Design, synthesis, biological evaluation and toxicity studies of N,N-disubstituted biguanides as quorum sensing inhibitors

作者：Singh Shaminder; Wanjari Pravin J; Bhatia Sonam; Sonwane Vijay C; Chakraborti Asit K; Bharatam Prasad V^*

来源：Medicinal Chemistry Research, 2015, 24(5): 1974-1987.

DOI：10.1007/s00044-014-1255-y

• Biguanides
• Microwave assisted synthesis
• Molecular docking
• Quorum sensing
• Chromobacterium violaceum
• TOPKAT analysis

A series of novel N,N-disubstituted biguanides (8a-8j) have been synthesized using varied secondary amines and cyanoguanidine under microwave irradiation. All the synthesized compounds were evaluated for quorum sensing inhibition (QSI) activity using Chromobacterium violaceum (ATCC12472)-based bioassay. Out of these ten compounds, two compounds 8a and 8g (IC50 = 179 and 120 A mu M) showed maximum QSI activity. Decrease in violacein production was observed in the range of 0.2-200 A mu M concentration for these respective compounds. The molecular docking studies revealed that N,N-disubstituted biguanides shared structural complementarity with CviR domain. Furthermore, TOPKAT analysis on Ames mutagenicity and carcinogenicity models had shown that this class of compounds has least probability (0.000-0.009) of exhibiting toxicity in experimental models.
The C6-AHL (native ligand) and CviR complex function as transcriptional activator of genes such as vioA, which is controlled by quorum sensing and leads to production of purple coloured pigment violacein. This pigment production is inhibited by the synthetic ligand 8g which binds in place of native AHL ligand and thereby interfere with the phenomenon of quorum sensing.

• 出版日期2015-5