Medapi Brahmam, Renuka Janupally, Saxena Shalini, Sridevi Jonnalagadda Padma, Medishetti Raghavender, Kulkarni Pushkar, Yogeeswari Perumal, Sriram Dharmarajan
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
Dr Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Zephase Therapeutics (an incubated company at the Dr Reddy's Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
Bioorg Med Chem. 2015 May 1;23(9):2062-78. doi: 10.1016/j.bmc.2015.03.004. Epub 2015 Mar 9.
Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC₅₀ of 0.95 ± 0.12 μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC₅₀ of 0.62 ± 0.16 μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG).
在当今对抗细菌耐药性的斗争中，具有良好治疗价值和新颖作用机制的抗生素正变得越来越重要。其中一个热门靶点是DNA促旋酶，目前它在新型抗菌药物的开发中已得到充分确立并经过临床验证。在本研究中，合成了一系列基于喹啉 - 氨基哌啶的48种脲和硫脲衍生物作为药效团杂合物，并对其生物活性进行了评估。发现化合物1-(4-氯苯基)-3-(1-(6-甲氧基-2-甲基喹啉-4-基)哌啶-4-基)硫脲(45)在体外对耻垢分枝杆菌GyrB表现出有前景的半数抑制浓度(IC₅₀)为0.95±0.12μM，并且与结核分枝杆菌(MTB)DNA促旋酶超螺旋的IC₅₀有良好相关性，为0.62±0.16μM。此外，化合物45在斑马鱼醚 - 去极化相关基因(zERG)中也表现出值得称赞的MTB最低抑菌浓度(MIC)、安全的真核细胞细胞毒性谱且无心脏毒性迹象。
