Synthesis of Novel 4‐Substituted Coumarins, Docking Studies, and DHODH Inhibitory Activity

• Published in: Journal of heterocyclic chemistry 2019-10, Vol.56 (10), p.2761-2771
• Main Authors: Patagar, Dayanand, Kusanur, Raviraj, Sitwala, Nikum D., Ghate, Manjunath D., Saravanakumar, Shanmugasundar, Nembenna, Sharanappa, Gediya, Piyush A.
• Format: Article
• Language: English
• Subjects: Amino acids; Antioxidants; Coumarin; Docking; Esters; Heterocyclic compounds; Hydrolysis; Malaria; Substitutes; Synthesis; Vector-borne diseases
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.3644

Coumarins are the important class of naturally occurring heterocyclic compounds. Activities like antioxidant, antibacterial, anti‐inflammatory, and anticancer have been reported for coumarin derivatives. Present work details the synthesis of substituted coumarin‐4‐pyrrolones as well as coumarin‐4‐acetyl amino acids and their DHODH inhibitory activity, which is a dual target for malaria and cancer. Coumarin‐4‐acetic acids (2a–c) were coupled with different methyl esters of α‐amino acids (3) giving rise to corresponding coumarin‐4‐acetyl amino acid methyl esters (4a–o), which on hydrolysis under basic condition underwent cyclization forming substituted dihydropyrrole‐2‐ones (5a–i), dihydroindolizine‐3‐ones (5j–l), and dihydropyrrolizin‐3‐one (5m–o). Acidic hydrolysis of the compounds (4a–o) yielded corresponding coumarin‐4‐acetyl amino acids (6a–f). The docking study was performed with the protein 4IGH (obtained from PDB) using Surflex–Dock module. The newly synthesized compounds were tested for DHODH inhibitory activity using Brequinar as the standard. Compound 6b showed remarkable inhibition compared with the standard, and the other compounds with terminal COOH showed moderate inhibition.