New Bioactive Ferrocene Incorporated N,N′- Disubstituted Ureas and Thioureas

Abstract

In the present work, the synthesis, characterization (FT-IR, multinuclear ( 1 H and 13 C) NMR, AAS, elemental analysis and single-crystal XRD), DNA binding (cyclic voltammetry, UV-Vis spectroscopy and viscometry) and in vitro biological screening of some ferrocene-based thioureas and ureas are reported. The ferrocene-incorporated N,N′- disubstituted thioureas 3a1-3d17 were derived by allowing the ferrocenyl anilines 2(a-d) to react with freshly prepared isothiocyanates in dry acetone. In the subsequent reactions, the deprotection of these thioureas 3a1-3d17 to the corresponding oxo analogues using NaOH (aq) and mercuric chloride led to the ferrocenyl ureas 4a1-4d17 in high yields. Crystallographic analyses of representative compounds revealed a supramolecular structure mediated by secondary non-covalent interactions (π---H and π---π), which facilitated the interaction of these molecules with biological macro-molecules like DNA. DNA binding is a pre-requisite for a compound to be used as an antitumor agent. The DNA binding studies performed by cyclic voltammetry and UV-Vis spectroscopy produced results that are in close agreement with one another for the binding constants (K) and an electrostatic mode of interaction was observed. The diffusion coefficients of the drug-DNA adducts are lower than is that for the free drug indicating slow diffusion of the comparatively high molecular weight drug towards the electrode in the cyclic voltammetric study. The small binding site size (s) values are also indicative of an electrostatic mode of interaction. The nature and the extent of interaction with DNA was further investigated by viscometry. The DFT/B3LYP method was used to determine the charge distribution and HOMO/LUMO energies of the optimized structure. The DFT calculated HOMO and LUMO energies correlate well with the experimentally determined redox potential values. The synthesized ferrocenyl derivatives exhibited good free radical scavenging activity against DPPH. These compounds were also screened for antimicrobial, cytotoxic (brine shrimps) and protein kinase inhibition potential and proved to be effective candidates in terms of microbial growth and protein kinase inhibition. The synthesized complexes were scanned for their in vitro cytotoxicity against human carcinoma cell line THP-1 (leukemia cells). The results showed a moderate level of XIcytotoxicity against the subjected cancer cell line as compared with the standard chemotherapeutic drug (cisplatin). The presence of electron-withdrawing substituents was found to exert profound influence on the therapeutic properties of these compounds, which might be attributable to the decrease in the basicity of the NH groups and an increase in their lipophilicity. These properties may prove valuable in the future design of new anticancer and antimicrobial drugs.