Design and synthesis of novel nitrothiazolacetamide conjugated to different thioquinazolinone derivatives as anti-urease agents

Abstract

The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones. Fourteen nitrothiazolacetamide bearing thioquinazolinones derivatives (8a-n) were synthesized through the reaction of isatoic anhydride with different amine, followed by reaction with carbon disulfide and KOH in ethanol. The intermediates were then converted into final products by treating them with 2-chloro-N-(5-nitrothiazol-2-yl)acetamide in DMF. All derivatives were then characterized through different spectroscopic techniques (¹H, ¹³C-NMR, MS, and FTIR). In vitro screening of these molecules against urease demonstrated the potent urease inhibitory potential of derivatives with IC₅₀ values ranging between 2.22 ± 0.09 and 8.43 ± 0.61 μM when compared with the standard thiourea (IC₅₀ = 22.50 ± 0.44 μM). Compound 8h as the most potent derivative exhibited an uncompetitive inhibition pattern against urease in the kinetic study. The high anti-ureolytic activity of 8h was confirmed against two urease-positive microorganisms. According to molecular docking study, 8h exhibited several hydrophobic interactions with Lys10, Leu11, Met44, Ala47, Ala85, Phe87, and Pro88 residues plus two hydrogen bound interactions with Thr86. According to the in silico assessment, the ADME-Toxicity and drug-likeness profile of synthesized compounds were in the acceptable range.

Figure 1

Chemical structures of some biologically active agents and commercial medicine against urease.

Figure 2

The synthetic path of the target compounds 8a-n.

Figure 3

The Lineweaver–Burk plot of compound 8h at different concentrations against urease of three independent experiments.

Figure 4

Double reciprocal Lineweaver–Burk plot of 8h against urease of three independent experiments.

Figure 5

Schematic view of jack bean urease domains.

Figure 6

Potential binding sites of jack bean urease detected by sitemap. In each site’s magnified image the hydrophob (yellow), H-bond acceptor (red), and H-bond donor (blue) parts have been indicated.

Figure 7

3D and 2D interactions of compound 8h in the [ESI] complex.