Parambi Della Grace Thomas, Cloete Stephanus J, Kumar Sunil, Alsahli Tariq Ghazi, Musa Arafa, Qasim Sumera, Kabier Muzammil, Sudevan Sachithra Thazhathuveedu, Parmbil Saranya Kattil, Petzer Anél, Petzer Jacobus P, Mathew Bijo
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia.
Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
J Comput Aided Mol Des. 2025 Sep 19;39(1):84. doi: 10.1007/s10822-025-00663-8.
A series of ten chloro- and bromo-substituted isatin derivatives were synthesized and evaluated for their ability to inhibit the monoamine oxidase (MAO) enzymes. All compounds demonstrated more potent inhibition of MAO-A compared to MAO-B. The most potent MAO-A inhibitor was HIB2 (IC = 0.037 μM), followed by HIB4 (IC = 0.039 μM), while HIB10 (IC = 0.125 μM) exhibited the most potent inhibition of MAO-B. HIB2 was identified as a specific MAO inhibitor with a selectivity index of 29 for MAO-A over MAO-B. The enzyme-inhibitor dissociation constants (K) for HIB2 and HIB10 were 0.031 μM and 0.036 μM, respectively, for MAO-A and MAO-B. Both HIB2 and HIB10 exhibited competitive and reversible inhibition. An analysis of the ADMET and PAMPA suggested that HIB2 is permeable to the blood-brain barrier (BBB). Molecular docking analysis revealed that HIB2 forms stable hydrogen bonds with Asn181 and Gln215 in the MAO-A ligand-protein complex. Dynamic analysis indicated the stability of HIB2 with MAO-A. These findings suggest that HIB2 is potent reversible MAO-A inhibitor, making this class of compounds potential therapeutic agents for neurological disorders.
合成了一系列十种氯代和溴代异吲哚酮衍生物，并评估了它们抑制单胺氧化酶（MAO）的能力。与MAO-B相比，所有化合物对MAO-A的抑制作用更强。最有效的MAO-A抑制剂是HIB2（IC = 0.037 μM），其次是HIB4（IC = 0.039 μM），而HIB10（IC = 0.125 μM）对MAO-B的抑制作用最强。HIB2被鉴定为一种特异性MAO抑制剂，对MAO-A的选择性指数比对MAO-B高29。HIB2和HIB10对MAO-A和MAO-B的酶-抑制剂解离常数（K）分别为0.031 μM和0.036 μM。HIB2和HIB10均表现出竞争性和可逆性抑制。ADMET和PAMPA分析表明，HIB2可透过血脑屏障（BBB）。分子对接分析显示，HIB2在MAO-A配体-蛋白质复合物中与Asn181和Gln215形成稳定的氢键。动力学分析表明HIB2与MAO-A具有稳定性。这些发现表明，HIB2是一种有效的可逆MAO-A抑制剂，使这类化合物成为治疗神经疾病的潜在治疗剂。
