Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding

Shahul Hameed P; Praveena Manjrekar; Anandkumar Raichurkar; Vikas Shinde; Jayashree Puttur; Gajanan Shanbhag; Murugan Chinnapattu; Vikas Patil; Suresh Rudrapatana; Sreevalli Sharma; C N Naveen Kumar; Radha Nandishaiah; Prashanti Madhavapeddi; D Sriram; Suresh Solapure; Vasan K Sambandamurthy

doi:10.1021/ml500531p

Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding

ACS Med Chem Lett. 2015 May 22;6(7):741-6. doi: 10.1021/ml500531p. eCollection 2015 Jul 9.

Authors

Shahul Hameed P¹, Praveena Manjrekar¹, Anandkumar Raichurkar¹, Vikas Shinde¹, Jayashree Puttur¹, Gajanan Shanbhag¹, Murugan Chinnapattu¹, Vikas Patil¹, Suresh Rudrapatana¹, Sreevalli Sharma¹, C N Naveen Kumar¹, Radha Nandishaiah¹, Prashanti Madhavapeddi¹, D Sriram¹, Suresh Solapure¹, Vasan K Sambandamurthy¹

Affiliation

¹ AstraZeneca India Pvt. Ltd , Avishkar, Bellary Road, Bangalore-560024, India.

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.

Keywords: DNA gyrase; NBTIs; Tuberculosis; aminopiperidines; naphthyridones; type II topoisomerases.