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 1,3,5triaryl-2-pyrazolines (2a−2q) 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 (2a−2q) were characterized using a combination of several spectroscopic techniques including FT-IR, 1 H NMR, 13 C NMR, and EI-MS. All the synthesized compounds, except compound 2i, were potent against urease as compared to the standard inhibitor thiourea (IC 50 = 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 2b, 2g, 2m, and 2q having IC 50 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 (IC 50 = 21.37 ± 0.26 μM). 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 α-glucosidase inhibitory activity with the lowest IC 50 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 (IC 50 = 375.82 ± 1.76 μM). The compounds (2a− 2q) showed α-glucosidase IC 50 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 αglucosidase inhibiting properties. Compound 2m was a dual potent inhibitor against urease and α-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 α-glucosidase with minimum IC 50 values. The cytotoxicity of the compounds (2a−2q) was also investigated against human cell lines MCF-7 and HeLa. Compound 2l 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.

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“…The inhibition constant ( K i ) value was constructed by secondary plots of the inhibitor concentration [ I ] versus K m . 97 …”

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