Synthesis and Evaluation of 1,3,5-Triaryl-2-Pyrazoline Derivatives as Potent Dual Inhibitors of Urease and α-Glucosidase Together with Their Cytotoxic, Molecular Modeling and Drug-Likeness Studies

In the present work, a concise library of 1,3,5-triaryl-2-pyrazolines (2a-2q) was designed and synthesized by employing a multistep strategy, and the newly synthesized compounds were screened for their urease and alpha-glucosidase inhibitory activities. The compounds (2a-2q) were characterized using a combination of several spectroscopic techniques including FT-IR, 1H NMR C-13 NMR, and EI-MS. All the synthesized compounds, except compound 2i, were potent against urease as compared to the standard inhibitor thiourea (IC50 = 21.37 +/- 0.26 EM). These analogs disclosed varying degrees of urease inhibitory activities ranging from 9.13 +/- 0.25 to 18.42 +/- 0.42 mu M. Compounds 2b, 2g, 2m, and 2q having IC50 values of 9.36 +/- 0.27, 9.13 +/- 0.25, 9.18 +/- 0.35, and 9.35 +/- 0.35 mu M, respectively, showed excellent inhibitory activity as compared to standard thiourea (IC50 = 21.37 +/- 0.26 mu M). A kinetic study of compound 2g revealed that compound 2g inhibited urease in a competitive mode. Among the synthesized pyrazolines, the compounds 2c, 2k, 2m, and 2o exhibited excellent alpha-glucosidase inhibitory activity with the lowest IC50 values of 212.52 +/- 1.31, 237.26 +/- 1.28, 138.35 +/- 1.32, and 114.57 +/- 1.35 mu M, respectively, as compared to the standard acarbose (IC50 = 375.82 +/- 1.76 mu M). The compounds (2a2q) showed alpha-glucosidase IC50 values in the range of 114.57 +/- 1.35 to 462.94 +/- 1.23 mu M. Structure-activity relationship revealed that the size and electron-donating or -withdrawing effects of substituents influenced the activities, which led to the urease and aglucosidase inhibiting properties. Compound 2m was a dual potent inhibitor against urease and alpha-glucosidase due to the presence of 2-CF 3 electron-withdrawing functionality on the phenyl ring. To the best of our knowledge, these synthetic compounds were found to be the most potent dual inhibitors of urease and alpha-glucosidase with minimum IC50 values. The cytotoxicity of the compounds (2a-2q) was also investigated against human cell lines MCF-7 and HeLa. Compound 21 showed moderate cytotoxic activity against MCF-7 and HeLa cell lines. Moreover, in silico studies on most active compounds were also performed to understand the binding interaction of most active compounds with active sites of urease and alpha-glucosidase enzymes. Some compounds exhibited drug-like characteristics due to their lower cytotoxic and good ADME profiles.

Automated summary

In this study, a library of 1,3,5-triaryl-2-pyrazolines was designed and synthesized. These compounds were screened for their inhibitory activities against urease and alpha-glucosidase. Some compounds showed potent inhibitory activities, with the size and electron effects of substituents influencing the activities.