Medapi Brahmam, Meda Nikhila, Kulkarni Pushkar, Yogeeswari Perumal, Sriram Dharmarajan
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
Dr Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
Bioorg Med Chem. 2016 Feb 15;24(4):877-85. doi: 10.1016/j.bmc.2016.01.011. Epub 2016 Jan 7.
In this study we have designed p-phenylene diamine linked acridine derivative from our earlier reported quinoline-aminopiperidine hybrid MTB DNA gyrase inhibitors with aiming more potency and less cardiotoxicity. We synthesized thirty six compounds using four step synthesis from 2-chloro benzoic acid. Among them compound 4-chloro-N-(4-((2-methylacridin-9-yl)amino)phenyl)benzenesulphonamide (6) was found to be more potent with MTB DNA gyrase super coiling IC50 of 5.21±0.51μM; MTB MIC of 6.59μM and no zHERG cardiotoxicity at 30μM and 11.78% inhibition at 50μM against mouse macrophage cell line RAW 264.7.
在本研究中，我们基于之前报道的喹啉 - 氨基哌啶杂合型结核分枝杆菌（MTB）DNA促旋酶抑制剂，设计了对苯二胺连接的吖啶衍生物，旨在提高效力并降低心脏毒性。我们以2 - 氯苯甲酸为原料，通过四步合成法合成了36种化合物。其中，化合物4 - 氯 - N -（4 -（（2 - 甲基吖啶 - 9 - 基）氨基）苯基）苯磺酰胺（6）被发现具有更高的效力，其对MTB DNA促旋酶超螺旋的IC50为5.21±0.51μM；MTB MIC为6.59μM，在30μM时无zHERG心脏毒性，对小鼠巨噬细胞系RAW 264.7在50μM时的抑制率为11.78%。
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