title: Synthesis and molecular modeling studies of derivatives of a highly potent peptidomimetic vinyl ester as falcipain-2 inhibitors.
abstract: Herein we report the synthesis of a set of constrained peptidomimetics endowed with an electrophilic vinyl ester warhead and structurally related to a previously identified lead compound, a potent and irreversible inhibitor of falcipain-2 (FP-2). FP-2 is the main hemoglobinase of the malaria parasite P. falciparum. The new compounds were evaluated for their inhibition against FP-2, and the results were rationalized on the basis of docking experiments. These studies underscore the pivotal role of both the ester function at the P1' site and the trifluoromethyl group of the P3 side chain in determining the correct orientation of the Michael acceptor warhead in the catalytic site, and as a consequence, the potency of the inhibitors as well as their reversible or irreversible mode of inhibition.
authors: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università di Milano, Via Mangiagalli 25, 20133 Milano, Italy. roberta.ettari@unimi.it
authors: Roberta
authors: R
authors: Ettari
authors: Nicola
authors: N
authors: Micale
authors: Giovanni
authors: G
authors: Grazioso
authors: Floriana
authors: F
authors: Bova
authors: Tanja
authors: T
authors: Schirmeister
authors: Silvana
authors: S
authors: Grasso
authors: Maria
authors: M
authors: Zappalà
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D057786:Peptidomimetics; D003546:Cysteine Endopeptidases; C416224:falcipain 2