New class of potent antinociceptive and antiplatelet 10 H-phenothiazine-1-acylhydrazone derivatives

Abstract

In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives ( 6), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine ( 4) and other heterocyclic derivatives ( 3) and ( 5) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine ( 7) as starting material, through regioselective functionalization of the C-1 position of 10 H-phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is ( 6a) (IC 50=2.3 μM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para-substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative ( 6g) and hydrophobic bromo derivative ( 6b) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action.