176770-30-2Relevant academic research and scientific papers
3,6-Disubstituted coumarins as mechanism-based inhibitors of thrombin and factor Xa
Frédérick, Rapha?l,Robert, Séverine,Charlier, Caroline,De Ruyck, Jér?me,Wouters, Johan,Pirotte, Bernard,Masereel, Bernard,Pochet, Lionel
, p. 7592 - 7603 (2007/10/03)
In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (ki/KI = 37 000 M-1 s-1). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with α-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.
Esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as inhibitors of α-chymotrypsin: Significance of the "aromatic" nature of the novel ester-type coumarin for strong inhibitory activity
Pochet, Lionel,Doucet, Caroline,Schynts, Marc,Thierry, Nicole,Boggetto, Nicole,Pirotte, Bernard,Jiang, Kai Y.,Masereel, Bernard,De Tullio, Pascal,Delarge, Jacques,Reboud-Ravaux, Michèle
, p. 2579 - 2585 (2007/10/03)
A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine α-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependen
