The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents,RSC Medicinal Chemistry

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The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-10-13 00:00:00 , DOI: 10.1039/c7md00350a
Muzafar Ahmad Rather _{1,

2,

3,

4,

5} , Ali Mohd Lone _{3,

4,

5,

6} , Bisma Teli _{3,

4,

5,

6,

7} , Zubair Shanib Bhat _{1,

2,

3,

4,

5} , Paramjeet Singh _{3,

8,

9,

10} , Mubashir Maqbool _{1,

2,

3,

4,

5} , Bashir Ahmad Shairgojray _{3,

4,

5,

6} , Mohd Jamal Dar _{3,

7,

8,

9,

11} , Shajrul Amin _{12,

13,

14} , Syed Khalid Yousuf _{3,

4,

5,

6,

7} , Bilal A. Bhat _{3,

4,

5,

6,

7} , Zahoor Ahmad _{1,

2,

3,

4,

5}

Affiliation

The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against Mycobacterium tuberculosis H37Rv (M. tuberculosis) and identified the cyclohexane-1,3-dione-based structures 5 and 6 as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against M. tuberculosis lead to the identification of three lead antituberculosis agents (37, 39 and 41). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39) showed an MIC of 2.5 μg mL⁻¹, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria and even against M. smegmatis; thereby reflecting its highly specific antituberculosis activity.

中文翻译：

2-苯基氨基亚甲基-环己烷-1,3-二酮类化合物作为特定抗结核药物的合成，生物学评价和结构-活性关系

本研究利用基于全细胞的表型筛选了数千种针对结核分枝杆菌H37Rv（结核分枝杆菌）的小分子，并将环己烷-1,3-二酮结构5和6确定为命中。选定的命中分子用于进一步合成，并合成了四个家族下的37种化合物的文库，用于产生先导。对库的评价结核分枝杆菌导致的三个引抗结核剂（标识37，39和41）。最有潜力的化合物2-（（（（2-羟苯基）氨基）亚甲基）-5,5-二甲基环己烷-1,3-二酮（39）的MIC为2.5μgmL ^-1，这在已知的抗结核药乙胺丁醇，链霉素和左氧氟沙星的MICs范围内。另外，该化合物被证明对四种人类细胞系无毒（在50μM浓度下抑制率<20％）。像一线抗结核药（异烟肼，利福平和吡嗪酰胺）一样，该化合物对一般革兰氏阳性和革兰氏阴性细菌甚至对耻垢分枝杆菌均无活性。从而反映出其高度特异性的抗结核活性。

更新日期：2017-11-03

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