title: Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis.
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.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India. pravin.shirude@astrazeneca.com
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Shirude
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Kannan
authors.initials: K
authors.lastname: Murugan
authors.forename: Vikas
authors.initials: V
authors.lastname: Patil
authors.forename: Halesha
authors.initials: H
authors.lastname: Basavarajappa
authors.forename: Anandkumar V
authors.initials: AV
authors.lastname: Raichurkar
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.forename: Syeed
authors.initials: S
authors.lastname: Hussein
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: V K
authors.initials: VK
authors.lastname: Ramya
authors.forename: Chandan B
authors.initials: CB
authors.lastname: Narayan
authors.forename: Tanjore S
authors.initials: TS
authors.lastname: Balganesh
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
mesh_terms: D027081:DNA Gyrase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011719:Pyrazines; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase