Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo
We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1)...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-12, Vol.56 (23), p.9701-9708 |
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| container_title | Journal of medicinal chemistry |
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| creator | Shirude, Pravin S Shandil, Radha Sadler, Claire Naik, Maruti Hosagrahara, Vinayak Hameed, Shahul Shinde, Vikas Bathula, Chandramohan Humnabadkar, Vaishali Kumar, Naveen Reddy, Jitendar Panduga, Vijender Sharma, Sreevalli Ambady, Anisha Hegde, Naina Whiteaker, James McLaughlin, Robert E Gardner, Humphrey Madhavapeddi, Prashanti Ramachandran, Vasanthi Kaur, Parvinder Narayan, Ashwini Guptha, Supreeth Awasthy, Disha Narayan, Chandan Mahadevaswamy, Jyothi Vishwas, KG Ahuja, Vijaykamal Srivastava, Abhishek Prabhakar, KR Bharath, Sowmya Kale, Ramesh Ramaiah, Manjunatha Choudhury, Nilanjana Roy Sambandamurthy, Vasan K Solapure, Suresh Iyer, Pravin S Narayanan, Shridhar Chatterji, Monalisa |
| description | We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like” properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis. |
| doi_str_mv | 10.1021/jm401382v |
| format | Article |
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The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like” properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm401382v</identifier><identifier>PMID: 24215368</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alcohol Oxidoreductases ; Animals ; Antitubercular Agents - pharmacokinetics ; Antitubercular Agents - pharmacology ; Antitubercular Agents - therapeutic use ; Bacterial Proteins - antagonists & inhibitors ; Drug Discovery ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Indoles - chemical synthesis ; Indoles - pharmacokinetics ; Indoles - pharmacology ; Indoles - therapeutic use ; Mice ; Mycobacterium tuberculosis - drug effects ; Oxidoreductases - antagonists & inhibitors ; Rats ; Tuberculosis, Multidrug-Resistant - drug therapy</subject><ispartof>Journal of medicinal chemistry, 2013-12, Vol.56 (23), p.9701-9708</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-831455a5ea50305120ba01f49d7327950ae60bc30804bf1f657e78f05f062ed3</citedby><cites>FETCH-LOGICAL-a381t-831455a5ea50305120ba01f49d7327950ae60bc30804bf1f657e78f05f062ed3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm401382v$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm401382v$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24215368$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shirude, Pravin S</creatorcontrib><creatorcontrib>Shandil, Radha</creatorcontrib><creatorcontrib>Sadler, Claire</creatorcontrib><creatorcontrib>Naik, Maruti</creatorcontrib><creatorcontrib>Hosagrahara, Vinayak</creatorcontrib><creatorcontrib>Hameed, Shahul</creatorcontrib><creatorcontrib>Shinde, Vikas</creatorcontrib><creatorcontrib>Bathula, Chandramohan</creatorcontrib><creatorcontrib>Humnabadkar, Vaishali</creatorcontrib><creatorcontrib>Kumar, Naveen</creatorcontrib><creatorcontrib>Reddy, Jitendar</creatorcontrib><creatorcontrib>Panduga, Vijender</creatorcontrib><creatorcontrib>Sharma, Sreevalli</creatorcontrib><creatorcontrib>Ambady, Anisha</creatorcontrib><creatorcontrib>Hegde, Naina</creatorcontrib><creatorcontrib>Whiteaker, James</creatorcontrib><creatorcontrib>McLaughlin, Robert E</creatorcontrib><creatorcontrib>Gardner, Humphrey</creatorcontrib><creatorcontrib>Madhavapeddi, Prashanti</creatorcontrib><creatorcontrib>Ramachandran, Vasanthi</creatorcontrib><creatorcontrib>Kaur, Parvinder</creatorcontrib><creatorcontrib>Narayan, Ashwini</creatorcontrib><creatorcontrib>Guptha, Supreeth</creatorcontrib><creatorcontrib>Awasthy, Disha</creatorcontrib><creatorcontrib>Narayan, Chandan</creatorcontrib><creatorcontrib>Mahadevaswamy, Jyothi</creatorcontrib><creatorcontrib>Vishwas, KG</creatorcontrib><creatorcontrib>Ahuja, Vijaykamal</creatorcontrib><creatorcontrib>Srivastava, Abhishek</creatorcontrib><creatorcontrib>Prabhakar, KR</creatorcontrib><creatorcontrib>Bharath, Sowmya</creatorcontrib><creatorcontrib>Kale, Ramesh</creatorcontrib><creatorcontrib>Ramaiah, Manjunatha</creatorcontrib><creatorcontrib>Choudhury, Nilanjana Roy</creatorcontrib><creatorcontrib>Sambandamurthy, Vasan K</creatorcontrib><creatorcontrib>Solapure, Suresh</creatorcontrib><creatorcontrib>Iyer, Pravin S</creatorcontrib><creatorcontrib>Narayanan, Shridhar</creatorcontrib><creatorcontrib>Chatterji, Monalisa</creatorcontrib><title>Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo</title><title>Journal of medicinal chemistry</title><addtitle>J. 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| subjects | Alcohol Oxidoreductases Animals Antitubercular Agents - pharmacokinetics Antitubercular Agents - pharmacology Antitubercular Agents - therapeutic use Bacterial Proteins - antagonists & inhibitors Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Indoles - chemical synthesis Indoles - pharmacokinetics Indoles - pharmacology Indoles - therapeutic use Mice Mycobacterium tuberculosis - drug effects Oxidoreductases - antagonists & inhibitors Rats Tuberculosis, Multidrug-Resistant - drug therapy |
| title | Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo |
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