Chimenti Franco, Maccioni Elias, Secci Daniela, Bolasco Adriana, Chimenti Paola, Granese Arianna, Befani Olivia, Turini Paola, Alcaro Stefano, Ortuso Francesco, Cirilli Roberto, La Torre Francesco, Cardia Maria C, Distinto Simona
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Rome, Italy.
J Med Chem. 2005 Nov 17;48(23):7113-22. doi: 10.1021/jm040903t.
A novel series of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). All the synthesized compounds show high activity against both the MAO-A and the MAO-B isoforms with Ki values between 27 and 4 nM and between 50 and 1.5 nM, respectively, except for a few derivatives whose inhibitory activity against MAO-B was in the micromolar range. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation. The selectivity of the (-)-(S)-1 enantiomer against MAO-B increases twice and a half, while the selectivity of the (-)-(S)-4 enantiomer against MAO-A triples. Both the MAO-A and MAO-B isoforms respectively of the 1O5W and 1GOS models deposited in the Protein Data Bank were considered in the computational study. The docking study was carried out using several computational approaches with the aim of proposing possible binding modes of the MAO enantioselective compounds 1 and 4.
合成了一系列新型的1-硫代甲酰基-3,5-二芳基-4,5-二氢-(1H)-吡唑衍生物，并研究了它们选择性抑制单胺氧化酶（MAO）A和B同工型活性的能力。除少数对MAO-B的抑制活性在微摩尔范围内的衍生物外，所有合成化合物对MAO-A和MAO-B同工型均表现出高活性，其Ki值分别在27至4 nM和50至1.5 nM之间。由于知道立体化学可能是生物活性的重要调节剂，我们对最有效、选择性和手性的化合物进行了半制备色谱对映体分离。然后将分离出的对映体进行体外生物学评估。(-)-(S)-1对映体对MAO-B的选择性增加了两倍半，而(-)-(S)-4对映体对MAO-A的选择性增加了两倍。在计算研究中考虑了蛋白质数据库中存放的1O5W和1GOS模型的MAO-A和MAO-B同工型。使用几种计算方法进行对接研究，目的是提出MAO对映选择性化合物1和4可能的结合模式。
