Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase

Abstract

a b s t r a c tHuman neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC 50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.

Optimization of N-Benzoylindazole Derivatives as Inhibitors of Human Neutrophil Elastase

“…Keeping at positions 1 and 3 those substituents that produced the best results in the previous series, 25 we first introduced a variety of groups at position 5 of the indazole nucleus, such as nitro, bromine, chlorine, (substituted)amino, etc. (Table 1).…”

“…Thus the C-6 position seems to be modifiable, while the total inactivity of 7-substituted derivatives confirms that the position neighboring the amidic nitrogen must be unsubstituted to allow free rotation of N-CO bond, which is consistent with our previous observations with other N -bezoylindazole derivatives. 25 …”

“…Recently, we discovered that N -benzoylpyrazoles and N -benzoylindazoles are potent HNE inhibitors 25-27 . In the present studies, we further optimize HNE inhibitors with an N -benzoylindazole scaffold and evaluate their biological activity.…”

Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

“…Our research group is involved in the design and synthesis of small molecules with HNE inhibitory activity, and we have identified a number of new classes of inhibitors based on different bicyclic scaffolds [14–17]. The most potent compounds are N -benzoylindazole derivatives, which have IC 50 values in the low nanomolar range (IC 50  = 7–80 nM) [14, 16].…”

“…The most potent compounds are N -benzoylindazole derivatives, which have IC 50 values in the low nanomolar range (IC 50  = 7–80 nM) [14, 16]. Moreover, we recently reported new isoxazolone-based derivatives with HNE inhibitory activity in the low nanomolar range (IC 50  = 20–96 nM) [18].…”