SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL STUDIES OF NEW FERROCENE BASED GUANIDINES

Abstract

Four series of trisubstituted ferrocenyl guanidines g(1-18), h (1-18), i (1-6) & j (1-6) of general formula [RC6H5CONC(HN'C6H4C5H4FeC5H5)(HN''C6H5R1)] where R=3-Cl and R1= H, 3- CF3, 4-CF3, 4-NO2, 4-CH3, 2-CH3, 2,6-C2H5, 2-OCH3, 3-OCH3, 2-Cl, 2,3- (Cl)2, 2,4- (Cl)2, 2,5- (Cl)2, 2,6- (Cl)2, 3,4- (Cl)2, 3,5- (Cl)2, 2,4,5- (Cl)3, 2,4- (Br)2 have been synthesized and characterized by using elemental analysis, FT-IR, multinuclear (1H and C) NMR spectroscopy, UV-Visible spectrophotometery and cyclic voltammeter. Single crystal XRD was used for structural elucidation of some of the synthesized ferrocenyl guanidines. Based on the single crystal X-ray analysis most of the synthesized ferrocenyl guanidine have been stabilized by intermolecular as well as intramolecular hydrogen bonding and possesses interesting supramolecular chemistry having cylindrical cavities and empty spaces. In addition, a tetra substituted ferrocenyl guanidine (N-isopropyl-N-(4-ferrocenylphenyl)-N'-(2, 6-diethylphenyl)-N''-benzoyl guanidine) has also been synthesized and fully characterized. The preliminary investigation of the anticancer potency of the synthesized ferrocenyl guanidines has been carried out by determining their ability to bind with DNA and by the free radical scavenging activity. The DNA interaction studies performed by cyclic voltammetry and UV-Visible spectroscopy are in close agreement with the binding constants K (0.79 - 5.4) ×105 M-1 (CV) and (0.72 - 5.1) ×105 M-1 (UV-Visible). The results reveal that the ferrocenyl guanidines have strong binding ability with DNA as compared to the guanidines having no ferrocene. The presence of ferrocene is concluded to enhance the DNA binding activity of guanidines. This may be due to the fact that in the presence of ferrocene the delocalization of lone pair of nitrogen extended to Cp ring of ferrocene due to which the nitrogen become more polarized, stable and favorable for electrostatically bind with negatively charged DNA. The binding constants results show that the compounds having ferrocene at para position have slightly larger binding constants values as compared to the meta-ferrocenyl guanidines. This may be due to more delocalization of electron when the Cp ring of ferrocene is at para position. The compounds having electron withdrawing groups on the phenyl ring also have higher binding constant values as compared to those compounds having electron donating groups. This may also be due to the delocalization of lone pair of nitrogen on phenyl ring and making the nitrogen more polar. The free radical scavenging potentials of the selected synthesizes compounds was determined on a UV-Visible spectrophotometer by using DPPH as a free radical. The activity of ferrocene incorporated guanidines was found to be higher than guanidines without ferrocene. The compounds which have electron withdrawing groups showed an increase in the free radical scavenging potency. This might be due to the stabilization of resulting guanidine free radical in the presence of electronegative groups. Antimicrobial activities of the selective synthesized compounds were tested against five representatives, gram-positive (Staphylococcus aureus, Pseudomonas aerugnosa and Bacillus subtilis) and gram-negative (Klebsiella pneumonia and Escherchia coli) bacterial strains by disc diffusion method. Three fungal strains, fusarium moniliforme, aspergillus fumigates, aspergillus flavus were tested by using well diffusion method. The results revealed that the compounds having ferrocene and electron withdrawing groups showed moderate to good antibacterial activity as compared to the standard drug penicillin used. Significant antifungal activity was observed against aspergillus flavus and good against fusarium moniliforme and aspergillus fumigatus. The antifungal activity of these compounds was found comparable with the standard drug used (Terbinafin). Other compounds having electron donating groups were found to have a moderate or less activity against the tested bacteria and fungi. Exact mechanism of the structure-activity relationship was not yet developed but this might be due to a decrease in basicity, in turn an increase in the lipophilicity of the compounds in the presence of ferrocene and electron withdrawing substituents. Lipophilic compounds have more penetrating power across the cell membrane.