Acta Chimica Sinica ›› 2008, Vol. 66 ›› Issue (19): 2157-2162. Previous Articles     Next Articles

Original Articles

水溶性稠杂环均三唑并噻二唑体系的合成及生物活性(II): 环丙氟喹诺酮哌嗪衍生物

胡国强*,a 毋小魁a 谢松强a 杜钢军a 黄文龙b 张惠斌b   

  1. (a河南大学药物研究所 开封 475001)
    (b中国药科大学新药中心 南京 210009)
  • 投稿日期:2007-12-05 修回日期:2008-04-25 发布日期:2008-10-14
  • 通讯作者: 胡国强

Synthesis and Bioactivity of Water-soluble Fused s-Triazolo- thiadiazole Systems (II): Fluoroquinolone Piperazine Derivatives

HU, Guo-Qiang *,a WU, Xiao-Kui a XIE, Song-Qiang a DU, Gang-Jun a
HUANG, Wen-Long b ZHANG, Hui-Bin b

  1. (a Institute of Pharmacy, Henan University, Kaifeng 475001)
    (b Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009)
  • Received:2007-12-05 Revised:2008-04-25 Published:2008-10-14
  • Contact: HU, Guo-Qiang

To discover the novel bioactivities of quinolone derivatives substituted by a fused heterocyclic ring at the 3-position, the key intermediate of 3-(1-amino-5-mercapto-1H-1,3,4-triazol-2-yl)-7-chloro-1-
cyclopropyl-6-1,4-dihydroquinolin-4-one (4) was synthesized via a three-step procedure starting from 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1). Compound 4 was subjected to cyclocondensation with isonicotinic acid under microwave irradiation (MWI) to yield the fused system of 7-chloro-1-cyclopropyl-6-fluoro-3-[2-(pyridin-4-yl)-[1,3,4]-triazolo[2,1-b][1,3,4]thiadiazol-4-yl]- 1,4-hydroquinolin-4-one (5) in a higher yield than that of the classical thermal heating. However, it was surprisingly to find that condensation of the corresponding esters of 1 with hydrazine hydrate produced an unexpected product of pyrazoloquinolone 3 instead of its hydrazide 2. The following selective nucleophilic substitution of halogens at the quinolone framework of compound 5 with substituted piperazine under catalyst of PEG-600 and inorganic base gave the corresponding fluorinated free bases 6 successfully, which were subsequently transformed to the corresponding 6•HCl salts by the treatment with hydrochloride. The structures of new compounds synthesized were characterized by elemental analysis and spectral data, and their in vitro antibacterial and anticancer activities against the three cancer cell lines of CHO, HL60 and L1210 along with the two microorganisms of S. aureus and E.coli were also evaluated, respectively. The bioactive assay revealed that compounds 3 and 6, especially 6a and 6d exhibited a significant antitumor activity against HL60 with the IC50 values from 50.0 to 8.0 μmol/L. More interestingly, although the title compounds 6 showed a poorer inhibitory activity than ciprofloxacin, they had a stronger inhibitory activity against gram-negative E.coli than that of gram-positive S. aureus. Thus, the fused heterocycle-based substituted quinolones are valuable for further study.

Key words: quinolone, s-triazole, s-triazolothiadiazole, bioactivity evaluation