Novel urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation

• Published in: European journal of medicinal chemistry Vol. 124; pp. 622 - 636
• Main Authors: Perković, I., Antunović, M., Marijanović, I., Pavić, K., Ester, K., Kralj, M., Vlainić, J., Kosalec, I., Schols, D., Hadjipavlou-Litina, D., Pontiki, E., Zorc, B.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 29.11.2016; Elsevier
• Subjects: Antimicrobial activity; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidative activity; Antiproliferative activity; Apoptosis - drug effects; Bacteria - drug effects; Benzene - chemistry; Bis-urea; Breast Neoplasms - drug therapy; Cell Survival - drug effects; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; Halogens - chemistry; Humans; Life Sciences & Biomedicine; MCF-7 Cells; Microbial Sensitivity Tests; Pharmacology & Pharmacy; Primaquine; Primaquine - chemical synthesis; Primaquine - chemistry; Primaquine - pharmacology; Science & Technology; Urea; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; Antioxidative activity; Antimicrobial activity; TTC; Antiproliferative activity; LP; Primaquine; DMSO; AAPH; MCF-7; VRE; L1210; MTT; Molt4/C8; Bis-urea; HeLa; MSSA; DMEM; NCI-H460; FBS; BtH; IC50; MRSA; XTT; MDR; TBST buffer; PSA; PBS; BtcCl; DPPH; MR; MIC; SW620; VSE; CEM; DOX; HEK; TC; EMEM; Urea; Mia PaCa-2; LOX; NDGA; hRBCs; PG; VOR; PI; DRUG; EICOSANOIDS; CHLOROQUINE; CANCER; 1-BENZOTRIAZOLECARBOXYLIC ACID-CHLORIDE; ARYL; INHIBITORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.08.021

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 (IC50 0.1–2.6 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 (IC50 0.31 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). [Display omitted] •Novel hydroxyl- and halogenphenyl primaquine ureas and bis-ureas were synthesized.•Most of the compounds exerted potent cytostatic activity.•Several hits displayed extremely high selectivity against MCF-7.•Most derivatives showed high antioxidant activity in DPPH and LP assays.•Three compounds with PQ-urea scaffold exhibited weak antimicrobial activity.