Mehmood Rabia, Sadiq Amina, Alsantali Reem I, Mughal Ehsan Ullah, Alsharif Meshari A, Naeem Nafeesa, Javid Asif, Al-Rooqi Munirah M, Chaudhry Gul-E-Saba, Ahmed Saleh A
Department of Chemistry, Govt. College Women University, Sialkot 51300, Pakistan.
Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
ACS Omega. 2022 Jan 20;7(4):3775-3795. doi: 10.1021/acsomega.1c06694. eCollection 2022 Feb 1.
In the present work, a concise library of 1,3,5-triaryl-2-pyrazolines () 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 () were characterized using a combination of several spectroscopic techniques including FT-IR, H NMR, C NMR, and EI-MS. All the synthesized compounds, except compound were potent against urease as compared to the standard inhibitor thiourea (IC = 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 , and having IC 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 = 21.37 ± 0.26 μM). A kinetic study of compound revealed that compound inhibited urease in a competitive mode. Among the synthesized pyrazolines, the compounds , and exhibited excellent α-glucosidase inhibitory activity with the lowest IC 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 = 375.82 ± 1.76 μM). The compounds ( showed α-glucosidase IC 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 was a dual potent inhibitor against urease and α-glucosidase due to the presence of 2-CF 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 values. The cytotoxicity of the compounds () was also investigated against human cell lines MCF-7 and HeLa. Compound 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.
在本研究中，采用多步策略设计并合成了一个简洁的1,3,5 - 三芳基 - 2 - 吡唑啉类化合物库，并对新合成的化合物进行了脲酶和α - 葡萄糖苷酶抑制活性筛选。使用包括傅里叶变换红外光谱（FT - IR）、氢核磁共振（H NMR）、碳核磁共振（C NMR）和电子轰击质谱（EI - MS）在内的多种光谱技术对化合物进行了表征。与标准抑制剂硫脲（IC = 21.37 ± 0.26 μM）相比，除化合物 外，所有合成化合物对脲酶均具有强效抑制作用。这些类似物展现出不同程度的脲酶抑制活性，范围为9.13 ± 0.25至18.42 ± 0.42 μM。化合物 、 和 的IC值分别为9.36 ± 0.27、9.13 ± 0.25、9.18 ± 0.35和9.35 ± 0.35 μM，与标准硫脲（IC = 21.37 ± 0.26 μM）相比，显示出优异的抑制活性。对化合物 的动力学研究表明，化合物 以竞争模式抑制脲酶。在合成的吡唑啉类化合物中，化合物 、 和 表现出优异的α - 葡萄糖苷酶抑制活性，与标准阿卡波糖（IC = 375.82 ± 1.76 μM）相比，最低IC值分别为212.52 ± 1.31、237.26 ± 1.28、138.35 ± 1.32和114.57 ± 1.35 μM。化合物 显示出α - 葡萄糖苷酶IC值在114.57 ± 1.35至462.94 ± 1.23 μM范围内。构效关系表明，取代基的大小和供电子或吸电子效应影响了活性，进而导致了脲酶和α - 葡萄糖苷酶的抑制特性。由于苯环上存在2 - CF吸电子官能团，化合物 是一种对脲酶和α - 葡萄糖苷酶均有效的双重抑制剂。据我们所知，这些合成化合物被发现是脲酶和α - 葡萄糖苷酶最有效的双重抑制剂，IC值最低。还研究了化合物 对人细胞系MCF - 7和HeLa的细胞毒性。化合物 对MCF - 7和HeLa细胞系表现出中等细胞毒性活性。此外，还对最具活性的化合物进行了计算机模拟研究，以了解最具活性的化合物与脲酶和α - 葡萄糖苷酶活性位点的结合相互作用。一些化合物由于其较低的细胞毒性和良好的药物代谢动力学性质而表现出类药物特性。
