Synthesis of a Tetrahydronaphthyridine Spiropyrimidinetrione DNA Gyrase Inhibiting Antibacterial Agent - Differential Substitution at all Five Carbon Atoms of Pyridine.

Abstract

The synthesis of (-)-1, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (-)-1 was isolated as the thermodynamically most favored stereoisomer.

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

“…The immediate environment around the morpholine oxygen suggested a small accessible space for functionality in equatorial (or pseudo-equatorial) orientations. Hence compounds were made replacing the morpholine with substituted piperidines and piperazines (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)Table 4). The accessible space is bounded by the guanidine of the conserved R128 (R122 and R121 in S. aureus and E. coli, respectively) that displayed two occupancies for the sidechain guanidine in the moxifloxacin co-crystal structure with Mtb gyrase: one oriented towards a backbone DNA phosphate and the other to the carboxylate of the inhibitor, with the latter being chosen for the modelling.…”

Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

“…Since the mid-1960’s, only three agents introduced to the clinic have new modes-of-action or modes-of-inhibition, namely daptomycin, linezolid and bedaquiline, the first two for the treatment of resistant Gram-positive bacterial infections and the latter for the treatment of tuberculosis 3 . Spiropyrimidinetriones are a new class of bacterial type II topoisomerase inhibitors with a novel mode-of-inhibition that avoids cross-resistance to antibacterial agents currently in clinical use and offers the promise of additional oral treatment options for patients and prescribers 4 5 6 . ETX0914 ( 1, Fig.…”

Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones

“…SAR of SPTs with oxazolidinone and triazole substituents have been presented in the literature in the context of activity against Gram-positive and Gram-negative pathogens ( 18 , 19 ). Table 3 contains the data for miscellaneous other compounds, including 24, that has a difluorobenzene rather than a benzisoxazole scaffold while having the opposite absolute stereochemistry on the morpholine ring, which is known to be required for activity ( 20 , 21 ). As expected, 24 did not show activity at the highest concentration tested in any of the M. tuberculosis MIC assays, thereby serving as a negative control.…”