Organocomplexos de zinco contendo anti-inflamatório não esteroides e diiminas aromáticas planas: novos fármacos potenciais

Abstract

Strategies have been developing to obtain new medicines. Bioisosterism represents an approach used by the medicinal chemist 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 with examples of great improvements in therapeutic efficacy. Thus, this work aimed at the synthesis of new zinc complexes with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the chemical characterization and the previous toxicity by cytotoxicity, and evaluating 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 zinc neutral linker were obtained by the two-step solvent metalligand 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 complexes are binuclear systems of general formula [Zn(RCOO?)2N-binder]. In silico studies were performed to toxicity and physicochemical properties and biological target prediction. Cytotoxic was determined by MTT assay. Results indicated a relative absence of toxicity to these organometallic zinc derivatives. It is also observed that compound Zn-Diclof-Bipy and Zn-Diclof-Phen showed high potential to be submitted to studies of evaluation of biological activity, without potential theoretical toxic effects. Plasmidial 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 0 to 400 ?mol·L?1 in experiments with the presence and absence of light. Both experiments did not show significant differences (P ? 0.05) in induced DNA cleavage activity between the maximum study concentrations (400 ?mol·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 monitored 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, characterized and had their previous toxicities determined. These compounds are promising new drugs, with the next step being evaluations of their activity [resumo fornecido pelo autor].