Inhibition ofPlasmodium falciparumLysyl‐tRNA Synthetase via a Piperidine‐Ring Scaffold Inspired Cladosporin Analogues

Abstract

Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) represents a promising therapeutic anti-malarial target. Cladosporin was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X-ray crystallography reveal compounds that are moderate in potency. Co-crystals of ClaÀ B and ClaÀ C with PfKRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.Figure 1. The chemical structure and biological activity reported for febrifugine, halofuginone and the most potent quinazoline derivative (ln-5) of them. [9] ChemBioChem

Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development

“…EC 50 measures the concentration of the compound to obtain a 50% killing in a cell-based assay. The same group later reported another set of derivatives of cladosporin, Cla-B and Cla-C, where the tetrahydropyran frame was replaced with a piperidine ring having functional implications ( 55 ). Complex structures with Cla-B and Cla-C reveal similar binding orientations as Pf LysRS with cladosporin bound ( Table 1 ) ( 55 ).…”

“…The same group later reported another set of derivatives of cladosporin, Cla-B and Cla-C, where the tetrahydropyran frame was replaced with a piperidine ring having functional implications ( 55 ). Complex structures with Cla-B and Cla-C reveal similar binding orientations as Pf LysRS with cladosporin bound ( Table 1 ) ( 55 ). However, the orientation of the piperidine ring varies from that of the tetrahydropyran ring of the cladosporin.…”

Cladosporin, A Highly Potent Antimalaria Drug?

“…Other modifications, such as morpholine ring substitution (78), carboxylation (79) or exo-methylene decoration (80) towards the piperidine ring, all abolished the inhibitory activity (Figure 9). [74] It is noteworthy that based on the cellular target of cladosporin, a library of ~13,000 compounds against recombinant PfKRS was screened, and compound 81 was identified to have a comparable inhibitory activity and similar structure as cladosporin, but it was more tractable in the in vitro assay using mouse liver microsomes. Further optimisation of 81 led to the derivative 82, in which fluorine was added to the phenyl and cyclohexyl rings to block hydroxylations in the metabolic breakdown.…”

“…Figure9. The structures of cladosporin derivatives and their activities towards PfKRS (part IV) [74]. NI indicates no inhibition.…”

Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis

“…Based on their catalytic mechanisms and three-dimensional structures, aaRSs are known to possess three sub-sites of-1) ATP, 2) amino acid, and 3) tRNA binding pocket, in addition to other subsites [3,5]. Several parasite aaRSs are currently being investigated as potential drug targets [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Parasite species targeted include obligate intracellular apicomplexans that cause malaria (Plasmodium spp), toxoplasmosis (Toxoplasma gondii), and cryptosporidiosis (Cryptosporidium spp) [22][23][24][25].…”