Ultrasound promoted synthesis of N-(substituted phenyl)-2-(7‑hydroxy-4-methyl-2H-chromen-2-ylidene)hydrazine-1-carboxamides as cytotoxic and antioxidant agents

Abstract

New N-(substituted phenyl)-2-(7‑hydroxy-4-methyl-2H-chromen-2-ylidene)hydrazine-1-carboxamides (5a-l) was synthesized in two steps using environmentally friendly ultrasound irradiation. The first step involved solvent free synthesis of 7‑hydroxy-4-methyl-2H-chromen-2-one (3) by using catalytic amount (10% mol) of FeCl3. The second step involved condensation of intermediate 3 and hydrazine carboxamide HCl analogues (4a-l) under ultrasonic influence in the water-ethanol (2:1) solvent system to obtain the title compounds (5a-l) in good yield. The structure of prepared compounds (5a-l) was confirmed by spectroscopic study. The synthetic strategy described here has many advantages, including a simple procedure and high conversion with quick reaction times. The cytotoxicity was tested on 60 NCI cancer cell lines at 10 µM and N-(4-chlorophenyl)-2-(7‑hydroxy-4-methyl-2H-chromen-2-ylidene)hydrazine-1-carboxamide (5b) showed promising activity with maximum sensitivity against CCRF-CEM, UO-31, RPMI-8226, NCI-H522, and HL-60(TB) with growth percent (GP) of 17.50, 79.67, 80.59, 82.35, and 83.70 respectively. In a DPPH free radical scavenging assay, the compounds 5b and 5d showed promising antioxidant activity with IC50 values of 16.32±1.29 and 14.28±1.82 M, respectively. The binding affinity of the target ligands (5a-l) against the active site of FGFR was also investigated using molecular docking. Within the active site of FGFR4, the ligand 5b interacted with four H-bonds with Asp630 (carbonyl function), Glu520 (with amide NH and ArNH), and Ile609 (phenol function), while an imine “N” showed two salt bridges with Asp630 and Glu520.