Synthesis and Structure–Activity Relationships of Varied Ether Linker Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

Abstract

New analogues of antitubercular drug PA-824 were synthesized, featuring alternative side chain ether linkers of varying size and flexibility, seeking drug candidates with enhanced metabolic stability and high efficacy. Both α-methyl substitution and removal of the benzylic methylene were broadly tolerated in vitro, with a biaryl example of the latter class exhibiting an 8-fold better efficacy than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection and negligible fragmentation to an alcohol metabolite in liver microsomes. Extended linkers (notably propenyloxy, propynyloxy, and pentynyloxy) provided greater potencies against replicating M. tb (monoaryl analogues), with propynyl ethers being most effective under anaerobic (nonreplicating) conditions (mono/biaryl analogues). For benzyloxybenzyl and biaryl derivatives, aerobic activity was maximal with the original (OCH(2)) linker. One propynyloxy-linked compound displayed an 89-fold higher efficacy than the parent drug in the acute model, and it was slightly superior to antitubercular drug OPC-67683 in a chronic infection model.

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

“…Fortunately, treatment of 104 with hydrofluoric acid in acetonitrile 36 gave a much better result (95% yield), and 26 was easily converted into various heteroaryl ether targets (27, 29-31) via sodium hydride-catalysed S N Ar reactions on the haloheterocycles 105-108. 37 The isomeric pyridine 28 was also obtained in moderate yield (25%) by reaction of 6-(trifluoromethyl)pyridin-3-ol and sodium hydride with the known 30 epoxide 109 (Scheme 2D). By way of comparison, epoxides 98 and 109 each afforded comparable yields (55% and 51%) for scale-up of racemic VL lead 7.…”

“…To circumvent any similar complications in the preparation of the 3-pyridyl targets (37,40 and 41), a modified strategy was adopted (Scheme 3C). Here, 6-bromopyridin-3-ol (122) was first protected (as the ethoxymethyl ether, 123) and then Suzuki-coupled with arylboronic acids.…”

“…This design concept was based on some partial success with employing trifluoromethylpyridine as a more soluble substitute for trifluoromethoxyphenyl in our previous TB studies. 20,21,37 Pleasingly, pyridine 27 (L. inf IC 50 0.24 µM) was slightly more potent than both 7 and the direct phenyl equivalent 22, and was 3-fold more soluble than 7…”

Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs

“…In this study we report a 2-nitroimidazooxazine derivative with modification at the C-7 position that exhibited better activity than PA-824 against Mycobacterium tuberculosis (Mtb) H37Rv strain in vitro. From 7a as a key intermediate, we functionalized with benzyl ether (8), phenyl ether (9), benzyl carbonate (10) and benzyl carbamate (11). Among the 23 compounds produced, 8a-R (MIC = 0.078 lM) with trifluoromethoxy benzyl group was 5-fold more potent than PA-824 (MIC = 0.390 lM) in the in vitro assays against the wild-type Mtb, and the phenyl ether compound 9g-R (MIC = 0.050 lM) exhibited the most potent antimycobacterial activity.…”

“…When the side-chains of (hetero)biaryl ether were introduced instead of the benzyl ether of PA-824, these scaffolds exhibit better in vitro and in vivo ADME properties as well as potency compared to their parent compounds. [7][8][9][10][11] In the PA-824 derivatives containing (hetero)biaryl side-chains, TBA-354, ((S)-2-nitro-6-((6-(4-(trifluoromethoxy) phenyl)pyridin-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine), is currently in clinical trials. 11 Furthermore, the introduction of benzyloxymethyl, biphenyl or (hetero)biaryl groups at the C-7 position of the 2-nitrodihydro-5H-imidazo[2,1-b] [1,3]oxazine ring has been reported.…”