Novel Schiff base-bridged multi-component sulfonamide imidazole hybrids as potentially highly selective DNA-targeting membrane active repressors against methicillin-resistant Staphylococcus aureus.

Affiliation

Hu Y(1), Pan G(1), Yang Z(1), Li T(2), Wang J(2), Ansari MF(2), Hu C(3), Yadav Bheemanaboina RR(4), Cheng Y(5), Zhou C(2), Zhang J(6).
Author information:
(1)State Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology, Shenzhen 518055, China; Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, China.
(2)School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
(3)Dongguan School Affiliated to South China Normal University, Dongguan 523755, China.
(4)Sokol Institute for Pharmaceutical Life Sciences, Department of Chemistry and Biochemistry, Montclair State University, NJ 07043, USA.
(5)School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
(6)State Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology, Shenzhen 518055, China; Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, China. Electronic address: [Email]

Abstract

A new type of Schiff base-bridged multi-component sulfonamide imidazole hybrids with antimicrobial potential was developed. Some target compounds showed significant antibacterial potency. Observably, butylene hybrids 4h exhibited remarkable inhibitory efficacy against clinical MRSA (MIC = 1 µg/mL), but had no significant toxic effect on normal mammalian cells (RAW 264.7). The highly active molecule 4h was revealed by molecular modeling study that it could insert into the base-pairs of DNA hexamer duplex and bind with the ASN-62 residue of human carbonic anhydrase isozyme II through hydrogen bonding. Furthermore, further preliminary antibacterial mechanism experiments confirmed that compound 4h could effectively interfere with MRSA membrane and insert into bacterial DNA isolated from clinical MRSA strains through non-covalent bonding to produce a supramolecular complex, thus exerting its strong antibacterial efficacy by impeding DNA replication. These findings strongly implied that the highly active hybrid 4h could be used as a potential DNA-targeting template for the development of valuable antimicrobial agent.