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Design, synthesis of quinolinyl Schiff bases and azetidinones as enoyl ACP-reductase inhibitors

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Abstract

New series of quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehydes. In the reaction sequence, substituted acetanilides were cyclized to give 2-chloroquinoline-3-carbaldehydes 2ad, which were transformed to 6ad, which were then cyclized to give azetidinones 9ad. The key scaffolds viz., 2-methoxy derivatives 3ad, obtained from 2ad were converted to target Schiff bases 4ad, 5ad and azetidinones 7ad, 8ad in good yields. Structures of these compounds were established by FTIR, 1H NMR, 13C NMR and mass spectrometry. The compounds 4ad to 9ad were evaluated for in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Vibrio cholera and antitubercular activity against Mycobacterium tuberculosis H37Rv. The Schiff bases and azetidinone derivatives exhibited good antibacterial and antitubercular activities. Bacterial enoyl ACP-reductase catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antimicrobial agents. Molecular docking into active site of enoyl ACP-reductase was performed on 2H7M.PDB and 4JX8.PDB files to understand ligand–protein interactions. The compounds obtained from the present research can be used as scaffolds in fragment-based design of new potent drugs.

Graphical Abstract

Molecular modeling, synthesis, spectral, antimicrobial studies of quinolinyl Schiff bases and azetidinones using crystal structure of E. coli and M. tuberculosis enoyl ACP-reductase (4JX8/2H7M PDB) and compared with in vitro antimicrobial activity.

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Acknowledgments

The authors gratefully acknowledge the financial support from the Indian Council of Medical Research, New Delhi, India (File No. 64/4/2011-BMS, IRIS Cell No. 2010-08710) and Rajiv Gandhi University of Health Sciences, Bangalore, India for a partial financial support [File No RGUHS/R&D/RG/P25/2011-12 dated 07/12/2011]. We thank Dr. V. H. Kulkarni, Principal and Mr. H. V. Dambal, President, S. E. T’s College of Pharmacy, Dharwad, India, for providing facilities. We also thank Dr. A. M. Godbole (S. E. T’s College of Pharmacy, Dharwad, India) for co-operation and Dr. K. G. Bhat (Maratha Mandal’s Dental College, Hospital and Research Centre, Belgaum, India) for providing facilities for antibacterial and antitubercular activity tests. Director, SAIF, Indian Institute of Technology, Chennai, Tamil Nadu, India and Director, USIC, Karnatak University Dharwad, India have provided NMR and mass spectral data. Dr. W.E. Rudzinski (Texas State University, San Marcos, USA) helped in mass spectral analysis. Mr. S. A. Tiwari provided the technical assistance to this project.

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Correspondence to Shrinivas D. Joshi.

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This paper is affectionately dedicated to my teacher Dr. V. H. Kulkarni for his service to Pharmacy Profession.

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Joshi, S.D., More, U.A., Parkale, D. et al. Design, synthesis of quinolinyl Schiff bases and azetidinones as enoyl ACP-reductase inhibitors. Med Chem Res 24, 3892–3911 (2015). https://doi.org/10.1007/s00044-015-1432-7

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