin nucleus at C-3 with heterocyclic five membered ring the compounds 19-24 results in wide spectrum antibacterial activity against all tested Gram positive and Gram negative compared to heterocyclic six membered ring the compound 9 and the carbonocyclic ring the compound 23. Compounds possessing aliphatic side chains exhibit less antibacterial activity against all tested Gram positive and Gram negative bacteria.

Experimental
General Melting points were determined on a Stuart melting point apparatus and are uncorrected. IR spectra were recorded in KBr using a FT-IR 5300 spectrometer and Perkin Elmer spectrum RXIFT-IR system (ν, cm -1 ). The 1 H NMR at (300 MHz) and 13 C NMR spectra (75MHz) were recorded in CDCl 3 & DMSO-d 6 on a Varian Mercury VX-300 NMR spectrometer. Chemical shifts (δ) are related to that of the solvent. Mass spectra were measured on a Shimadzu GMMS-QP-1000 EX mass spectrometer at 70eV. The elemental analyses were performed at the micro analytical center, Cairo University.