Novel urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation.
A series of novel compounds 3a-j and 6a-j with primaquine and hydroxyl or halogen substituted benzene moieties bridged by urea or bis-urea functionalities were designed, synthesized and evaluated for biological activity. The title compounds were prepared using benzotriazole as the synthon, through several synthetic steps. 3-[3,5-Bis(trifluoromethyl)phenyl]-1-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}urea (3j) was the most active urea and 1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-3-[3-(trifluoromethyl)phenyl]urea (6h) the most active bis-urea derivative in antiproliferative screening in vitro against eight tested cancer cell lines. Urea derivatives 3a-g with hydroxy group or one halogen atom showed moderate antiproliferative effects against all the tested cell lines, but stronger activity against breast carcinoma MCF-7 cell line, while trifluoromethyl derivatives 3h-j showed antiproliferative effects against all the tested cell lines in low micromolar range. Finally, bis-ureas with hydroxy and fluoro substituents 6a-d showed extreme selectivity and chloro or bromo derivatives 6e-g high selectivity against MCF-7 cells (IC500.1-2.6 μM). p-Fluoro derivative 6d, namely 3-(4-fluorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea, is the most promising compound. Further biological experiments showed that 6d affected cell cycle and induced cell death of MCF-7 cell line. Due to its high activity against MCF-7 cell line (IC500.31 μM), extreme selectivity and full agreement with the Lipinski's and Gelovani's rules for prospective small molecular drugs, 6d may be considered as a lead compound in development of breast carcinoma drugs. Urea 3b and almost all bis-ureas showed high antioxidant activity in DPPH assay, but urea derivatives were more active in lipid peroxidation test. Only few compounds exhibited weak inhibition of soybean lipoxygenase. Compound 3j exhibited the strongest antimicrobial activity in susceptibility assay in vitro (MIC = 1.6-12.5 μg ml-1).
University of Zagreb, Faculty of Pharmacy and Biochemistry, A. Kovačića 1, HR-10 000 Zagreb, Croatia.
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Perković
University of Zagreb, Faculty of Science, Horvatovac 102 1, HR-10 000 Zagreb, Croatia.
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Antunović
University of Zagreb, Faculty of Science, Horvatovac 102 1, HR-10 000 Zagreb, Croatia.
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Marijanović
University of Zagreb, Faculty of Pharmacy and Biochemistry, A. Kovačića 1, HR-10 000 Zagreb, Croatia.
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Pavić
Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
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Ester
Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
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Kralj
Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
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Vlainić
University of Zagreb, Faculty of Pharmacy and Biochemistry, Schrottova 39, HR-10 000 Zagreb, Croatia.
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Kosalec
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
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Schols
School of Pharmacy, Faculty of Health Sciences, Aristotles University of Thessaloniki, GR-54 124 Thessaloniki, Greece.
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Hadjipavlou-Litina
School of Pharmacy, Faculty of Health Sciences, Aristotles University of Thessaloniki, GR-54 124 Thessaloniki, Greece.
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Pontiki
University of Zagreb, Faculty of Pharmacy and Biochemistry, A. Kovačića 1, HR-10 000 Zagreb, Croatia. Electronic address: bzorc@pharma.hr.
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Zorc
D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001419:Bacteria / Q000187:drug effects; D001554:Benzene / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D008826:Microbial Sensitivity Tests; D011319:Primaquine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006219:Halogens; D014508:Urea; D001554:Benzene; D011319:Primaquine
Antimicrobial activity; Antioxidative activity; Antiproliferative activity; Bis-urea; Primaquine; Urea