CuCl2-catalyzed inexpensive, faster and ligand/additive free synthesis of isoquinolin-1(2H)-one derivatives via the coupling–cyclization strategy: Evaluation of a new class of compounds as potential PDE4 inhibitors

B. Thirupataiah, Guntipally Mounika, Gangireddy Sujeevan Reddy, Jetta Sandeep Kumar, Ravikumar Kapavarapu, Raghavender Medishetti, Jayesh Mudgal, Jessy E. Mathew, Gautham G. Shenoy, C. Mallikarjuna Rao, Kiranam Chatti, Kishore V. L. Parsa, Manojit Pal

Research output: Contribution to journalArticlepeer-review

Abstract

In spite of possessing a wide range of pharmacological properties the anti-inflammatory activities of isoquinolin-1(2H)-ones were rarely known or explored earlier. PDE4 inhibitors on the other hand in addition to their usefulness in treating inflammatory diseases have been suggested to attenuate the cytokine storm in COVID-19 especially TNF-α. In our effort, a new class of isoquinolin-1(2H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4. Accordingly, for the first time a CuCl2-catalyzed inexpensive, faster and ligand/additive free approach has been developed for the synthesis of these predesigned isoquinolin-1(2H)-one derivatives via the coupling–cyclization strategy. Thus, the CuCl2-catalyzed reaction of 2-iodobenzamides with appropriate terminal alkynes proceeded with high chemo and regioselectivity affording the desired compounds in 77–84% yield within 1–1.5 h. The methodology also afforded simpler isoquinolin-1(2H)-ones devoid of aminosulfonyl moiety showing a broader generality and scope of this approach. Several of the synthesized compounds especially 3c, 3k and 3s showed impressive inhibition (83–90%) of PDE4B when tested at 10 µM in vitro whereas compounds devoid of aminosulfonyl moiety was found to be less active. In spite of high inhibition showed at 10 µM these compounds did not show proper concertation dependent inhibition below 1 µM that was reflected in their IC50 values e.g. 2.43 ± 0.32, 3.26 ± 0.24 and 3.63 ± 0.80 µM for 3k, 3o and 3s respectively. The anti-inflammatory potential of these compounds was indicated by their TNF-α inhibition (60–50% at 10 µM). The in silico docking studies of these molecules suggested good interactions with PDE4B and selective inhibition of PDE4B by 3k over PDE4D that was supported by in vitro assay results. These observations together with the favorable ADME and safety predicted for 3k in silico not only suggested 3k as an interesting hit molecule for further studies but also reveal the first example of isoquinolin-1(2H)-one based inhibitor of PDE4B.

Original languageEnglish
Article number105265
JournalBioorganic Chemistry
Volume115
DOIs
Publication statusPublished - 10-2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'CuCl<sub>2</sub>-catalyzed inexpensive, faster and ligand/additive free synthesis of isoquinolin-1(2H)-one derivatives via the coupling–cyclization strategy: Evaluation of a new class of compounds as potential PDE4 inhibitors'. Together they form a unique fingerprint.

Cite this