Second generation of primaquine ureas and bis-ureas as potential antimycobacterial agents

  • Kristina Pavić
  • Zrinka Rajić
  • Hana Michnová
  • Josef Jampílek
  • Ivana Perković
  • Branka ZorcEmail author
Original Article


Here, we describe design and synthesis of twelve novel compounds bearing primaquine motif and hydroxy- or halogenamine linked by an urea or bis-urea spacer. Preparation of ureas 3af started with the conversion of primaquine to benzotriazolide 2 and aminolysis of the later compound by 4-(2-aminoethyl)phenol or amino alcohols bearing fluorine atom, cycloalkyl or trifluoromethyl group under microwave irradiation. The four-step sequence leading to bis-ureas 6af included preparation of benzotriazolide 2 and two intermediates, semicarbazide 4 and benzotriazole bis-urea 5, which upon aminolysis with the same aminophenol or amino alcohols gave the title compounds. Antimycobacterial screening detected three active compounds against Mycobacterium marinum and M. tuberculosis, namely 3b, 3f and 6f, derived from cyclobutyl amino alcohol or amino phenol.

Graphical abstract


Primaquine Urea Amino alcohol Fluorine Antimycobacterial screening 



The study was supported by the Croatian Science Foundation through the research project IP-09-2014-1501, Comenius University in Bratislava (Grant UK/229/2018), Faculty of Pharmacy of Comenius University in Bratislava (Grant FaFUK/9/2018) and SANOFI-AVENTIS Pharma Slovakia, s.r.o. We thank Marijeta Kralj and Lidija Uzelac for performing cytotoxicity evaluation.

Supplementary material

11030_2018_9899_MOESM1_ESM.docx (2.8 mb)
Supplementary material 1 (DOCX 2855 kb)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry, Faculty of Pharmacy and BiochemistryUniversity of ZagrebZagrebCroatia
  2. 2.Department of Pharmaceutical Chemistry, Faculty of PharmacyComenius UniversityBratislavaSlovakia

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