Functionalized furo[3,2-c]coumarins as anti-proliferative, anti-lipolytic, and anti-inflammatory compounds: Synthesis and molecular docking studies

Abstract

Abstract A simple and facile synthesis of a series of functionalized furo [3,2-c]coumarins 3a-j was successfully accomplished. A one-pot three component condensation reaction of substituted benzaldehydes with 2 equiv. of 4-hydroxycoumarin in DMSO solvent and in the presence of iodine at 80\u202f°C lead to the preparation of the target compounds 3a-j. Moderate reaction conditions were used, the work-up method was smooth and simple and the desired target compounds were obtained in excellent yields. The in\xa0vitro antiproliferative activity of the novel synthesized target compounds was evaluated against five colorectal cancer cell lines; HT29, HCT116, SW620, SW480 and CACO2 using Sulforhodamine B (SRB) colorimetric assay. Murine RAW264.7\u202fcells were used in anti-inflammatory and antiglycation in\xa0vitro bioassays. Compounds 3g and 3h showed outstanding antiproliferative activity in 3 out of 5 colorectal cancer cells. The non-selective cytotoxicity of the 3b compound in PDL fibroblasts was comparable to that of cisplatin. Moreover, the target compounds were also evaluated for antilipolytic activity alongside the pancreatic lipase (PL) inhibitor orlistat as a standard drug. Compounds 3f, 3h, and 3j displayed good PL inhibition. With appreciable safety profile, the remarkable anti-inflammatory activities of all tested furocoumarins were Incomparably exceeding indomethacin efficacy (IC50 value of 212\u202f±\u202f8\u202fμM) using Griess assay. Like aminoguanidine (IC50 value of 3.1\u202f±\u202f0.35\u202fμM); Furocoumarin compound 3g; among the rest, could impressively exert a moderate protection against methylglyoxal-induced carbonyl toxicity (IC50 value of 364.6\u202f±\u202f32.8\u202fμM). Molecular docking studies were performed on pancreatic lipase enzyme. The most potent inhibitor 3h showed a good fitting within the binding site of PL.