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

Abstract

In the present work, a concise library of 1,3,5-triaryl-2-pyrazolines (<b>2a-2q</b>) was designed and synthesized by employing a multistep strategy, and the newly synthesized compounds were screened for their urease and α-glucosidase inhibitory activities. The compounds (<b>2a-2q</b>) were characterized using a combination of several spectroscopic techniques including FT-IR, ¹H NMR, ¹³C NMR, and EI-MS. All the synthesized compounds, except compound <b>2i,</b> were potent against urease as compared to the standard inhibitor thiourea (IC₅₀ = 21.37 ± 0.26 μM). These analogs disclosed varying degrees of urease inhibitory activities ranging from 9.13 ± 0.25 to 18.42 ± 0.42 μM. Compounds <b>2b, 2g, 2m</b>, and <b>2q</b> having IC₅₀ values of 9.36 ± 0.27, 9.13 ± 0.25, 9.18 ± 0.35, and 9.35 ± 0.35 μM, respectively, showed excellent inhibitory activity as compared to standard thiourea (IC₅₀ = 21.37 ± 0.26 μM). A kinetic study of compound <b>2g</b> revealed that compound <b>2g</b> inhibited urease in a competitive mode. Among the synthesized pyrazolines, the compounds <b>2c, 2k, 2m</b>, and <b>2o</b> exhibited excellent α-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 μM, respectively, as compared to the standard acarbose (IC₅₀ = 375.82 ± 1.76 μM). The compounds (<b>2a-2q)</b> showed α-glucosidase IC₅₀ values in the range of 114.57 ± 1.35 to 462.94 ± 1.23 μM. Structure-activity relationship revealed that the size and electron-donating or -withdrawing effects of substituents influenced the activities, which led to the urease and α-glucosidase inhibiting properties. Compound <b>2m</b> was a dual potent inhibitor against urease and α-glucosidase due to the presence of 2-CF₃ 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 α-glucosidase with minimum IC₅₀ values. The cytotoxicity of the compounds (<b>2a-2q</b>) was also investigated against human cell lines MCF-7 and HeLa. Compound <b>2l</b> 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 α-glucosidase enzymes. Some compounds exhibited drug-like characteristics due to their lower cytotoxic and good ADME profiles.