The nitroimidazole scaffold has attracted great interest in the last decade, which ultimately led to the discovery of the successful drug Delamanid for multi-drug resistant tuberculosis (MDR-TB). Herein, we report medicinal chemistry on a 6-nitro-2,3-dihydroimidazooxazole (NHIO) scaffold with SAR on the novel series of triazolyl- and isoxazolyl-based NHIO compounds. In the present study, 41 novel triazolyl- and isoxazolyl-based NHIO compounds were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The active compounds with MIC of 0.57–0.13 μM were further screened against dormant, as well as against resistant strains of MTB. Based on the overall in vitro profile, five compounds were studied for in vivo oral pharmacokinetics, wherein two compounds: 1g and 2e showed a good PK profile. In in vivo efficacy studies in the intra-nasal model of acute infection, 1g showed 1.8 and 1 log CFU reduction with respect to the untreated and early control, respectively. The lead compound 1g also showed an additive to synergistic effect in combination studies with first line-TB drugs and no CYP inhibition. From the present studies, the compound 1g represents another alternative lead candidate in this class and needs further detailed investigation.

Synthesis of new generation triazolyl- and isoxazolyl-containing 6-nitro-2,3-dihydroimidazooxazoles as anti-TB agents: in vitro, structure–activity relationship, pharmacokinetics and in vivo evaluation

The present invention relates to a method for the production of 2-halo-4-nitroimidazole and intermediates thereof. Further, the present invention relates to a production process of 1,4-dinitroimidazole comprising subjecting 4-nitroimidazole to nitration reaction. Furthermore, the present invention relates to a production process of 4-nitroimidazole comprising subjecting imidazole to nitration reaction.

Methods for the production of 2-halo-4-nitroimidazole and intermediates thereof

Determination and correlation solubility of 4-nitroimidazole in twelve pure solvents from 278.15 K to 323.15 K

In this paper, 1-methyl-2,4,5-triiodoimidazole (1) was nitrified with various nitrating reagents. 1-Methyl-2,4,5-triiodoimidazole mononitrate (2), 2,4-diiodo-1-methyl-5-nitroimidzole (3), 2,5-diiod...

The nitration of 1-methyl-2,4,5-triiodoimidazole and its oxidation by-product under nitration conditions

This invention relates to a process for the production of a compound of formula (I) wherein X is Cl or Br, comprising the steps of : (i) nitration of a compound of formula (II) to obtain a compound of formula (III) with the aid of nitric acid in a mixture of acetic acid and acetic anhydride (ii) thermally rearranging the compound of formula (III) into a compound of formula (IV) (iii) reacting the compound of formula (IV) with a chlorinating or bromating agent. The invention provides a more efficient process than the existing processes.

Method for the production of 2-halogeno-4-nitroimidazole

Methylation of 2-chloro-4-nitroimidazole (6), obtained from imidazole in four steps, either with dimethyl sulphate or with diazomethane affords a mixture of 2-chloro-l-methyl-5-nitroimidazole (10) and the 4-nitro-isomer (7). The corresponding dinitro compounds 11 and 8 are formed in the methylation of 2,4-dinitroimidazole (5), 8 being converted to 7 by the action of POCl3. Reaction of 10 with the sodium salt of N-methanesulphonyl-2-imidazolidinone provides the potent amoebicide, 1-methylsulphonyl-3-(1-methyl-5-nitroimidazol-2-yl)-2-imidazolidinone (2). The isomer 14 is synthesised from 7 in low yield. Ethylation of 5 leads to preponderant N-alkylation, providing a mixture of l-ethyldinitroimidazoles (9) and (12), but a small amount of N,C-diethyl derivative 15 is also obtained. The formation of 15 from 5 is rationalised. The diiodination product of imidazole is shown to be 4,5-diiodoimidazole (19), nitric acid transforming it to 4-iodo-5-nitroimidazole (20). Methylation of 20 affords a mixture of isomeric 1 -methyliodonitro derivatives (21) and (22). The structures of 21 and 22 are established by 13C NMR data as well as by conversion into morpholine derivatives 26 and 24 respectively which also arise from 1-methylchloronitroimidazoles (25) and (23). A mechanism is proposed for the reported conversion of 5 into 4-chloro-5-nitroimidazole (32) in boiling 2-chloroethanol.

V. V. Iyer

Papers

Nitroimidazoles. part xi. some halonitro- and dinitroimidazoles