engleski

Biological activity of novel primaquine-cinnamic acid conjugates of the amide type

Novel primaquine-cinnamic acid (PQ-CADs) conjugates of the amide type 1a–k, bearing cinnamoyl moiety at the one and primaquine moiety at the other side, prepared by our research group (1) were evaluated for biological activity. Their antiproliferative activity was evaluated in vitro on five different types of human tumor cell lines: lymphoblastic leukemia (CEM), cervical carcinoma (HeLa), lung carcinoma (NCI-H460), colon carcinoma (SW 620), breast carcinoma (MCF-7) and murine lymphocytic leukemia (L1210), and compared with the standard anticancer drugs (sorafenib, cisplatin and 5- fluorouracil) and PQ. Practically all PQ-CAD amides were active against MCF-7 in low micromolar concentrations, with o-fluoro derivative 1h as the most active compound (IC50 1.1 ± 0.6 M). Activity against HeLa varied noticeably: 1a and 1h showed strong activity in low micromolar concentrations (IC50 4.0 ± 0.9 M and 2.1 ± 2.1 M, respectively). Other amides were either inactive (1c-e) or exerted very weak activity (the rest of the compounds). All compounds showed weak activity against L1210 and CEM, and no activity against H460 cell line. Similarly, most of the amide derivatives were inactive against SW 620. However, 1a and 1i showed mild and again, 1h very strong activity (IC50 0.3 ± 0.1 M) against the same cell line. Compounds 1a–k were evaluated against a broad variety of viruses (herpes simplex virus type 1 (KOS), herpes simplex virus 2 (G), herpes simplex virus 1 TK–(KOS) ACVr, vaccinia virus, adeno virus 2 and human coronavirus (229E) in HEL cell cultures) and their activities were compared with reference compounds. However, amide derivatives 1a-k were inactive towards all tested viruses. All PQ-CAD amides did not display cytotoxic effects based on the inhibition of HEL growth. The results of cytotoxicity measurements were expressed as minimum cytotoxic concentrations (MCC) and were equal or higher than 100 µM. For the measurement of the antioxidant potentials of the new PQ-CADs 1a–k two different assays were used: interaction with the stable 1, 1- diphenyl-2-picrylhydrazyl (DPPH) free radical, and interaction with 2, 2’- azobis(2- amidinopropane)dihydrochloride (AAPH), used as a source of peroxyl radicals. Antioxidant potentials of PQ-CADs were compared to nordihydroguaiaretic acid (NDGA) and Trolox. DPPH-reducing ability (RA) of the amide derivatives 1a–k was very low or missing at 50 µM. However, an increase was observed at 100 µM. The highest activity was presented by the unsubstituted derivative 1a (53 %). The results of the interaction with AAPH showed that all amide derivatives significantly inhibited lipid peroxidation (LP) (32–87 %). Compound 1f with a benzodioxole ring exhibited the highest activity. In addition, all prepared compounds were evaluated for their ability to inhibit soybean lipoxygenase (LOX). From the tested compounds, all amides, with the exception of 1j, were inactive (10–45 % at 100 µM).

primaquine ; cinnamic acid derivatives ; amides ; antiproliferative activity ; antiviral activity ; antioxidative activity

Poster je izlagan i na 6. simpoziju studenata farmacije i medicinske biokemije FARMEBS 2017, Zagreb, 27.5.2017. http://farmebs.pharma.hr/SAZECI.html