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

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Abstract

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 3a–f 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 6a–f 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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000, Zagreb, Croatia

    Kristina Pavić, Zrinka Rajić, Ivana Perković & Branka Zorc

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, 83 232, Bratislava, Slovakia

    Hana Michnová & Josef Jampílek

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  1. Kristina Pavić
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Correspondence to Branka Zorc.

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Pavić, K., Rajić, Z., Michnová, H. et al. Second generation of primaquine ureas and bis-ureas as potential antimycobacterial agents. Mol Divers 23, 657–667 (2019). https://doi.org/10.1007/s11030-018-9899-z

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