New tailored substituted benzothiazole Schiff base Cu(II)/Zn(II) antitumor drug entities: effect of substituents on DNA binding profile, antimicrobial and cytotoxic activity

Abstract

New tailored Cu(II) & Zn(II) metal-based antitumor drug entities were synthesized from substituted benzothiazole o‒vanillin Schiff base ligands. The complexes were thoroughly characterized by elemental analysis, spectroscopic studies {IR, ¹H & ¹³C NMR, ESI−MS, EPR} and magnetic susceptibility measurements. The structure activity relationship (SAR) studies of benzothiazole Cu(II) & Zn(II) complexes having molecular formulas [C₃₀H₂₂CuN₅O₇S₂], [C₃₀H₂₀Cl₂CuN₅O₇S₂], [C₃₀H₂₀CuF₂N₅O₇S₂], [C₃₀H₂₂N₄O₄S₂Zn], [C₃₀H₂₀Cl₂N₄O₄S₂Zn], and [C₃₀H₂₀F₂N₅O₇S₂Zn], with CT‒DNA were performed by employing absorption, emission titrations, and hydrodynamic measurements. The DNA binding affinity was quantified by K _b and K _sv values which gave higher binding propensity for chloro-substituted Cu(II) [C₃₀H₂₀Cl₂CuN₅O₇S₂] complex, suggestive of groove binding mode with subtle partial intercalation. Molecular properties and drug likeness profile were assessed for the ligands and all the Lipinski’s rules were found to be obeyed. The antimicrobial potential of ligands and their Cu(II) & Zn(II) complexes were screened against some notably important pathogens viz., E. coli, S. aureus, P. aeruginosa, B. subtilis, and C. albicans. The cytotoxicity of the complexes [C₃₀H₂₀Cl₂CuN₅O₇S₂], [C₃₀H₂₀CuF₂N₅O₇S₂], [C₃₀H₂₀Cl₂N₄O₄S₂Zn], and [C₃₀H₂₀F₂N₅O₇S₂Zn] were evaluated against five human cancer cell lines viz., MCF‒7 (breast), MIA‒PA‒CA‒2 (pancreatic), HeLa (cervix) and Hep‒G2 (Hepatoma) and A498 (Kidney) by SRB assay which revealed that chloro-substituted [C₃₀H₂₀Cl₂CuN₅O₇S₂] complex, exhibited pronounced specific cytotoxicity with GI₅₀ value of 4.8 μg/ml against HeLa cell line. Molecular docking studies were also performed to explore the binding modes and orientation of the complexes in the DNA helix.

Keywords:

• Benzothiazole Cu(II) & Zn(II) Schiff base complexes
• structure activity relationship
• antimicrobial studies
• cytotoxicity
• molecular docking

Acknowledgments

The authors are grateful to SAIF Panjab University, Chandigarh, for providing elemental analysis, ESI–MS and NMR facilities. We are also thankful to Department of Chemistry, Aligarh Muslim University for providing the FT‒IR, UV–Vis, and EPR facility. The author (Siffeen Zehra) sincerely acknowledges financial support from University Grants Commission (UGC), New Delhi, for providing the fellowship and the Department of Chemistry, AMU through UGC assisted DRS–SAP, DST‒FIST and DST PURSE Programme. The authors are highly thankful to Anticancer Drug screening facility (ACDSF) of ACTREC, Tata Memorial Centre, Navi Mumbai for carrying out in vitro anticancer activity of complexes by SRB assay.