Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis.
| Title: | Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis. |
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| Authors: | Shirude PS; Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India. pravin.shirude@astrazeneca.com; Madhavapeddi P; Tucker JA; Murugan K; Patil V; Basavarajappa H; Raichurkar AV; Humnabadkar V; Hussein S; Sharma S; Ramya VK; Narayan CB; Balganesh TS; Sambandamurthy VK |
| Source: | ACS chemical biology [ACS Chem Biol] 2013 Mar 15; Vol. 8 (3), pp. 519-23. Date of Electronic Publication: 2012 Dec 31. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, D.C. : American Chemical Society, c2006- |
| MeSH Terms: | DNA Gyrase/*metabolism ; Mycobacterium tuberculosis/*drug effects ; Mycobacterium tuberculosis/*growth & development ; Pyrazines/*pharmacology ; Topoisomerase II Inhibitors/*pharmacology; Mycobacterium tuberculosis/enzymology ; Pyrazines/chemistry ; Topoisomerase II Inhibitors/chemistry ; Dose-Response Relationship, Drug ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship |
| Abstract: | Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions. |
| Substance Nomenclature: | 0 (Pyrazines); 0 (Topoisomerase II Inhibitors); EC 5.99.1.3 (DNA Gyrase) |
| Entry Date(s): | Date Created: 20121228 Date Completed: 20141224 Latest Revision: 20130315 |
| Update Code: | 20260130 |
| DOI: | 10.1021/cb300510w |
| PMID: | 23268609 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't