Zinc organocomplexes containing non-steroid anti-inflammatories and plane aromatic diimines: New potential drugs

Abstract

Abstract Strategies have been developing to obtain new medicines. Bioisosterism represents an approach used by medicinal chemists for the rational modification of lead compounds into safer and more clinically effective agents. Evidently, the synthesis of organocomplexes has been an important strategy in the planning of new drugs, and there are examples of great improvements in therapeutic efficacy. Thus, this work is aimed at the synthesis of new zinc complexes with nonsteroidal anti-inflammatory drugs (NSAIDs), the chemical characterization and the previous toxicity by cytotoxicity, and an evaluation of the ability of these compounds to interact with DNA. As a result, four new zinc II ternary complexes containing the NSAIDs diclofenac (Diclof) and ibuprofen (Ibup) and a zinc neutral linker were obtained by the two-step solvent metal–ligand complexation method (1. Zn-Ibup-Bipy, 2. Zn-Ibup-Phen, 3. Zn-Diclof-Bipy, 4. Zn-Diclof-Phen). Molecular structures were determined by NMR, FTIR, and HR-MS which demonstrated that the complexes are binuclear systems of the general formula [Zn(RCOO−)2N-binder]. In silico studies were performed for toxicity and physicochemical properties and biological target prediction. Cytotoxicity was determined by the MTT assay. The results indicated a relative absence of toxicity for these organometallic zinc derivatives. It was also observed that the compounds Zn-Diclof-Bipy and Zn-Diclof-Phen showed high potential without theoretical toxic effects, and they should be submitted to studies for evaluation of biological activity. Plasmidi DNA breakdown capacities were evaluated by producing single and double breaks (DNA FII and FIII) from plasmid incubation with complex solutions in the concentration range of 0 to 400\xa0μmol·L−1 in experiments with the presence and absence of light. Both experiments did not show significant differences (P\xa0≤\xa00.05) in induced DNA cleavage activity between the maximum study concentrations (400\xa0μmol·L−1) and the negative controls for both complexes. The types of complex 1 and 2 interactions with the secondary DNA structure were determined by titrating a CT-DNA solution with complex solutions and monitoring by circular dichroism spectrometry. Complex 1 was not cytotoxic at the concentrations tested against the Vero cell line. The results showed that both complexes interact with the grooves of the secondary structure of CT-DNA by electrostatic attraction but without evidence of alteration in the primary structure. Thus, four new compounds were synthesized and characterized, and their previous toxicities were determined. These compounds are promising new drugs, and the next step is to evaluate their activity.