Design, Synthesis, Antitumor, and Antiplasmodial Evaluation of New 7-Chloroquinoline–Benzimidazole Hybrids
Luka Krstulović,
Vesna Rastija,
Lais Pessanha de Carvalho,
Jana Held,
Zrinka Rajić,
Zorislava Živković,
Miroslav Bajić,
Ljubica Glavaš-Obrovac
Affiliations
Luka Krstulović
Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia
Vesna Rastija
Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, Vladimira Preloga 1, HR-31000 Osijek, Croatia
Lais Pessanha de Carvalho
Institute of Tropical Medicine, University of Tuebingen, Wilhelmstrasse 27, D-72074 Tuebingen, Germany
Jana Held
Institute of Tropical Medicine, University of Tuebingen, Wilhelmstrasse 27, D-72074 Tuebingen, Germany
Zrinka Rajić
Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10000 Zagreb, Croatia
Zorislava Živković
General County Hospital of Našice, Bana Jelačića 10, HR-31500 Našice, Croatia
Miroslav Bajić
Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia
Ljubica Glavaš-Obrovac
Department of Medicinal Chemistry, Biochemistry, and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia
Newly synthesized 7-chloro-4-aminoquinoline–benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC50 value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure–activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R2 = 0.886; Rext2 = 0.937; F = 41.589) and Dd2 strain (R2 = 0.859; Rext2 = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities.
