MymA Bioactivated Thioalkylbenzoxazole Prodrug Family Active against Mycobacterium tuberculosis

Abstract

Screening of a GSK-proprietary library against intracellular Mycobacterium tuberculosis identified 1, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.

Tunable heteroaromatic azoline thioethers (HATs) for cysteine profiling

“… 58 Some of the heteroaromatic thioethers such as 2-(thioalkyl)benzoxazole act as prodrugs and undergo S-oxidation during metabolism forming active sulfone drugs. 59 …”

Bioinformatic Mining and Structure-Activity Profiling of Baeyer-Villiger Monooxygenases from Mycobacterium tuberculosis

“…We then focused on the human pathogen M. tuberculosis , which encodes 6 BVMOs as confirmed in our analysis. Earlier studies have demonstrated that M. tuberculosis uses two of these BVMOs, EthA and MymA, to activate ETH, highlighting their importance for the pharmacological mechanism of this class of TB drugs ( 3 – 5 , 20 , 21 ). Later it was shown that some other proteins, including Rv0565c, can also activate this drug ( 6 ).…”

“…Among the drugs known to be effective, several must be bioactivated by M. tuberculosis to become highly toxic to the pathogen. This is particularly the case for ethionamide (ETH), isoxyl (ISO), and thiacetazone (TAC), known anti-TB prodrugs, but also newly identified compounds active against M. tuberculosis ; all are activated through oxidation by a peculiar class of monooxygenases, the Baeyer-Villiger monooxygenases (BVMOs) ( 2 , 3 ). Indeed, the M. tuberculosis genome includes at least three BVMO genes that can activate ETH: rv3854c (also known as ethA for ETH activator) ( 4 ), rv3083 (also known as mymA ) ( 5 ), and rv0565c ( 6 ).…”

“…EthA and MymA are both type I BVMOs, which means that they both harbor a Rossmann fold and are dependent on flavin adenine dinucleotide (FAD) cofactor and NADPH electron donor ( 7 ). Moreover, both enzymes have been recognized as important for developing anti- M. tuberculosis inhibitors with improved efficacy and reduced toxicity ( 3 , 5 ). Phenotypic analyses of ethA and mymA deletion mutants strongly indicate their involvement in lipid metabolism, including metabolism of mycolic acids ( 8 – 10 ).…”

New frontiers in flavin-dependent monooxygenases

“…The increased resistance of mymA mutants suggested that this compound was bioactivated by MymA, presumably to the corresponding sulfoxide and sulfone (Fig. 13) [98]. However, the catalytic mechanism remains to be elucidated.…”