Synthesis, Self-Assembly, and Biological Activities of Pyrimidine-Based Cationic Amphiphiles

Ankita Singh; Shashwat Malhotra; Devla Bimal; Lydia M Bouchet; Stefanie Wedepohl; Marcelo Calderón; Ashok K Prasad

doi:10.1021/acsomega.0c03623

Synthesis, Self-Assembly, and Biological Activities of Pyrimidine-Based Cationic Amphiphiles

ACS Omega. 2021 Jan 2;6(1):103-112. doi: 10.1021/acsomega.0c03623. eCollection 2021 Jan 12.

Authors

Ankita Singh¹, Shashwat Malhotra^{1

2}, Devla Bimal¹, Lydia M Bouchet³, Stefanie Wedepohl³, Marcelo Calderón^{4

5}, Ashok K Prasad¹

Affiliations

¹ Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India.
² Kirori Mal College, Department of Chemistry, University of Delhi, Delhi 110007, India.
³ Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin 14195, Germany.
⁴ POLYMAT and Applied Chemistry Department, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel de Lardizabal 3, Donostia-San Sebastián 20018, Spain.
⁵ IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain.

Abstract

Pyrimidine-based cationic amphiphiles (PCAms), i.e., di-trifluoroacetic acid salts of N1-[1'-(1″,3″-diglycinatoxy-propane-2″-yl)-1',2',3'-triazole-4'-yl]methyl-N3-alkylpyrimidines have been synthesized utilizing naturally occurring biocompatible precursors, like glycerol, glycine, and uracil/ thymine in good yields. Synthesized PCAms consist of a hydrophilic head group comprising TFA salt of glyceryl 1,3-diglycinate and hydrophobic tail comprising of C-7 and C-12 N3-alkylated uracil or thymine conjugated via a 4-methylene-1,2,3-triazolyl linker. The physicochemical properties of all PCAms, such as critical aggregation concentration, hydrodynamic diameter, shape, and zeta potential (surface charge) were analyzed. These PCAms were also evaluated for their anti-proliferative and anti-tubercular activities. One of the synthesized PCAm exhibited 4- to 75-fold more activity than first-line anti-tubercular drugs streptomycin and isoniazid, respectively, against the multidrug resistant clinical isolate 591 of Mycobacterium tuberculosis.