Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents.,Chemical Biology & Drug Design

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Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-06-08 , DOI: 10.1111/cbdd.13739
Oluseye K Onajole ₁ , Shichun Lun ₂ , Young Ju Yun ₃ , Damkam Y Langue ₁ , Michelle Jaskula-Dybka ₁ , Adrian Flores ₁ , Eriel Frazier ₁ , Ashle C Scurry ₁ , Ambernice Zavala ₁ , Karen R Arreola ₁ , Bryce Pierzchalski ₁ , A Jean-Luc Ayitou ₃ , William R Bishai _{2,

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Affiliation

Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug‐resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti‐tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2‐a ]pyridinecarboxamide derivatives for their anti‐tuberculosis properties. These compounds were designed based on reported anti‐tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2‐a ]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti‐TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates of Mtb . Compounds 15 and 16 showed excellent activities against multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.

中文翻译：

新型咪唑并 [1,2-a] 吡啶甲酰胺作为有效抗结核药物的设计、合成和生物学评价。

结核病 (TB) 是一种高度传染性疾病，几个世纪以来一直困扰着人类。结核病耐多药菌株的出现不利于抗击结核病，可用的安全治疗选择很少。作为鉴定强效抗结核药物的持续努力的一部分，我们合成并筛选了一系列新型咪唑并 [1,2- a ] 吡啶甲酰胺衍生物的抗结核特性。这些化合物是根据已报道的吲哚甲酰胺 (I2C) 和咪唑并[1,2- a ] 吡啶甲酰胺 (IPAs) 的抗结核特性设计的。在本系列中，我们鉴定了化合物15和16对 H37Rv 结核菌株具有优异的抗结核活性（MIC = 0.10–0.19 μM）；针对选定的Mtb临床分离株进一步筛选了这些化合物。化合物15和16对结核的多重耐药 (MDR) 和广泛耐药 (XDR) 菌株显示出优异的活性（MIC 范围：0.05-1.5 μM），并具有优异的选择性指数。此外，对化合物16 的初步 ADME 研究显示出有利的药代动力学特性。

更新日期：2020-07-10

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