Synthesis and biological activity of novel Schiff bases derived from metronidazole

A number of novel Schiff bases (5a-i) and (7a-d) derived from metronidazole were synthesized. Reaction of 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester toluene-4-sulfonate with 4-hydroxybenzaldehyde and with 3-hydroxybenzaldehyde in the presence of a base afforded 4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)benzaldehyde (5) and 3-(2-(2-methyl-5-nitro-1H -imidazol-1-yl)ethoxy) benzaldehyde (7), respectively. The reaction of aldehydes 5 and 7 with a number of primary aromatic amines produced Schiff bases 5a-i and 7a-d, respectively. Structures of these compounds were confirmed through different spectroscopic methods such as ¹H-NMR, ¹³C-NMR, mass spectrometry, and also by elemental analyses. The prepared compounds were evaluated in vitro for their antigiardial, anti-trichomonal, antibacterial, and antifungal activities. Compounds 5e, 5g, 5i, 7a, 7b, 7c, and 7d exhibited remarkable antigiardial activity and were found to be more active than metronidazole with IC₅₀ of 7.2, 3.3, 1.5, 5.8, 4.5, 2.9, and 3.8 μg/mL, respectively. Compounds 5a and 5c also exhibited antigiradial activity with similar IC₅₀ values compared to the reference drug metronidazole with IC₅₀ of 7.2 μg/mL. The other compounds 5b, 5d, 5f, and 5 h also showed antigiardial activity but with higher IC₅₀ compared to the reference drug. Compounds were also tested for their anti-trichomonal activity, they, however, exhibited higher IC₅₀ compared to the reference drug metronidazole (7.4 μg/mL), except for compound 5a which exhibited anti-trichomonal activity with an IC₅₀ of 6.3 μg/mL. On the bases of preliminary screening, the newly synthesized compounds exhibited moderate to potent antimicrobial activities. Compound 5e inhibited the growth of Methicillin resistant Staphylococcus aureus (MRSA) and Bacillus cereus and compound 5c inhibited Candida Pathogenic fungus at 50 μg/mL compared with the positive control (Nystatin) which inhibits Candida at 25 μg/mL.