Development of quinoline‐based hybrid as inhibitor of methionine aminopeptidase 1 fromLeishmania donovani

Abstract

Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N‐terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani (LdMetAP1), we have synthesized a series of quinoline‐based hybrids, that is (Z)‐5‐((Z)‐benzylidine)‐2‐(quinolin‐3‐ylimino)thiazolidin‐4‐ones (QYT‐4a‐i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT‐4h) against LdMetAP1. The compound QYT‐4h showed nearly 20‐fold less potency for human MetAP1 and had drug‐like features. Time–course kinetic assays suggested QYT‐4h acting through a competitive mode by binding to the metal‐activated catalytic site. Notably, QYT‐4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of LdMetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT‐4h for LdMetAP1. Through molecular modelling and docking studies, we found QYT‐4h binding at the LdMetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small‐molecule inhibitors for selective targeting of LdMetAP1 which may find use to effectively eliminate leishmaniasis.

Antileishmanial Activity of Cinnamic Acid Derivatives against Leishmania infantum

“…The AAP homolog in P. falciparum is a validated molecular target for the development of antimalarial drug candidates [ 34 ]. In L. donovani and L. major , potent inhibitors have been reported for leucine aminopeptidase and methionine aminopeptidases 1 and 2 [ 35 , 37 , 44 ].…”

The Bioactivity of Thiazolidin-4-Ones: A Short Review of the Most Recent Studies

“…Bhat et al conducted synthesis of quinoline-thiazolidin-4-one hybrids (91a-91f and 92-94) (Figure 40) and carried out their inhibitory activity towards LdMetAP1 and HsMetAP1 in vitro [97]. Tested hybrids inhibited LdMetAP1 with IC 50 values in the range of 3.0-123.4 µM and HsMetAP1-54.2->200 µM.…”

Structural and Functional Basis of Potent Inhibition of Leishmanial Leucine Aminopeptidase by Peptidomimetics

“…Since tryptophan fluorescence is strongly influenced by its local environment, we titrated the LdLAP with the aminopeptidase inhibitors and recorded fluorescence measurements by monitoring a decrease in intensity. The relative fluorescence intensity obtained by [(F 0 − F)/F 0 ], where F 0 and F were the fluorescence intensities in the absence and presence of the substrates, was plotted against the inhibitor concentration as shown earlier, 40 and the quenching and association constants were calculated by Stern−Volmer and modified Stern−Volmer plots, respectively. 5.7.…”