title: Benzimidazoles: novel mycobacterial gyrase inhibitors from scaffold morphing.
abstract: Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure-activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Shahul
authors: S
authors: Hameed P
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Anandkumar
authors: A
authors: Raichurkar
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Prashanti
authors: P
authors: Madhavapeddi
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Sreenivasaiah
authors: S
authors: Menasinakai
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Sreevalli
authors: S
authors: Sharma
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Parvinder
authors: P
authors: Kaur
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Radha
authors: R
authors: Nandishaiah
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Vijender
authors: V
authors: Panduga
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Jitendar
authors: J
authors: Reddy
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: Vasan K
authors: VK
authors: Sambandamurthy
authors: AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore 560024, India.
authors: D
authors: D
authors: Sriram
keywords: DNA gyrase; NBTIs; Tuberculosis; aminopiperidines; benzimidazoles; type II topoisomerases