Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities

被引:38
|
作者
Wang, Pengxu [1 ,2 ]
Batt, Sarah M. [3 ]
Wang, Bin [4 ]
Fu, Lei [4 ]
Qin, Rongfei [1 ,2 ]
Lu, Yu [4 ]
Li, Gang [1 ,2 ]
Besra, Gurdyal S. [3 ]
Huang, Haihong [1 ,2 ]
机构
[1] Peking Union Med Coll & Chinese Acad Med Sci, Beijing Key Lab Act Subst Discovery & Druggabil E, Inst Mat Med, Beijing 100050, Peoples R China
[2] Peking Union Med Coll & Chinese Acad Med Sci, Chinese Acad Med Sci, Key Lab AntiDR TB Innovat Drug Res, Beijing 100050, Peoples R China
[3] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England
[4] Capital Med Univ, Beijing Chest Hosp, Beijing TB & Thorac Tumor Res Inst, Dept Pharmacol,Beijing Key Lab Drug Resistance TB, Beijing 101149, Peoples R China
基金
英国医学研究理事会;
关键词
KILL MYCOBACTERIUM-TUBERCULOSIS; DRUG-RESISTANT; CELL-WALL; IDENTIFICATION; TARGETS;
D O I
10.1021/acs.jmedchem.1c00263
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-beta-D-ribose 2'-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds 23j, 24f, 25a, and 25b exhibited potent in vitro activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02-0.12 mu g/mL) and drug-resistant (MIC = 0.031-0.24 mu g/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC50) = 0.2-0.9 mu g/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-a-go-go related gene (hERG) channel. The representative compound 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.
引用
收藏
页码:6241 / 6261
页数:21
相关论文
共 50 条
  • [1] Discovery of novel pyrimidinetrione derivatives as DprE1 inhibitors with potent antimycobacterial activities
    Liang, Jing
    Liu, Yang
    Guan, Qing
    Li, Yan
    Zheng, Meng-Zhu
    Zhang, Xiao-Lian
    Chen, Li-Xia
    Li, Hua
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2025, 289
  • [2] Identification and Profiling of Hydantoins-A Novel Class of Potent Antimycobacterial DprE1 Inhibitors
    Rogacki, Maciej K.
    Pitta, Eleni
    Balabon, Olga
    Huss, Sophie
    Lopez-Roman, Eva Maria
    Argyrou, Argyrides
    Blanco-Ruano, Delia
    Cacho, Monica
    Vande Velde, Christophe M. L.
    Augustyns, Koen
    Ballell, Lluis
    Barros, David
    Bates, Robert H.
    Cunningham, Fraser
    Van der Veken, Pieter
    JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (24) : 11221 - 11249
  • [3] Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity
    Manjunatha, M. R.
    Shandil, Radha
    Panda, Manoranjan
    Sadler, Claire
    Ambady, Anisha
    Panduga, Vijender
    Kumar, Naveen
    Mahadevaswamy, Jyothi
    Sreenivasaiah, M.
    Narayan, Ashwini
    Guptha, Supreeth
    Sharma, Sreevalli
    Sambandamurthy, Vasan K.
    Ramachandran, Vasanthi
    Mallya, Meenakshi
    Cooper, Christopher
    Mdluli, Khisi
    Butler, Scott
    Tommasi, Ruben
    Iyer, Pravin S.
    Narayanan, Shridhar
    Chatterji, Monalisa
    Shirude, Pravin S.
    ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (10): : 1480 - 1485
  • [4] Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-β-D-Ribose Oxidase (DprE1) Inhibitors
    Balabon, Olga
    Pitta, Eleni
    Rogacki, Maciej K.
    Meiler, Eugenia
    Casanueva, Ruth
    Guijarro, Laura
    Huss, Sophie
    Maria Lopez-Roman, Eva
    Santos-Villarejo, Angel
    Augustyns, Koen
    Ballell, Lluis
    Barros Aguirre, David
    Bates, Robert H.
    Cunningham, Fraser
    Cacho, Monica
    Van der Veken, Pieter
    JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (10) : 5367 - 5386
  • [5] Design, Synthesis, and Molecular Docking of Novel Benzothiazinone Derivatives as DprE1 Inhibitors with Potential Antitubercular Activities
    Raghu, M. S.
    Jassim, Amar Yasser
    Kumar, K. Yogesh
    Alharethy, Fahd
    Prashanth, M. K.
    Jeon, Byong-Hun
    RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, 2025, 51 (01) : 65 - 78
  • [6] Identification of novel DprE1 inhibitors for the treatment of tuberculosis
    Franco, Jimmy
    Laverty, Daniel
    Daniels, Dave
    Wilsey, Claire
    Golijanin, Petar
    Gurka, Jessica
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 245
  • [7] Discovery of novel thiophene derivatives as potent neuraminidase inhibitors
    Zhong, Zhi Jian
    Hu, Xiao Tong
    Cheng, Li Ping
    Zhang, Xing Yong
    Zhang, Qiang
    Zhang, Ju
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2021, 225
  • [8] 4-Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity
    Naik, Maruti
    Humnabadkar, Vaishali
    Tantry, Subramanyam J.
    Panda, Manoranjan
    Narayan, Ashwini
    Guptha, Supreeth
    Panduga, Vijender
    Manjrekar, Praveena
    Jena, Lalit Kumar
    Koushik, Krishna
    Shanbhag, Gajanan
    Jatheendranath, Sandesh
    Manjunatha, M. R.
    Gorai, Gopinath
    Bathula, Chandramohan
    Rudrapatna, Suresh
    Achar, Vijayashree
    Sharma, Sreevalli
    Ambady, Anisha
    Hegde, Naina
    Mahadevaswamy, Jyothi
    Kaur, Parvinder
    Sambandamurthy, Vasan K.
    Awasthy, Disha
    Narayan, Chandan
    Ravishankar, Sudha
    Madhavapeddi, Prashanti
    Reddy, Jitendar
    Prabhakar, K. R.
    Saralaya, Ramanatha
    Chatterji, Monalisa
    Whiteaker, James
    McLaughlin, Bob
    Chiarelli, Laurent R.
    Riccardi, Giovanna
    Pasca, Maria Rosalia
    Binda, Claudia
    Neres, Joao
    Dhar, Neeraj
    Signorino-Gelo, Francois
    McKinney, John D.
    Ramachandran, Vasanthi
    Shandil, Radha
    Tommasi, Ruben
    Iyer, Pravin S.
    Narayanan, Shridhar
    Hosagrahara, Vinayak
    Kavanagh, Stefan
    Dinesh, Neela
    Ghorpade, Sandeep R.
    JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (12) : 5419 - 5434
  • [9] DprE1 Inhibitors: Enduring Aspirations for Future Antituberculosis Drug Discovery
    Yadav, Saloni
    Soni, Aastha
    Tanwar, Omprakash
    Bhadane, Rajendra
    Besra, Gurdyal S.
    Kawathekar, Neha
    CHEMMEDCHEM, 2023, 18 (16)
  • [10] Discovery of Pyrazolopyridones as a Novel Class of Noncovalent DprE1 Inhibitor with Potent Anti-Mycobacterial Activity
    Panda, Manoranjan
    Ramachandran, Sreekanth
    Ramachandran, Vasanthi
    Shirude, Pravin S.
    Humnabadkar, Vaishali
    Nagalapur, Kavitha
    Sharma, Sreevalli
    Kaur, Parvinder
    Guptha, Supreeth
    Narayan, Ashwini
    Mahadevaswamy, Jyothi
    Ambady, Anisha
    Hegde, Naina
    Rudrapatna, Suresh S.
    Hosagrahara, Vinayak P.
    Sambandamurthy, Vasan K.
    Raichurkar, Anandkumar
    JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (11) : 4761 - 4771