title: Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding.
abstract: Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 μM) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Shahul
authors.initials: S
authors.lastname: Hameed P
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Praveena
authors.initials: P
authors.lastname: Manjrekar
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Shinde
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Puttur
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Gajanan
authors.initials: G
authors.lastname: Shanbhag
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Murugan
authors.initials: M
authors.lastname: Chinnapattu
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Patil
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Rudrapatana
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: C N Naveen
authors.initials: CN
authors.lastname: Kumar
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Nandishaiah
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: D
authors.initials: D
authors.lastname: Sriram
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.affiliation: AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
keywords: DNA gyrase; NBTIs; Tuberculosis; aminopiperidines; naphthyridones; type II topoisomerases