Synthesis, anti-bacterial and anti-protozoal activities of amidinobenzimidazole derivatives and their interactions with DNA and RNA

Journal of Enzyme Inhibition and Medicinal Chemistry

Luka Krstulović¹  Ivana Stolić¹  Miroslav Bajić¹  Jasminka Talapko²  Andrea Bistrović³  Silvana Raić-Malić³  Martin C. Taylor⁴  John M. Kelly⁴  Domagoj Drenjančević⁵ 

[1] Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia;Department of Microbiology and Parasitology, Faculty of Medicine, University of Osijek, Osijek, Croatia;Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia;Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, U;Department of Transfusion Medicine, Osijek University Hospital, Osijek, Croatia;Department of Microbiology and Parasitology, Faculty of Medicine, University of Osijek, Osijek, Croatia;

关键词: Benzimidazole;    1,2,3-triazole;    resistant bacteria;    antiprotozoal activity;    Trypanosoma brucei;    MRSA;   

DOI  :  10.1080/14756366.2018.1484733

来源: publisher

【 摘 要 】

Amidinobenzimidazole derivatives connected to 1-aryl-substituted 1,2,3-triazole through phenoxymethylene linkers 7a–7e, 8a–8e, and 9a–9e were designed and synthesised with the aim of evaluating their anti-bacterial and anti-trypanosomal activities and DNA/RNA binding affinity. Results from anti-bacterial evaluations of antibiotic-resistant pathogenic bacteria revealed that both o-chlorophenyl-1,2,3-triazole and N-isopropylamidine moieties in 8c led to strong inhibitory activity against resistant Gram-positive bacteria, particularly the MRSA strain. Furthermore, the non-substituted amidine and phenyl ring in 7a induced a marked anti-bacterial effect, with potency against ESBL-producing Gram-negative E. coli better than those of the antibiotics ceftazidime and ciprofloxacin. UV–Vis and CD spectroscopy, as well as thermal denaturation assays, indicated that compounds 7a and 8c showed also binding affinities towards ctDNA. Anti-trypanosomal evaluations showed that the p-methoxyphenyl-1,2,3-triazole moiety in 7b and 9b enhanced inhibitory activity against T. brucei, with 8b being more potent than nifurtimox, and having minimal toxicity towards mammalian cells.

【 授权许可】

CC BY