Bobesh Karyakulam Andrews, Renuka Janupally, Jeankumar Variam Ullas, Shruti Singh Kakan, Sridevi Jonnalagadda Padma, Yogeeswari Perumal, Sriram Dharmarajan
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
Eur J Med Chem. 2014 Oct 6;85:593-604. doi: 10.1016/j.ejmech.2014.08.018. Epub 2014 Aug 7.
Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.
细菌DNA促旋酶是开发新型抗菌药物的一个成熟且经过临床验证的靶点。我们致力于寻找合成性能更优、有可能实现从苗头化合物到先导化合物开发的化合物。以此为目标，通过分子杂交策略设计了一系列1-(2-(4-氨基哌啶-1-基)乙基)-1,5-萘啶-2(1H)-酮衍生物，并经过九步反应合成，得到了低纳摩尔活性和良好抗菌活性的产物。化合物1-(4-氟苯基)-3-(1-(2-(7-甲氧基-2-氧代-1,5-萘啶-1(2H)-基)乙基)哌啶-4-基)脲(35)成为最有前景的抑制剂，对结核分枝杆菌DNA促旋酶的IC50为78 nM，对结核分枝杆菌的MIC为0.62 μM，在真核细胞系中50 μM时无细胞毒性。
