Chalcone-Thiazole Hybrids: Rational Design, Synthesis, and Lead Identification against 5-Lipoxygenase

Abstract

A hybrid pharmacophore approach is used to design and synthesize novel chalcone-thiazole hybrid molecules. Herein, thiazole has been hybridized with chalcone to obtain a new class of 5-LOX inhibitors. In vitro biological evaluation showed that most of the compounds were better 5-LOX inhibitors than the positive control, Zileuton (IC₅₀ = 1.05 ± 0.03 μM). The best compounds in the series, namely, 4k, 4n, and 4v (4k: IC₅₀ = 0.07 ± 0.02 μM, 4n: IC₅₀ = 0.08 ± 0.05 μM, 4v: 0.12 ± 0.04 μM) are found to be 10 times more active than previously reported 2-amino thiazole (2m: IC₅₀ = 0.9 ± 0.1 μM) by us. Further, 4k has redox (noncompetitive) while 4n and 4v act through a competitive inhibition mechanism. SAR indicated that the presence of methoxy/methyl either in the vicinity of chalcone or both thiazole and chalcone contributed to the synergistic inhibitory effect.

Figure 1

Design of chalcone–thiazole hybrids via molecular hybridization.

Figure 2

Structures of reported 5-LOX inhibitors.

Figure 3

(a) Pharmacophoric model (Ph model) generated from known 5-LOX inhibitors in software MOE 2016.0801; (b) Ph model with geometric distances (A⁰) in a 3D spatial relationship; pharmacophore mapping of (c) 4k and (d) 4n with a Ph model. Pharmacophoric features: Hydrophobic (Hyd - green), H-bond acceptor (Acc2 - orange) and (blue in (Figure 3a)). Inhibitors superimposed in (Figure 3a) are Zileuton - magenta, Atreleuton - navy blue, Siteleuton - brown, di-o-prenylated - pink, and diarylsulfonylurea chalcone - black.

Scheme 1. Synthesis of Chalcone-Thiazole Hybrid (4a–w) Derivatives

Figure 4

Lineweaver–Burk plots for inhibitors at 0, 2, and 5 μM concentrations: (a) 4k, (b) 4n, (c) 4v. [S] = concentration of the substrate (AA, in μM), V = reaction rate.

Figure 5

Pseudoperoxidase activity plots for the consumption of 13(S)-HpODE (at 234 nm; control subtracted) by (a) Zileuton, (b) 4k, (c) 4n, (d) 4v, (e) 4b, (f) 4h, (g) 4m, (h) 4f, and (i) 4p as a function of time (in sec).

Figure 6

Binding modes of compounds with amino acid residues of 5-LOX (pdb ID 3O8Y). (a) Ligplot interaction of 4n. (b) Docked pose of 4n. (c) Ligplot interaction of 4v. (d) Docked pose of 4v. Dotted lines indicate interactions. Colors depicted are hydrogen: cyan, carbon: gray, nitrogen: blue, oxygen: red, sulfur: yellow.