Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.
Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.
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DOI：
10.1021/acs.jmedchem.2c00352
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发表时间：
2023-01-12
影响因子：
7.3
通讯作者：
North, E. Jeffrey
中科院分区：
文献类型：
--
作者：
Bhattarai, Pankaj;Hegde, Pooja;Li, Wei;Prathipati, Pavan Kumar;Stevens, Casey M.;Yang, Lixinhao;Zhou, Hinman;Pandya, Amit;Cunningham, Katie;Grissom, Jenny;Sotelo, Mariaelena Roman;Sowards, Melanie;Calisto, Lilian;Destache, Christopher J.;Rocha-Sanchez, Sonia;Gumbart, James C.;Zgurskaya, Helen I.;Jackson, Mary;North, E. Jeffrey
由结核分枝杆菌（M.tb）引起的结核病（TB）是发展中国家的主要死亡原因之一。非结核分枝杆菌（NTM）感染正在上升，并捕食患有结构性肺病（如慢性阻塞性肺病（COPD）和囊性纤维化）的患者。所有分枝杆菌感染都需要长期的治疗方案，并伴有不良副作用。因此，迫切需要具有新的作用机制的新的抗分枝杆菌化合物。已发表的吲哚-2-甲酰胺（IC）具有抑制必需转运蛋白MmpL 3的作用，对全细胞结核分枝杆菌显示出良好的效力，但水溶性差。该项目的重点是保留所需的MmpL 3抑制药效团，并通过减少亲脂性原子来增加分子杂原子百分比。我们评估了与亲脂性头部基团偶联的吡咯、扁桃酸、咪唑和乙酰胺官能团，其中基于铅乙酰胺的化合物保持对分枝杆菌病原体的高效力，相对于其吲哚-2-甲酰胺类似物具有改善的体外ADME谱，是无细胞毒性的，并且被确定为MmpL 3抑制剂。
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.
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影响因子：
3.5
作者：
Brown, Joshua R.;North, Elton J.;Hurdle, Julian G.;Morisseau, Christophe;Scarborough, Jerrod S.;Sun, Dianqing;Kordulakova, Jana;Scherman, Michael S.;Jones, Victoria;Grzegorzewicz, Anna;Crew, Rebecca M.;Jackson, Mary;McNeil, Michael R.;Lee, Richard E.
通讯作者：
Lee, Richard E.
影响因子：
7.3
作者：
Kondreddi, Ravinder Reddy;Jiricek, Jan;Smith, Paul W.
通讯作者：
Smith, Paul W.
影响因子：
6.7
作者：
Matta, Cherif F.;Arabi, Alya A.;Weaver, Donald F.
通讯作者：
Weaver, Donald F.
影响因子：
3.5
作者：
Franz, Nicholas D.;Belardinelli, Juan Manuel;North, E. Jeffrey
通讯作者：
North, E. Jeffrey
影响因子：
4.9
作者：
Pandya, Amit N.;Prathipati, Pavan K.;North, E. Jeffrey
通讯作者：
North, E. Jeffrey