title: Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy.
abstract: Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Kale
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Manoj G
authors.initials: MG
authors.lastname: Kale
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Shahul P
authors.initials: SP
authors.lastname: Hameed
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: M R
authors.initials: MR
authors.lastname: Manjunatha
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: B K
authors.initials: BK
authors.lastname: Kishore Reddy
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Malolanarasimhan
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Shinde
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Krishna
authors.initials: K
authors.lastname: Koushik
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Lalit Kumar
authors.initials: LK
authors.lastname: Jena
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sreenivasaiah
authors.initials: S
authors.lastname: Menasinakai
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Halesha
authors.initials: H
authors.lastname: Basavarajappa
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Nandishaiah
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: K N
authors.initials: KN
authors.lastname: Mahesh Kumar
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Samit
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vijaykamal
authors.initials: V
authors.lastname: Ahuja
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sheshagiri
authors.initials: S
authors.lastname: Gaonkar
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: C N
authors.initials: CN
authors.lastname: Naveen Kumar
authors.affiliation: Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Ogg
authors.affiliation: Biosciences, Infection iMed, AstraZeneca, Waltham, MA, USA.
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sunita M
authors.initials: SM
authors.lastname: de Sousa
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India. Electronic address: Sandeep.ghorpade@astrazeneca.com.
authors.forename: Sandeep R
authors.initials: SR
authors.lastname: Ghorpade
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011728:Pyridones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D014508:Urea
keywords: DNA gyrase; GyrB; Thiazolopyridone ureas; Tuberculosis