2. Academic Validation
  3. Ultrasound assisted rapid synthesis of mefenamic acid based indole derivatives under ligand free Cu-catalysis: Their pharmacological evaluation

Ultrasound assisted rapid synthesis of mefenamic acid based indole derivatives under ligand free Cu-catalysis: Their pharmacological evaluation

  • Bioorg Med Chem Lett. 2020 May 15;30(10):127112. doi: 10.1016/j.bmcl.2020.127112.
Rapolu Venkateshwarlu 1,  Shambhu Nath Singh 2,  Vidavalur Siddaiah 3,  Hindupur Ramamohan 2,  Rambabu Dandela 4,  Kazi Amirul Hossain 5,  P Vijaya Babu 5,  Manojit Pal 6
Affiliations

Affiliations

  • 1 Custom Pharmaceutical Services and Dr. Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India; Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India.
  • 2 Custom Pharmaceutical Services and Dr. Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India.
  • 3 Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India.
  • 4 Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indianoil Odisha Campus, Samantpuri, Bhubaneswar 751013, India. Electronic address: r.dandela@iocb.ictmumbai.edu.in.
  • 5 Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India.
  • 6 Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India. Electronic address: manojitpal@rediffmail.com.
PMID: 32209292 DOI: 10.1016/j.bmcl.2020.127112
Abstract

An improved and rapid synthesis of mefenamic acid based indole derivatives has been achieved via the ligand free Cu-catalyzed coupling-cyclization method under ultrasound irradiation. This simple, straightforward and inexpensive one-pot method involved the reaction of a terminal alkyne derived from mefenamic acid with 2-iodosulfanilides in the presence of CuI and K2CO3 in PEG-400. The reaction proceeded via an initial CC bond formation (the coupling step) followed by CN bond formation (the intramolecular cyclization) to afford the mefenamic acid based indole derivatives in good to acceptable yields. Several of these compounds showed inhibition of PDE4 in vitro and the SAR (Structure Activity Relationship) within the series is discussed. The compound 3d has been identified as a promising and selective inhibitor of PDE4B (IC50 = 1.34 ± 0.46 µM) that showed TNF-α inhibition in vitro (IC50 = 5.81 ± 0.24 µM) and acceptable stability in the rat liver microsomes.

Keywords

Cu; Indole; Mefenamic acid; PDE4; Ultrasound.

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