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Design, Synthesis and Biological Activity of Harmicens

Cancer and malaria are serious public health problems worldwide. The current treatment of these diseases faces many challenges, including drug resistance and high toxicity [1]. Therefore, the discovery of novel anticancer and antimalarial agents is of paramount importance. Herein, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids comprising scaffolds with pronounced anticancer and antimalarial properties, namely harmine and ferrocene [2]. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), while the synthesis of amide-type harmicens was carried out by applying coupling reaction. The novel compounds were characterized by standard methods (1H and 13C NMR, IR, MS). The antimalarial activity of the prepared compounds was evaluated in vitro against the erythrocytic and hepatic stages of the Plasmodium life cycle, as well as the antiproliferative activity against a panel of human tumour cell lines (MCF-7, HepG2, HCT116, SW620, Hek293T). The results showed that the harmicens exerted moderate antiplasmodial activity (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range). Cell localization experiments showed clearly that HCT116-selective harmicene 1 had penetrated the nucleus. It induced G1 cell cycle arrest after 24 h, followed by G2/M arrest, which is in accordance with its localizations within the cell. The effect of nonselective compound 2 on the cell cycle was less pronounced.

harmine, ferrocene, hybrid compound, antiproliferative activity, intracellular localization, cell cycle, antimalarial activity

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