Novel tetrahydropyrimidinyl-substituted benzimidazoles and benzothiazoles: synthesis, antibacterial activity, DNA interactions and ADME profiling.

Autor:	Rep V; Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb Marulićev trg 19 10000 Zagreb Croatia sraic@fkit.hr., Štulić R; Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb Marulićev trg 19 10000 Zagreb Croatia sraic@fkit.hr., Koštrun S; Selvita d.o.o Prilaz baruna Filipovića 29 10000 Zagreb Croatia., Kuridža B; Ruđer Bošković Institute, Division of Organic Chemistry and Biochemistry Bijenička cesta 54 10000 Zagreb Croatia Marijana.Radic@irb.hr., Crnolatac I; Ruđer Bošković Institute, Division of Organic Chemistry and Biochemistry Bijenička cesta 54 10000 Zagreb Croatia Marijana.Radic@irb.hr., Radić Stojković M; Ruđer Bošković Institute, Division of Organic Chemistry and Biochemistry Bijenička cesta 54 10000 Zagreb Croatia Marijana.Radic@irb.hr., Paljetak HČ; Department for Intercellular Communication, Center for Translational and Clinical Research, University of Zagreb School of Medicine Šalata 2 10000 Zagreb Croatia., Perić M; Department for Intercellular Communication, Center for Translational and Clinical Research, University of Zagreb School of Medicine Šalata 2 10000 Zagreb Croatia., Matijašić M; Department for Intercellular Communication, Center for Translational and Clinical Research, University of Zagreb School of Medicine Šalata 2 10000 Zagreb Croatia., Raić-Malić S; Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb Marulićev trg 19 10000 Zagreb Croatia sraic@fkit.hr.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2022 Jul 15; Vol. 13 (12), pp. 1504-1525. Date of Electronic Publication: 2022 Jul 15 (Print Publication: 2022).
DOI:	10.1039/d2md00143h
Abstrakt:	A series of tetrahydropyrimidinyl-substituted benzimidazoles attached to various aliphatic or aromatic residues via phenoxymethylene were synthesised to investigate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. The influence of the type of substituent at the C-3 and C-4 positions of the phenoxymethylene linker on the antibacterial activity was observed, showing that the aromatic moiety improved the antibacterial potency. Of all the evaluated compounds, benzoyl-substituted benzimidazole derivative 15a was the most active compound, particularly against the Gram-negative pathogens E. coli (MIC = 1 μg mL -1 ) and M. catarrhalis (MIC = 2 μg mL -1 ). Compound 15a also exhibited the most promising antibacterial activity against sensitive and resistant strains of S. pyogenes (MIC = 2 μg mL -1 ). Significant stabilization effects and positive induced CD bands strongly support the binding of the most biologically active benzimidazoles inside the minor grooves of AT-rich DNA, in line with docking studies. The predicted physico-chemical and ADME properties lie within drug-like space except for low membrane permeability, which needs further optimization. Our findings encourage further development of novel structurally related 5(6)-tetrahydropyrimidinyl substituted benzimidazoles in order to optimize their antibacterial effect against common respiratory pathogens. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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