Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.
Eur J Med Chem. 2016 Oct 4;121:169-180. doi: 10.1016/j.ejmech.2016.05.032. Epub 2016 May 20.
The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 μg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.
新型抗结核药物的开发一直是一个巨大的挑战，主要是因为目前可用的药物出现了耐药性。在这项研究中，通过基于配体的计算机筛选方法，从 Asinex 和 ZINC 库以及内部库中筛选了 60 种化合物。在结核分枝杆菌 H37Ra ATCC 25177 菌株中的生物测定实验中，（±）-1-（4-氯苯基）-2-（1H-咪唑-1-基）乙基-4-（3,4-二氯苯基）哌嗪-1-羧酸酯（5i）和 3-（4-氯苯基）-5-（2,4-二甲基嘧啶-5-基）-2-甲基吡唑并[1.5-a]嘧啶-7(4H)-酮（42）表现出最强的活性，其最低抑菌浓度（MIC）分别为 4 和 2μg/mL。这些分子为进一步优化有效的抗结核药物提供了一个良好的起点。
