Thielavins A, J and K: α-Glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora.

Bioassay-guided fractionation of the bio-active organic extract obtained from solid-media culture of MEXU 27095, an endophytic fungus isolated from the Mexican medicinal plant Hintonia latiflora (Rubiaceae), led to separation of three tridepsides which were identified as thielavins A, J and K. All three compounds inhibited Saccharomyces cerevisieae α-glucosidase (αGHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1μM, respectively. Their inhibitory action was higher than that of acarbose (IC50=545μM), used as a positive control. Kinetic analysis established that the three compounds acted as non-competitive inhibitors with ki values of 27.8, 66.2 and 55.4μM, respectively (α=1.0, 1.2, 0.7, respectively); acarbose behaved as competitive inhibitor with a ki value of 156.1μM. Thielavin J inhibited the activity of α-glucosidase from Bacillus stearothermophilus (αGHBs) with an IC50 of 30.5μM, being less active than acarbose (IC50=0. 015μM); in this case, compound (2) (ki=20.0μM and α=2.9) and acarbose (ki=0.008μM and α=1.9) behaved as non-competitive inhibitors. Docking analysis predicted that all three thielavins and acarbose bind to homologated αGHBs and to αGHY (PDB: 3A4A) in a pocket close to the catalytic site for maltose and isomaltose, respectively. The α-glucosidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced a noted antihyperglycemic action during an oral sucrose tolerance test (3.1, 10.0 and 31.6mg/kg) in normal and nicotinamide-streptozotocin diabetic mice. In addition, at a dose of 10mg/kg, it provoked a moderate hypoglycemic activity in diabetic mice.