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

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Abstract

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 µM) showed maximum QSI activity. Decrease in violacein production was observed in the range of 0.2–200 µM 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.

Graphical abstract

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.

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Acknowledgments

S. Singh is thankful to Council of Scientific and Industrial Research (CSIR), India, S. Bhatia is thankful to Department of Science and Technology (DST), and P. J. Wanjari is grateful to National Institute of Pharmaceutical Education and Research (NIPER) S.A.S.-Nagar, India for financial support.

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Authors and Affiliations

  1. Bio-chemical Engineering Research and Process Development Centre (BERPDC), Institute of Microbial Technology, Sector 39A, Chandigarh, 160036, India

    Shaminder Singh & Vijay C. Sonwane

  2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160062, Punjab, India

    Pravin J. Wanjari, Sonam Bhatia, Asit K. Chakraborti & Prasad V. Bharatam

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  1. Shaminder Singh
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  2. Pravin J. Wanjari
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  3. Sonam Bhatia
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  6. Prasad V. Bharatam
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Correspondence to Prasad V. Bharatam.

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Singh, S., Wanjari, P.J., Bhatia, S. et al. Design, synthesis, biological evaluation and toxicity studies of N,N-disubstituted biguanides as quorum sensing inhibitors. Med Chem Res 24, 1974–1987 (2015). https://doi.org/10.1007/s00044-014-1255-y

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