α-Glucosidase and Nitric Oxide Inhibitory Activities of Pyranocoumarins and Carbazoles From the Roots of Clausena excavata and the Semisynthetic Analogs of Clausarin and Nordentatin.

Phytochemical investigation of the methanol extract of Clausena excavata roots led to the isolation of six pyranocoumarin derivatives, including xanthyletin (1), kinocoumarin (2), clausarin (3), nordentatin (4), dentatin (4a), and citrusarin A (5), and three carbazole alkaloids, that is, heptaphylline (6), 7-methoxymukonal (7), and clausine K (8). Seven new semisynthetic analogs of compounds 2, 3, and 4 (2a, 3b-3d, and 4b-4d) were prepared through methylation, etherification, and basic hydrolysis for biological assays. Compounds 2, 6, 3b, 3c, 4b, and 4c displayed stronger α-glucosidase inhibitory activity than the positive control, acarbose (IC50 391.47 µM), with IC50 values in the range of 32.89-92.55 µM. Molecular docking suggested that these compounds bind near the enzyme's active site via van der Waals forces, hydrogen bonds, and hydrophobic interactions. Compound 3 showed the strongest nitric oxide (NO) inhibitory activity (IC50 = 27.95 µM), followed by 3d (IC50 = 33.62 µM) and 4 (IC50 = 35.41 µM). For the two compounds tested for cytotoxicity against A549 cells, 3b (IC50 = 11.71 µM) was more potent than cisplatin (IC50 = 21.56 µM), whereas 4b (IC50 = 22.39 µM) showed similar activity to cisplatin. Drug-likeness and pharmacokinetic properties of the isolated and semisynthetic compounds were also evaluated.