Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors

Abstract

A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC50s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).

Optimization of a binding fragment targeting the “enlarged methionine pocket” leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors

“…The compounds shown in Table 2 were tested using a human lymphoblast cell line (CRL-8155) and a hepatocellular carcinoma cell line (Hep G2) following procedures described previously. 7,14 Compounds 5b and 5c had CC 50 s (concentration to cause 50% cytotoxicity) close to or greater than 40 μM, whereas compounds 11 and 13 had CC 50 s of ~20 μM, and compound 5p had CC 50 of ~10 μM. Overall, these compounds exhibited low toxicities to mammalian cell lines.…”

“…7 Two series of compounds were designed and demonstrated to be potent Tb MetRS inhibitors. The most potent compound in each series is shown in Figure 1.…”

“…The synthesis was following previously reported procedures. 7 In brief, ( S )-tert-butyl piperidin-3-ylcarbamate reacted with 2-bromo-5-chloro-3H-imidazo[4,5-b]pyridine through nucleophilic substitution reaction, and the following Boc removal provided intermediate 4 . Reductive amination of 4 with various substituted benzaldehydes afforded the final products 5a-5p .…”

“…7,12 As shown in Table 1, most of the compounds are very potent inhibitors of Tb MetRS, exhibiting IC 50 s below 50 nM (the enzyme concentration used in the assay). Compounds 5k and 5l were found to have significantly reduced inhibitory potency compared to 1 , with IC 50 s >300 nM.…”

“…7,9,13 The results are shown in Table 1 and the inhibition curves of compounds with EC 50 < 100 nM are shown in Figure s1 (Supporting Information). Compounds with larger groups at the 3- and 5-positions, such as bromo and cyano ( 5a-5c ), were tolerated by the enzyme, but had higher EC 50 values by 2–3 folds.…”