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.

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

“…(S) 4S,4',1',2,3',4,4a,4',6Hspiro[isoxazolo[4,4]oxazino [4,3-a]quinoline-5,5'-pyrimidin]-8-yl)pyrrolidine-3carboxylic acid (20). To a solution of ethyl (S)- 12,171.84,168.53,166.26,153.13 (d,J = 12.5 Hz),150.55,135.71,134.24 (d,J = 239.9 Hz),123.38,114.28,105.67,72.57,72.45,72.13,64.92,56.81 (d,J = 9.2 Hz), 53.46, 44.29, 39.07, 33.71, 33.41, 18.64, 18.60 2,4,4a-tetrahydro-2'H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino [4,3-a] 168.11,166.19,153.12 (d,J = 12.5 Hz),149.98,135.64,134.31 (d,J = 240.5 Hz),123.16,114.34,105.95,72.54,72.15,68.18,64.93,56.85 (d,J = 10.5 Hz),53.58,51.12,39.06,35.99,…”

“…The compound shows broad-spectrum activity against a variety of Gram-positive and Gram-negative pathogens and has progressed to phase 3 clinical trials for the treatment of uncomplicated urinary tract infections and urogenital gonorrhea . The quite diverse class of compounds represented by gepotidacin has been referred to as “novel bacterial topoisomerase inhibitors” (NBTIs), with several members having been identified with Mtb activity. − The SPT zoliflodacin, the leading compound of a fourth class of type II topoisomerase inhibitors, is currently in phase 3 clinical trials as a single-dose cure for uncomplicated gonorrhoea . We have recently published an exploration of SPTs for the treatment of TB wherein activity was seen for a variety of analogues, including zoliflodacin and the methyloxadiazole analogue 5 of Figure .…”

Editorial: Medicinal Chemistry Research in India

“…The compound has shown anti-TB activity in an acute mouse model of TB following oral administration of a compound. 5 Singh and co-workers did extensive medicinal chemistry on the 6-nitro-2,3-dihydroimidazooxazole scaffold with the aim to produce a compound with enhanced solubility and generated a series of polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole analogues. The optimized compound has shown good activity against sensitive and resistant (Rif R and MDR) and dormant strains of MTB along with a good safety index.…”

“…The best identified compound also inhibits Mtb DNA gyrase. The compound has shown anti-TB activity in an acute mouse model of TB following oral administration of a compound . Singh and co-workers did extensive medicinal chemistry on the 6-nitro-2,3-dihydroimidazooxazole scaffold with the aim to produce a compound with enhanced solubility and generated a series of polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole analogues.…”

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

“…Substitutions on the naphthyridone ring on the left-hand side of this class of NBTIs have been found to improve the selectivity against hERG binding and one such optimized NBTI (NBTI-7, compound 11, Figure 3) has potent antimycobacterial activity [40] (Table 1). GSK2140944 has broad spectrum activity against a number of Grampositive and Gram-negative drug-resistant isolates, with satisfactory cardiac parameters against hERG [35].…”