New 3‐unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation

Abstract

Human neutrophil elastase (HNE) is a proteolytic enzyme belonging to the serine protease family and is involved in a variety of pathologies. Thus, compounds able to inhibit HNE represent promising therapeutics for the treatment of inflammatory diseases. Here, we report the further elaboration of our previously reported 3-methylisoxazolone derivatives, synthesizing a new series of 3-nor-derivatives bearing different substituents at the 4-phenyl ring. The most potent compounds 3a, 3g, and 3h, had IC 50 values of 16, 11, and 18 nM, respectively. Molecular modeling studies and molecular dynamic (MD) simulations demonstrated no substantial differences between the 3-methylisoxazole derivatives previously tested and the corresponding 3-unsubstituted derivatives in the snapshot conformations sampled during the MD simulations, which is consistent with their similar levels of HNE inhibitory activity.Thus, we conclude that the isoxazolone scaffold is a good scaffold for developing HNE inhibitors, as it tolerates several modifications when adhering to basic scaffold requirements, and the resulting derivatives are quite potent HNE inhibitors. K E Y W O R D Shuman neutrophil elastase inhibitors, molecular and crystal structures, molecular modeling

Ebselen analogues with dual human neutrophil elastase (HNE) inhibitory and antiradical activity

“…9,14,15 In 2020, Laforge and co-workers 16 published an interesting study suggesting that compounds with synergistic HNE inhibitory and antioxidant activities could have therapeutic potential for the treatment of Covid-19. Based on our previous experience in developing potent HNE inhibitors, 17,18 we initiated a new strategy to synthesize novel ebselen-containing seleno derivatives of our previously reported HNE inhibitors (Fig. 2).…”

Affinity of Antifungal Isoxazolo[3,4-b]pyridine-3(1H)-Ones to Phospholipids in Immobilized Artificial Membrane (IAM) Chromatography

“…Isoxazolone derivatives have numerous medicinal applications, mainly due to their antibacterial [ 1 , 2 , 3 ], antitubercular [ 1 ], fungicidal [ 4 ], antileukemic [ 1 ], anticancer [ 5 ], antioxidant [ 6 , 7 , 8 ], antiandrogenic [ 9 ], and antinociceptive activities [ 7 ], among many others [ 10 , 11 , 12 ].…”

A Combined Crystallographic and Computational Study on Dexketoprofen Trometamol Dihydrate Salt

“…X-ray crystallography is the key to studying structure-property relationships and single crystal X-ray diffraction (SCXRD) is the method of choice for molecular and crystal structure determination when crystals are available, as well as X-ray powder diffraction (XRPD), which provides an alternative valuable tool for the characterization of crystalline powder materials [10]. Both of these techniques [11][12][13][14][15], complemented by differential scanning calorimetry [16][17][18], solid state NMR [19], IR-UV and Raman spectroscopy [20][21][22] and modelling [23][24][25][26][27][28][29], can be successfully used to characterize the solid state features and behavior (e.g., phase stability, polymorphism, phase transformation) of a large variety of compounds including APIs' key precursors, well-known APIs as well as new promising active pharmaceutical compounds.…”