Synthesis and Structure–Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum

Abstract

The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.

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

“…Previous inhibition studies show that cross inhibition of PfA-M1/PfA-M17 is achievable by targeting these catalytic zinc ion/s [9,10,[12][13][14][15], and led us to develop ((4-(1H-pyrazol-1-yl)phenyl)(amino)methyl)phosphonic acid (1) (Fig. 1C) (PfA-M1 K i = 104 µM and PfA-M17 K i = 0.011 µM), which binds within the S1 pocket of both enzymes [16]. However, differences in the compound binding profiles of the enzymes meant that compound elaboration tended toward improved inhibition of one enzyme target at the expense of the other.…”

<i>In silico</i> Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of <i>Plasmodium falciparum</i> M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile

“…The training and validation sets of aminophosphonic and amino-hydroxamic analogues inhibitors of pfA-M17 used in this study were selected from literature [12,13]. The inhibitory potencies of these derivatives cover sufficiently broad range of activity to allow reliable QSAR models to be built (11 ≤ K i ≤ 1000001 nM and 8 ≤ K i ≤ 501000 nM respectively).…”

“…Thereafter phosphonic arginine inhibitors were designed (K i ≥ 11 nM) (compound 2 in Figure 1) probing the S1 pocket at the enzyme active site for a better insight into the interactions and structural requirements for nanomolar range potency [12]. X-rays crystal structure of pfA-M17 in complex with 2 confirmed these interactions particularly the coordination of 2 to the catalytic zinc ion through the aminophosphonate moiety [12].…”

“…The X-rays crystal structure analysis of pfA-M17 (PDB code 4K3N) active site reveals, besides the two catalytic zinc ions in coordination with Asp 459, Lys 374, Asp 379, Asp 399, Glu 461, also a narrow hydrophobic S1 pocket with residues Met 392, Met 396, Phe 398 (suitable for stacking interaction), Thr 486, Gly 489, Leu 492, and Phe 583 and no suitable polar hydrogen-bonding partners (acceptor or donor) to interact with any charged P1 sidechain [9,12,13] and finally a S1' cavity with hydrophobic residues namely Ala 460 and Ile 547. (1), phosphonic arginine core (2) and amino-hydroxamic acid core (3).…”

“…Thereafter phosphonic arginine inhibitors were designed (K i ≥ 11 nM) (compound 2 in Figure 1) probing the S1 pocket at the enzyme active site for a better insight into the interactions and structural requirements for nanomolar range potency [12]. X-rays crystal structure of pfA-M17 in complex with 2 confirmed these interactions particularly the coordination of 2 to the catalytic zinc ion through the aminophosphonate moiety [12]. More recently, the same authors extended their investigations by replacing the phosphonic acid Zinc Binding Group (ZBG) present in 2 with an aminohydroxamic acid analogue of aminophosphonic in order to probe the S1' pocket of pfA-M17 for additional affinity.…”