Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG)

Abstract

A series of trisubstituted thiazoles have been identified as potent inhibitors of Plasmodium falciparum (Pf) cGMP-dependent protein kinase (PfPKG) through template hopping from known Eimeria PKG (EtPKG) inhibitors. The thiazole series has yielded compounds with improved potency, kinase selectivity and good in vitro ADME properties. These compounds could be useful tools in the development of new anti-malarial drugs in the fight against drug resistant malaria.

Keywords: Malaria; PfPKG; Plasmodium falciparum; Thiazole.

Figure 1

Structure and in vitro data of compounds of 1 (data unpublished) and 2.

Figure 2

Structure and in vitro data of thiazole 3.

Figure 3

Compounds 3 (left) and 9d (right) docked into an apo crystal structure of PfPKG (PDB:5DYK) using Schrodinger GlideSP. The protein surface is coloured by electrostatic potential (red negative, blue positive) and ligand H-bonding interactions are shown in magenta (distance in angstroms), with aromatic interactions in cyan.

Figure 4

Compounds 3 (left) and 23 (right) docked into an apo crystal structure of PfPKG (PDB:5DYK) using Schrodinger GlideSP. The protein surface is coloured by electrostatic potential (red negative, blue positive) and ligand H-bonding interactions are shown in magenta (distance in angstroms).

Figure 5

Selectivity of compounds 9c, 16a and 23 against a panel of human kinases at a concentration of 100 nM. Red is >90% inhibition; yellow between 90% and 70% inhibition, green <70% inhibition, white—not tested

Scheme 1

Reagents and conditions (a) LiHMDS (1M in THF), THF, 0 °C to r.t., 25%; (b) (i) (Me)₃SiCl, (ⁿBu)₄NBr, DMSO, THF, 0 °C to r.t., (ii) tert-butyl 4-carbamothioyl-piperidine-1-carboxylate, EtOH, reflux, 79%; (c) (i) 4M HCl/dioxane (ii) HCHO, Na(OAc)₃BH, AcOH, CH₂Cl₂, 47%; (d) (i) H₂O₂, Na₂WO₄.2H₂O, AcOH; (ii) NH₄OAc, 130 °C or AlkNH₂, THF, 70 °C or ArNH₂, TFA, ^sBuOH, 130 °C, 10-45%.

Scheme 2

Reagents and conditions (a) LiHMDS (1M in THF), THF, 0 °C to r.t., 80%; (b) (i) (Me)₃SiCl, (ⁿBu)₄NBr, DMSO, THF, 0 °C to r.t., (ii) tert-butyl 4-carbamothioylpiperidine-1-carboxylate, EtOH, reflux, 25%; (c) (i) 4M HCl/dioxane (ii) HCHO, Na(OAc)₃BH, AcOH, CH₂Cl₂; (d) (i) H₂O₂, Na₂WO₄.2H₂O, AcOH; (ii) NH₄OAc, 130 °C or AlkNH₂, THF, 70 °C or ArNH₂, TFA, ^sBuOH, 130°C,12-35% from (14)

Scheme 3

Reagents and conditions (a) (i) H-cube, 10% Pd/C, 1 atm, r.t. (ii) methyl chloroformate, pyridine, CH₂Cl₂, 0 °C to r.t., 94%; (b) LiHMDS (1M in THF), THF, 0 °C to r.t., 67%; (c) (i) (Me)₃SiCl, (ⁿBu)₄NBr, DMSO, THF, 0 °C to r.t., (ii) tert-butyl 4-carbamothioylpiperidine-1-carboxylate, EtOH, reflux; (d) (i) 4M HCl/dioxane (ii) HCHO, Na(OAc)₃BH, AcOH, CH₂Cl₂; (e) MeSO₂Cl, Et₃N, CH₂Cl₂, 0 °C to r.t. 13% from (19); (f) 2M NaOH (aq), dioxane, 80 °C, 49%; (g) (i) H₂O₂, Na₂WO₄.2H₂O, AcOH; (ii) cyclopropylmethylamine, THF, 70 °C, 11% from (21)