Fe(III)-catalyzed regioselective and faster synthesis of isocoumarins with 3-oxoalkyl moiety at C-4: Identification of new inhibitors of PDE4

B. Thirupataiah, Harshavardhan Bhuktar, Guntipally Mounika, Gangireddy Sujeevan Reddy, Jetta Sandeep Kumar, Sharda Shukla, Kazi Amirul Hossain, Raghavender Medishetti, Snigdha Samarpita, Mahaboobkhan Rasool, P. C. Jagadish, Gautham G. Shenoy, Kishore V.L. Parsa, Manojit Pal

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3 Citations (Scopus)

Abstract

In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl3 catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of C[sbnd]O and C[sbnd]C bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the C6H4NHSO2R2-m moiety at C-3 position of the isocoumarin ring was favorable when the R2 was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC50 values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.

Original languageEnglish
Article number105667
JournalBioorganic Chemistry
Volume121
DOIs
Publication statusPublished - 04-2022

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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