Jayaprakash Venkatesan, Sinha Barij N, Ucar Gulberk, Ercan Ayse
Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
Bioorg Med Chem Lett. 2008 Dec 15;18(24):6362-8. doi: 10.1016/j.bmcl.2008.10.084. Epub 2008 Nov 1.
3,5-Diaryl carbothioamide pyrazolines designed as mycobactin analogs (mycobacterial siderophore) were reported to be potent antitubercular agents under iron limiting condition in our earlier study. Clinical complications of newly introduced antibiotic Linezolid, due its MAO inhibitory activity, prompted us to evaluate our compounds for their MAO-inhibitory activity against rat liver MAO-A and MAO-B as pyrazolines were reported to be antidepressants and MAO inhibitors. The present study carried out with this pilot library of 32 compounds will provide us with necessary information for designing antitubercular molecules with reduced MAO-inhibitory activity and also help us in identifying a selective MAO-B inhibitor which has potential clinical utility in neurodegenerative disorders. Thirty-two compounds analyzed has shown spectrum of activity from selective to nonselective against two isoforms of rat liver MAO-A and MAO-B and also as competitive, reversible to non-competitive, irreversible. It is also interesting to note that anti-tubercular compound 11, 14 and 16 were also found to be selective inhibitors of rat liver MAO-B. Docking studies with human MAO shows that compound 11 interacts with the catalytic site of both the isoforms, suggesting compound 11 as nonselective inhibitor of human MAO isoforms.
在我们早期的研究中，设计为分枝杆菌铁载体类似物的3,5 - 二芳基碳硫酰胺吡唑啉在铁限制条件下被报道为有效的抗结核药物。新引入的抗生素利奈唑胺因其单胺氧化酶（MAO）抑制活性而产生临床并发症，这促使我们评估我们的化合物对大鼠肝脏MAO - A和MAO - B的MAO抑制活性，因为据报道吡唑啉是抗抑郁药和MAO抑制剂。用这个包含32种化合物的先导库进行的本研究将为我们提供必要的信息，以设计出具有降低MAO抑制活性的抗结核分子，同时也有助于我们鉴定出一种在神经退行性疾病中具有潜在临床应用价值的选择性MAO - B抑制剂。对32种化合物的分析表明，它们对大鼠肝脏MAO - A和MAO - B的两种同工酶具有从选择性到非选择性的活性谱，并且其抑制类型从竞争性、可逆性到非竞争性、不可逆性。同样有趣的是，抗结核化合物11、14和16也被发现是大鼠肝脏MAO - B的选择性抑制剂。对人MAO的对接研究表明，化合物11与两种同工酶的催化位点相互作用，表明化合物11是人MAO同工酶的非选择性抑制剂。
