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Insights into antioxidant and cytostatic activity of the novel primaquine ureidoamides

In the last decade our research group has designed and prepared almost a hundred of various primaquine (PQ) derivatives and evaluated their cytostatic and antioxidant activity. Many compounds from the different series of PQ derivatives showed prominent cytostatic and/or antioxidant activity.[1– 6] The latest series of compounds synthesized by our group are PQ hybrids of ureidoamide type bearing amino acid moiety in the central part of the structure.[7] Although they were primarily designed as potential antimalarial drugs, we wanted to explore their cytostatic and antioxidant activities as well. The antioxidant properties of novel PQ hybrids 1a-g were investigated using two different assays: interaction with DPPH free radical and AAPH. DPPH-reducing ability of the ureidoamide derivatives 1a-g was very low possibly due to stereochemical reasons. However, all derivatives significantly inhibited lipid peroxidation (77–99%) with the exception of the compound 1a (15%), the only derivative of an aliphatic amino acid. In the latter experiment AAPH was used as a free radical initiator to follow oxidative changes of linoleic acid to conjugated diene hydroperoxide. Compound 1c was the most potent (99%). Furthermore, all tested compounds, except of 1a again, appeared to be potent LOX inhibitors (40–71 μΜ). Derivative 1c was the most potent LOX inhibitor with an IC50 value of 40 μΜ followed by 1e and 1f. It seems that the presence of the chloride atom in the molecule, and not its position, influence the inhibition. The antiproliferative activity of the compounds 1a-g was evaluated in vitro on three types of human tumor cell lines: NCI-H460, MCF-7 and SW620. In general, most of the compounds displayed weak, and only several compounds, along with PQ, showed moderate antiproliferative activity on all tested cell lines. Compound 1e showed the strongest activity against SW620, and moderate against other tested cell lines. Compounds 1d and 1e were generally the most active. The weak antiproliferative activity of the novel PQ hybrids 1a-g favours the hypothesis that the general cytotoxicity is not the reason for their prominent antimalarial activity against erythrocytic stages of P. falciparum.[8]

primaquine ; ureidoamide ; amino acid ; antioxidative activity ; cytostatic activity

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