Synthesis and Structure−activity Relationships of Antitubercular 2-Nitroimidazooxazines Bearing Heterocyclic Side Chains

Abstract

Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility.

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

“…While benzyl ether 8a-R, 8c-R and 8d-R did generally followed the same trend of increase potency with higher C log P that has also been reported in literlatures, [9][10][11] compound 8b-R and 8f-R, which had C log P values of 4.00 and 4.07, respectively, showed reduced activities than 8a-R (C log P = 3.21) despite having higher lipophilicites compare with 8a-R. The observed inhibition activities of 9 correlated well with C log P compared to 8.…”

“…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.…”

“…23 To our knowledge, the carbonate linkage between the nitroimidazooxazine ring and benzyl group in PA-824 analogs has not been published, but linkages have been introduced, such as amides, carbamates, thiourea or urea. [7][8][9][10][11] We attempted to obtain carbonate analog 10-R from 7a with a substituted benzyl halide and Ag 2 CO 3 in DMF with catalytic amounts of tetrabutylammonium iodide. The carbamate analog 11-R was prepared from 7a with isocyanate by CuI-catalyzed condensation.…”

6.13 Use of Carbonyl Derivatives for Heterocyclic Synthesis

“…Unfortunately, these two general synthetic routes typically afford regioisomeric mixtures of products. Several methods exist which prepare the pyrazole ring through stepwise additions of substituted hydrazines to unsaturated ketones, followed by cyclization using oxidative (Scheme 12), 50,51 Vilsmeier-Haack (Scheme 13), 52 or Dieckmann (Scheme 14) conditions. 53 These options allow one to synthesize ring systems with useful functional group for subsequent transformations in a more regiocontrolled manner.…”

Stereochemistry at the Forefront in the Design and Discovery of Novel Anti-tuberculosis Agents

“…Like compound 39, another active nitroimidazole compound is PA-824 (34) which exhibits high in vitro and in vivo activities, but lacks any mutagenic features and is currently in phase II clinical trials as well. Recently, there has been a great deal of research pertaining to the modification of PA-824 [71][72][73][74][75]. It is believed that the stereochemistry of these molecules is also important as in the case of OPC-67683 (41).…”