Pasha Anam Rubbab, Ullah Saeed, Halim Sobia Ahsan, Khan Ajmal, Hussain Javid, F El-Kott Attalla, Naseer Muhammad Moazzam, Eltantawy Waleed, Al-Harrasi Ahmed, Shafiq Zahid
Institute of Chemical Sciences, Bahauddin Zakariya University, Multan-60800, Pakistan.
Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman.
Curr Med Chem. 2024 Oct 14. doi: 10.2174/0109298673325023240909101327.
Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia.
The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde- based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in-vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 μM).
Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 μM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 μM) indicated competitive inhibition of the aforementioned enzyme.
Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.
脯氨酰特异性寡肽酶（POP）是大脑中高表达的酶之一，是治疗中枢神经系统疾病（尤其是自闭症谱系障碍、精神分裂症、帕金森病、阿尔茨海默病和痴呆症）的重要靶点。
本研究旨在研究基于2,4-双（三氟甲基）苯甲醛的硫代半卡巴腙作为POP抑制剂来治疗上述疾病。使用了多种技术，如核磁共振（NMR）、质谱（MS）和傅里叶变换红外光谱（FTIR）来对合成化合物进行结构确证。经过体外评估，发现所有这些化合物都是POP酶的显著抑制剂（IC50 = 10.14 - 41.73 μM）。
化合物3a是该系列中活性最高的化合物（IC50为10.14 ± 0.72 μM）。对活性最高的3a进行的动力学研究（Ki = 13.66 ± 0.0012 μM）表明其对上述酶具有竞争性抑制作用。
此外，分子对接显示硫代半卡巴腙部分在这些分子与POP酶活性位点的结合中起着显著作用。
