Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis.
Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis.
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DOI：
10.1039/c6ob00821f
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发表时间：
2016-07-07
影响因子：
3.2
通讯作者：
Sucheck SJ
中科院分区：
文献类型：
--
作者：
Thanna S;Knudson SE;Grzegorzewicz A;Kapil S;Goins CM;Ronning DR;Jackson M;Slayden RA;Sucheck SJ
结核病及其耐药形式比任何其他传染病都要多。这一事实强调了需要确定治疗结核病的新药。2-已报道氨基噻吩（2AT）抑制Pks 13，一种经验证的抗TB药物靶标。我们合成了42个2AT化合物的库。其中，化合物33对结核分枝杆菌（Mtb）H37 RV显示出显著的效力（MIC = 0.23 μM），并且对耐异烟肼、利福平和氟喹诺酮类的Mtb菌株显示出令人印象深刻的效力（MIC = 0.20-0.44 μM）。推测化合物33的作用位点是Pks 13或分枝菌酸生物合成途径中的较早酶。该推断基于化合物33与已知的Pks 13抑制剂的结构相似性，这被分枝菌酸生物合成研究所证实，该研究表明该化合物强烈抑制Mtb中所有形式的分枝菌酸的生物合成。总而言之，这些研究表明33代表了一种有前途的抗结核药物，其活性远低于对人类单核细胞的毒性。
Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.