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European journal of medicinal chemistry v.143, 2018년, pp.769 - 779   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Primaquine hybrids as promising antimycobacterial and antimalarial agents

Pavić, Kristina (University of Zagreb, Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10 000 Zagreb, Croatia ) ; Perković, Ivana (University of Zagreb, Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10 000 Zagreb, Croatia ) ; Pospíšilová, Šárka (Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojárov 10, 83232 Bratislava, Slovakia ) ; Machado, Marta (Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal ) ; Fontinha, Diana (Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal ) ; Prudêncio, Miguel (Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal ) ; Jampilek, Josef (Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojárov 10, 83232 Bratislava, Slovakia ) ; Coffey, Aidan (Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork, Ireland ) ; Endersen, Lorraine (Department of Biological Sci ) ; Rimac, Hrvoje ; Zorc, Branka ;
  • 초록  

    Abstract Four series of primaquine (PQ) derivatives were screened for antitubercular and antiplasmodial activity: amides 1a-k , ureas 2a-s , semicarbazides 3a-c and bis -ureas 4a-u . Antimycobacterial activity of PQ derivatives against Mycobacterium tuberculosis (MTB), M. avium complex (MAC) and M. avium subsp. paratuberculosis (MAP) were evaluated in vitro and compared with PQ and the standard antitubercular drugs. In general, the PQ derivatives showed higher potency than the parent compound. Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even higher than the relevant drug ciprofloxacin, and weak or no activity against MTB and MAC. bis -Trifluoromethylated cinnamamide 1k showed low cytotoxicity and high activity against all three Mycobacterium species and their activities were comparable or slightly higher than those of the reference drugs. PQ urea derivatives with hydroxyl, halogen and trifluoromethyl substituents on benzene ring 2f-p exerted very strong antimycobacterial activity towards all tested mycobacteria, stronger than PQ and the relevant standard drug(s). Unfortunately, these compounds had relatively high cytotoxicity, except bromo 2l and trifluoromethyl 2m , 2n derivatives. In general, meta- substituted derivatives were more active than analogues para- derivatives. Phenyl ureas were also more active than cycloalkyl or hydroxyalkyl ureas. Semicarbazide 3a showed similar activity as PQ, while the other two semicarbazides were inactive. Bis -urea derivatives 4 were generally less active than the urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis -urea derivatives, only p -Cl/ m -CF 3 phenyl derivative 4p , benzhydryl derivatives 4t and 4u and bis -PQ derivative 4s showed high activity, higher than all three reference drugs. After comparison of activity and cytotoxicity, urea 2m and bis -urea 4u could be considered as the most promising agents. Antimalarial potential of PQ derivatives in vitro against the liver stage of P. berghei was evaluated as well. 3-(4-Chlorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea ( 4l ) was the most active compound (IC 50 = 42 nM; cytotoxicity/activity ratio >2000). Our results bring new insights into development of novel anti-TB and antimalarial compounds. Highlights Antimycobacterial and antiplasmodial properties of 55 primaquine derivatives were evaluated. 13 hits displayed high antitubercular activity. Primaquine-chlorophenyl bis -urea was active against liver-stage P. berghei in nanomolar scale. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    Primaquine .   Hybrid .   Antimycobacterial activity .   Antiplasmodial activity.  

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