Novel N-linked aminopiperidine-based gyrase inhibitors with improved hERG and in vivo efficacy against Mycobacterium tuberculosis.
Hameed P S, Patil V, Solapure S, Sharma U, Madhavapeddi P, Raichurkar A, Chinnapattu M, Manjrekar P, Shanbhag G, Puttur J, Shinde V, Menasinakai S, Rudrapatana S, Achar V, Awasthy D, Nandishaiah R, Humnabadkar V, Ghosh A, Narayan C, Ramya VK, Kaur P, Sharma S, Werngren J, Hoffner S, Panduga V, Kumar CN, Reddy J, Kumar K N M, Ganguly S, Bharath S, Bheemarao U, Mukherjee K, Arora U, Gaonkar S, Coulson M, Waterson D, Sambandamurthy VK, de Sousa SM.
DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.