European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-08-23 , DOI: 10.1016/j.ejmech.2020.112772 Chhuttan L Meena 1 , Padam Singh 1 , Ravi P Shaliwal 1 , Varun Kumar 1 , Arun Kumar 1 , Anoop Kumar Tiwari 1 , Shailendra Asthana 1 , Ramandeep Singh 1 , Dinesh Mahajan 1
Herein, we report the synthesis and anti-tubercular studies of novel molecules based on thiophene scaffold. We identified two novel small molecules 4a and 4b, which demonstrated 2-fold higher in vitro activity (MIC99: 0.195 μM) compared to first line TB drug, isoniazid (0.39 μM). The identified leads demonstrated additive effect with front line TB drugs (isoniazid, rifampicin and levofloxacin) and synergistic effect with a recently FDA-approved drug, bedaquiline. Mechanistic studies (i) negated the role of Pks13 and (ii) suggested the involvement of KatG in the anti-tubercular activity of these identified leads.
中文翻译:
噻吩基小分子的合成和评估,作为结核分枝杆菌的有效抑制剂。
在这里,我们报告基于噻吩支架的新型分子的合成和抗结核研究。我们确定了两个新的小分子图4a和4b中,这表明高2倍的体外(MIC活动99:0.195 μ相比第一线TB药物,异烟肼(0.39 M) μ M)。鉴定出的线索证明与一线结核病药物(异烟肼,利福平和左氧氟沙星)具有加合作用,与最近获得FDA批准的药物bedaquiline具有协同作用。机理研究(i)否定了Pks13的作用,并且(ii)建议KatG参与这些已鉴定导线的抗结核活性。