N-Arylacetamide derivatives of methyl 1,2-benzothiazine-3-carboxylate as potential drug candidates for urease inhibition

Abstract

Urease enzyme is an infectious factor that provokes the growth and colonization of virulence pathogenic bacteria in humans. To overcome the deleterious effects of bacterial infections, inhibition of urease enzyme is one of the promising approaches. The current study is designed to synthesize new 1,2-benzothiazine-N-arylacetamide derivatives 5(a-n) that can effectively provide a new drug candidate to avoid bacterial infections by urease inhibition. After structural elucidation by FT-IR, proton and carbon-13 NMR and mass spectroscopy, the synthesized compounds 5(a-n) were investigated to evaluate their inhibitory potential against urease enzyme. In vitro analysis against positive control of thiourea indicated that all the synthesized compounds have strong inhibitory strengths as compared to the reference drug. Compound 5k, being the most potent inhibitor, strongly inhibited the urease enzymes and revealed an IC₅₀ value of 9.8 ± 0.023 µM when compared with the IC₅₀ of thiourea (22.3 ± 0.031 µM)-a far more robust inhibitory potential. Docking studies of 5k within the urease active site revealed various significant interactions such as H-bond, π-alkyl with amino acid residues like Val744, Lys716, Ala16, Glu7452, Ala37 and Asp730.

Keywords: benzothiazine; docking; synthesis; thiourea; urease; ureolytic.

Scheme 1.

Synthetic route for methyl 1,2-benzothiazine-N-arylacetamides 5(a-n).

Figure 1.

Rationale of current work.

Figure 2.

Three- and two-dimensional visualization of compound 5k against urease.

Figure 3.

Three- and two-dimensional visualization of compound 5a against urease.

Figure 4.

Three- and two-dimensional visualization of compound 5l against urease.

Figure 5.

The molecular dynamic simulation study of docked complex 5k with urease. Deformability (a), β-factor (b), eigen values (c), variance (d), covariance map (e) and elastic network (f). In (d), green colour indicates cumulative variances and red colour indicates individual variances, while in (f) darker grey area represents high stiff regions. In (e), covariance map represents correlated, anticorrelated or uncorrelated motions shown in red, blue or white colour, respectively.