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Sulfonamides and carbamates of 3-fluoro-4-morpholinoaniline (linezolid intermediate): synthesis, antimicrobial activity and molecular docking study

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Abstract

The precursor compound 3-fluoro-4-morpholinoaniline (7) is an important intermediate of the antibiotic drug linezolid and was synthesized initially by the substitution of morpholine (5) on 1,2-difluoro-4-nitrobenzene (4) under neat conditions, resulting in 4-(2-fluoro-4-nitrophenyl)morpholine (6) followed by its nitro group reduction with Fe/NH4Cl. A series of new sulfonamides (9a–e) and carbamates (11a–e) have been synthesized in good yields (75–89%) by the reaction of substituted aryl sulfonyl chlorides (8a–e) and substituted aryl/acyclic chloroformates (10a–e) with precursor compound 7, respectively, for biological interest. Structures of the title products were elucidated by spectroscopic data such as IR, NMR (1H and 13C NMR) and mass and elemental analyses. The antimicrobial potency of title products was examined by the screening of growth of zone of inhibition against four bacteria and four fungi, and minimum inhibitory concentration (MIC) was also determined. Most of the compounds showed good to potent antimicrobial activity, whereas the title products, 9d and 9e against bacterial strains, and 9a, 9b, 9d and 11a against fungi, exhibited promising activity in the MIC range of 6.25–25.0 µg/mL. The whole biological activity results revealed that the sulfonamide derivatives behaved as potent antifungal agents as compared to the carbamate derivatives. Molecular docking studies of the crystal structure of topoisomerase II gyrase A complexed with natural inhibitor, clorobiocin (1kzn), using the molecular operating environment (MOE) programme were performed in order to predict the affinity and orientation of the synthesized compounds at the active enzyme site. The test compounds showed good binding affinities and formed hydrogen bonds with a surrounding of amino acids at the active sight, whereas compounds 9d (−189.0 kcal/mol) and 11a (−280.3 kcal/mol) exhibited high binding affinities and good agreement with in vitro antimicrobial screening.

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Acknowledgements

The authors gratefully acknowledge the Department of Bioinformatics and Department of Botany, S. V. University, Tirupati, for their support in the screening of the docking study and biological activity, respectively. The authors also express thanks to Hyderabad Central University and Osmania University for providing instrumentation facilities for recording spectroscopic data.

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Authors and Affiliations

  1. Department of Chemistry, Sri Venkateswara Arts College (TTDs), Tirupati-517 502, Andhra Pradesh, India

    Dasari Balija Janakiramudu & Ponne Venkata Chalapathi

  2. Chemical Research & Development, Micro Labs Limited, Bommasandra-Jigani Link Road, Bangalore-560 105, Karnataka, India

    Devineni Subba Rao & Chilukuru Srikanth

  3. Department of Bioinformatics, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India

    Saddala Madhusudhana

  4. Department of Botany, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India

    Poojary Sreenivasa Murthy & Mundla Nagalakshmidevamma

  5. Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India

    Chamarthi Naga Raju

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  1. Dasari Balija Janakiramudu
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Janakiramudu, D.B., Subba Rao, D., Srikanth, C. et al. Sulfonamides and carbamates of 3-fluoro-4-morpholinoaniline (linezolid intermediate): synthesis, antimicrobial activity and molecular docking study. Res Chem Intermed 44, 469–489 (2018). https://doi.org/10.1007/s11164-017-3114-1

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