Synthesis of Novel Hybrids of Quinazoline and Artemisinin with High Activities against Plasmodium falciparum, Human Cytomegalovirus, and Leukemia Cells

被引:63
作者
Froehlich, Tony [1 ,2 ]
Reiter, Christoph [1 ,2 ]
Ibrahim, Mohammad M. [1 ,2 ,3 ]
Beutel, Jannis [1 ,2 ]
Hutterer, Corina [4 ]
Zeittraeger, Isabel [4 ]
Bahsi, Hanife [4 ]
Leidenberger, Maria [5 ]
Friedrich, Oliver [5 ]
Kappes, Barbara [5 ]
Efferth, Thomas [6 ]
Marschall, Manfred [4 ]
Tsogoeva, Svetlana B. [1 ,2 ]
机构
[1] Friedrich Alexander Univ Erlangen Nurnberg, Organ Chem Chair 1, Henkestr 42, D-91054 Erlangen, Germany
[2] Friedrich Alexander Univ Erlangen Nurnberg, ICMM, Henkestr 42, D-91054 Erlangen, Germany
[3] Univ Al al Bayt, Dept Chem, Fac Sci, POB 130040, Al Mafraq 25113, Jordan
[4] Friedrich Alexander Univ Erlangen Nurnberg, Inst Clin & Mol Virol, Schlossgarten 4, D-91054 Erlangen, Germany
[5] Friedrich Alexander Univ Erlangen Nurnberg, Inst Med Biotechnol, Paul Gordon Str 3, D-91052 Erlangen, Germany
[6] Johannes Gutenberg Univ Mainz, Inst Pharm & Biochem, Dept Pharmaceut Biol, Staudinger Weg 5, D-55128 Mainz, Germany
来源
ACS OMEGA | 2017年 / 2卷 / 06期
关键词
ANTIMALARIAL-DRUG; QINGHAOSU ARTEMISININ; MULTIDRUG-RESISTANCE; POTENT ANTIMALARIAL; ANTIVIRAL THERAPY; IN-VITRO; DERIVATIVES; MOLECULES; DISCOVERY; AGENTS;
D O I
10.1021/acsomega.7b00310
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Many quinazoline derivatives have been synthesized over the last few decades with great pharmacological potential, such as antimalarial, anti-inflammatory, antimicrobial, anticancer, and antiviral. But so far, no quinazoline-artemisinin hybrids have been reported in the literature. In the present study, five novel quinazoline-artemisinin hybrids were synthesized and evaluated for their in vitro biological activity against malarial parasites (Plasmodium falciparum 3D7), leukemia cells (CCRF-CEM and CEM/ADR5000), and human cytomegalovirus. Remarkably, hybrid 9 (EC50 = 1.4 nM), the most active antimalarial compound of this study, was not only more potent than artesunic acid (EC50 = 9.7 nM) but at the same time more active than the clinically used drugs dihydroartemisinin (EC50 = 2.4 nM) and chloroquine (EC50 = 9.8 nM). Furthermore, hybrids 9 and 10 were the most potent compounds with regard to anticytomegaloviral activity (EC50 = 0.15-0.21 mu M). They were able to outperform ganciclovir (EC50 = 2.6 mu M), which is the relevant standard drug of antiviral therapy, by a factor of 12-17. Moreover, we identified a new highly active quinazoline derivative, compound 14, that is most effective in suppressing cytomegalovirus replication with an EC50 value in the nanomolar range (EC50 = 50 nM). In addition, hybrid 9 exhibited an antileukemia effect similar to that of artesunic acid, with EC50 values in the low micromolar range, and was 45 times more active toward the multidrug-resistant CEM/ADR5000 cells (EC50 = 0.5 mu M) than the standard drug doxorubicin.
引用
收藏
页码:2422 / 2431
页数:10
相关论文
共 63 条
[1]   Synthesis of 3-(2-pyridyl)-2-substituted-quinazolin-4(3H)-ones as new analgesic and anti-inflammatory agents [J].
Alagarsamy, V. ;
Solomon, V. Raja ;
Murugan, M. ;
Sankaranarayanan, R. ;
Periyasamy, P. ;
Deepa, R. ;
Anandkumar, T. Durai .
BIOMEDICINE & PHARMACOTHERAPY, 2008, 62 (07) :454-461
[2]  
[Anonymous], 1979, CHINESE MED J-PEKING, V92, P811
[3]   Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives [J].
Asif, Mohammad .
INTERNATIONAL JOURNAL OF MEDICINAL CHEMISTRY, 2014, 2014
[4]   Genetic Predisposition Favors the Acquisition of Stable Artemisinin Resistance in Malaria Parasites [J].
Beez, Dorothee ;
Sanchez, Cecilia P. ;
Stein, Wilfred D. ;
Lanzer, Michael .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011, 55 (01) :50-55
[5]   Synthesis of novel 4,6-disubstituted quinazoline derivatives, their anti-inflammatory and anti-cancer activity (cytotoxic) against U937 leukemia cell lines [J].
Chandrika, P. Mani ;
Yakaiah, T. ;
Rao, A. Raghu Ram ;
Narsaiah, B. ;
Reddy, N. Chakra ;
Sridhar, V. ;
Rao, J. Venkateshwara .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2008, 43 (04) :846-852
[6]   Total regression of brain metastases in non-small cell lung cancer patients harboring EGFR mutations treated with gefitinib without radiotherapy: Two case reports Case Reports [J].
Chonan M. ;
Narita N. ;
Tominaga T. .
BMC Research Notes, 9 (1)
[7]  
Coatney G. R., 1950, Journal of the National Malaria Society, V9, P183
[8]   Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells [J].
Efferth, T .
CURRENT DRUG TARGETS, 2006, 7 (04) :407-421
[9]   The antiviral activities of artemisinin and artesunate [J].
Efferth, Thomas ;
Romero, Marta R. ;
Wolf, Dana G. ;
Stamminger, Thomas ;
Marin, Jose J. G. ;
Marschall, Manfred .
CLINICAL INFECTIOUS DISEASES, 2008, 47 (06) :804-811
[10]   Prediction of broad spectrum resistance of tumors towards anticancer drugs [J].
Efferth, Thomas ;
Konkimalla, V. Badireenath ;
Wang, Yi-Fen ;
Sauerbrey, Axel ;
Meinhardt, Silke ;
Zintl, Felix ;
Mattern, Juegen ;
Volm, Manfred .
CLINICAL CANCER RESEARCH, 2008, 14 (08) :2405-2412