Toxicity Assessment of a Derivative Designed by Using the Privileged Structure Dihydropyridine: LQFM310, a Nifedipine Analog.

Abstract

The privileged structures, such as dihydropyridine, are present in bioactive compounds exhibiting biological activities by interacting with multiple pharmacological targets. The dihydropyridine-containing compounds are usually related to the calcium channel-blocking abilities in the treatment of cardiovascular diseases, such as nifedipine. Other pharmaceutical applications have been described for these compounds, being a starting point for the obtaining of new drug candidates. The privileged structures are usually related to nontoxic effects; however, other chemical groups of dihydropyridine-containing compounds may result in impairment of the safety profile, such as nifedipine, described as teratogenic and embryotoxic in vivo. Here, we designed LQFM310 through the molecular hybridization strategy by incorporating the dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate scaffold from nifedipine and butyl hydroxytoluene (BHT). As the phenolic hydroxyl from BHT is capable of conferring antioxidant activity, the electrochemical analysis was performed. In addition, the toxicological profile of LQFM310 was investigated by using the embryo-larval stage of zebrafish (Danio rerio) and compared to nifedipine. As a result, LQFM310 demonstrated the antioxidant potential and did not induce significant lethal or sublethal effects in the toxicological assay. However, nifedipine induced 100% mortality in embryos and larvae from 25 μM for 96 h post fertilization (hpf) and sublethal effects at 10 μM. Therefore, LQFM310 demonstrated a safer profile than nifedipine in the zebrafish-based toxicity model, identifying that the nitroaromatic scaffold may be responsible for the toxicity effect of nifedipine. Considering the presence of privileged structures as dihydropyridine, LQFM310 is a promising compound for investigation in pharmacology assays of several diseases.