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Synthesis and structure–activity relationship of amidine derivatives of 3, 4-ethylenedioxythiophene as novel antibacterial agents


Stolić, Ivana; Čipčić Paljetak, Hana; Perić, Mihaela; Matijašić, Mario; Stepanić, Višnja; Verbanac, Donatella; Bajić, Miroslav
Synthesis and structure–activity relationship of amidine derivatives of 3, 4-ethylenedioxythiophene as novel antibacterial agents // European journal of medicinal chemistry, 90 (2015), 68-81 doi:10.1016/j.ejmech.2014.11.003 (međunarodna recenzija, članak, znanstveni)


Naslov
Synthesis and structure–activity relationship of amidine derivatives of 3, 4-ethylenedioxythiophene as novel antibacterial agents

Autori
Stolić, Ivana ; Čipčić Paljetak, Hana ; Perić, Mihaela ; Matijašić, Mario ; Stepanić, Višnja ; Verbanac, Donatella ; Bajić, Miroslav

Izvornik
European journal of medicinal chemistry (0223-5234) 90 (2015); 68-81

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Thiophene. amidine; minor groove binders; minimum inhibitory concentration; antibacterial activity; DNA binding

Sažetak
Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3, 4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and ≤0.25 μg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4–32 μg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (ΔTm of 15.4 °C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3, 4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti



POVEZANOST RADA


Projekt / tema
053-0982914-2965 - Dizajn i sinteza bisamidina sa protutumorskim djelovanjem (Miroslav Bajić, )

Ustanove
Veterinarski fakultet, Zagreb,
Institut "Ruđer Bošković", Zagreb,
Medicinski fakultet, Zagreb

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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