Design, Synthesis, Biological evaluation of Isonicotinoyl-pyrazolyl-coumarin derivatives and computational study

Abstract

• A series of new Scaffold isonicotinoyl-pyrazolyl-coumarin dyads was synthesized. • The structures of the new hybrid compounds were performed by spectroscopic means. • All the compounds were screened in vitro for their potential Antifungal and Antioxidant activities. • Theoretical calculations were done for the molecules geometries. • Synthesized compounds were docked with fungal protein (Phytase A) from Aspergillus niger using AutoDock 4 software A new series of 3-(5-Hydroxy-1-isonicotinoyl-3-methyl-4,5-dihydro-1 H -pyrazol-5-yl)-2 H -chromen-2-one derivatives 3a-g was efficiently synthesized under environmentally friendly reaction conditions by reaction of 3-acetoacetylcoumarin derivatives 1a-g with isoniazid 2 . The reaction is conveniently performed at room temperature using Knorr pyrazole syntheses. The key features of this approach are its operational simplicity, the facile access to the desired products, and the good to excellent yields. The structures of the newly synthesized compounds were established by 1 H, 13 C, 2D NMR spectroscopy and mass spectrometry. 1 H- 15 N HMBC experiments were also conducted to assess the regiochemistry of final compounds. All the synthesized compounds were evaluated for their in vitro antifungal activity against both Candida albicans and Aspergillus niger strains and compared to the standard drug Ketoconazole. Among all the compounds, 3d and 3e were the most effective, showing high potential antigungal inhibitory activities with respective MIC values of 15.62 µg ml −1 for 3e against Aspergillus niger. All the newly synthesized derivatives 3a-g are evaluated for their antioxidant activity and showed good activity. SAR studies demonstrated that the presence of nitro and hydroxyl groups in the aromatic ring of the coumarin and pyrazoline rings conferred enhanced antioxidant and antifungal activity. In addition, molecular docking studies were performed for compound 3e to evaluate its potential as an inhibitor of the fungal protein (Phytase A) from Aspergillus niger and the results suggested that our isonicotinoyl-pyrazolyl-coumarin may act as promising antifungal agent.