Two-Pronged Attack: Dual Inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a Novel Series of Hydroxamic Acid-Based Inhibitors

Abstract

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

“…Lead compounds 2 and 3 were previously reported to inhibit Pf-3D7 with IC 50 values of 783 nM and 227 nM, respectively [17]. The N-pivaloyl series demonstrates superior activity against Pf-3D7 growth compared to the N-Boc series, which we predict to be the result of better cellular penetration and stability.…”

Preparation of Enantiomerically Pure Perfluorobutanesulfinamide and Its Application to the Asymmetric Synthesis of α-Amino Acids

“…Tetrahydrofuran and diethyl ether were purified by passage through activated alumina using a solvent purification system. [Cp*RhCl 2 ] 2 , 28 AgB(C 6 F 5 ) 4 , 29 benzoylpyrrolidine, 30 azobenzenes, 31 sulfoximine, 32 N -aryl-1 H -pyrazoles, 33 and 1-benzyl-4-phenyl-1 H -1,2,3-triazoles 34 were synthesized according to published procedures. 1,2-Dichloroethane (DCE) was deoxygenated by sparging with nitrogen gas followed by storage over activated 3 Å molecular sieves for 48 h prior to use.…”

“…In a N 2 -filled glovebox, perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv), the indicated 1-aryl-1 H -pyrazole ( 10e–10i ) 33 (0.300 mmol, 2.0 equiv), [Cp*RhCl 2 ] 2 (9.3 mg, 0.015 mmol, 0.10 equiv), and AgB(C 6 F 5 ) 4 (62.0 mg, 0.060 mmol, 0.40 equiv, 23.8 % w/w toluene) were added to a 0.5–2.0 mL microwave vial equipped with a triangular magnetic stir bar followed by the addition of 1,2-dichloroethane (200 μL, [sulfinyl imine] = 0.75 M). The vial was sealed and removed from the glovebox.…”

“…The general procedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0 equiv) and 1-(4-(1 H -pyrazol-1-yl)phenyl)ethan-1-one 33b (55.9 mg, 0.300 mmol, 2.0 equiv). Purification by preparative thin-layer silica gel chromatography using 25% EtOAc/hexanes afforded the product 11h (50.6 mg, 61% yield) as a light yellow waxy solid.…”

X‐ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti‐malarial drug targets PfA‐M1 and PfA‐M17

“…The M1 alanyl and M17 leucyl aminopeptidase families are highly conserved between malarial species, and therefore represent exciting targets for novel anti‐malarials . Inhibitors of Pf A‐M1 (peptidase clan MA, subclan MA(E); MAL13P1.56, http://plasmodb.org) and Pf A‐M17 (peptidase clan MF; Pf14_0439, http://plasmodb.org), have been demonstrated to be effective treatments for in vitro and murine models of malaria …”