Novel pyrimidine linked acyl thiourea derivatives as potent α-amylase and proteinase K inhibitors: design, synthesis, molecular docking and ADME studies

Abstract

To discover promising therapeutic agents, novel diaryl pyrimidine linked acyl thiourea derivatives (6a–j) were designed and synthesized via straightforward and multistep synthesis. The structure of these derivatives (6a–j) was confirmed by FTIR, ¹H, and ¹³C NMR spectroscopic techniques. The in vitro biological screening of these compounds was carried out to assess their bacterial, α-amylase, and proteinase K inhibition potential. The results manifested that the developed molecules (6a–j) possessed a remarkable inhibition potential against targeted α-amylase and proteinase K enzymes. The compounds 6j and 6g were found to be the most potent α-amylase inhibitors with IC₅₀ values of 1.478 ± 0.051 and 1.509 ± 0.039 μM, respectively. Meanwhile, the compounds 6a, 6f, and 6e having IC₅₀ values of 1.790 ± 0.079, 1.794 ± 0.080, and 1.795 ± 0.080 μM, respectively, showed high proteinase K inhibitory activity. A moderate antibacterial activity is also displayed by these compounds (6a–j). The different substitution on the framework of pyrimidine linked acyl thiourea pharmacophore, provided the valuable basis for structure–activity relationship studies. Additionally, to identify the binding affinities of our desired compounds, molecular docking study was used. ADME analysis was also conducted to explore the physicochemical properties. Hence, these studies shed light on the significance of pyrimidine-based acyl thiourea to attain potent efficacy in drug discovery.