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

Abstract

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.

Quantum chemical computations, fluorescence spectral features and molecular docking of two biologically active heterocyclic class of compounds

“…By using standard methods, we synthesized two coumarin derivatives viz, 3-[2-Oxo-2-(2-oxo-2H-chromen-3-yl)-ethylidene]-1,3dihydro-indol-2-one (3OCE) and 3-[2-Oxo-2-(3-oxo-3H-benzo[f]chromen-2-yl)-ethylidene]-1,3-dihydro-indol-2-one (3OBC) [63,65]. Solvents of different dielectric constant such as methanol (ML), acetonitrile (AN), ethanol (EL), dimethyl formamide (DMF), dimethyl sulphoxide (DMS), tetrahydrafuran (THF) and ethyl acetate (EA) are all of spectroscopic grade.…”

“…The crystal structure of galactose binding 10. These parameters infer that the coumarin compounds will bind strongly with periplasmic proteins of the blood [64,65].…”

“…Apart from that, quantum chemical computations were carried out using Gaussian 09 program like Mulliken charges, theoretical ground state dipole moment, NBO, MEP, NLO properties and Fukai calculations. Because of the polar nature and biological activity [65] of these coumarin compounds we planned to study the biophysical properties by docking with periplasmic proteins which are the major components of blood.…”

Application of Amino Acids in the Structural Modification of Natural Products: A Review

“…Additionally, antifungal experiments have shown that these compounds have moderate or even excellent antibacterial activity against common clinical pathogens. Further, Patagar et al ( 2019 ) designed and synthesized substituted coumarin-4-acetyl amino acids and determined their inhibitory activity against DHODH, a dual-target compound for malaria and cancer. The DHODH inhibitory activity of the newly synthesized compound was then determined.…”

Understanding the binding interaction between phenyl boronic acid P1 and sugars: determination of association and dissociation constants using S–V plots, steady‐state spectroscopic methods and molecular docking

“…The mechanism of the interaction between boronic acid and sugars through intermediates tetrahedral boronate 2 and boronate esters 3 and 4 is shown in Scheme 1. [ 2–4,19–41 ]…”