Fragment-Based Design of Symmetrical Bis-benzimidazoles as Selective Inhibitors of the Trimethoprim-Resistant, Type II R67 Dihydrofolate Reductase was written by Bastien, Dominic;Ebert, Maximilian C. C. J. C.;Forge, Delphine;Toulouse, Jacynthe;Kadnikova, Natalia;Perron, Florent;Mayence, Annie;Huang, Tien L.;Vanden Eynde, Jean Jacques;Pelletier, Joelle N.. And the article was included in Journal of Medicinal Chemistry in 2012.Synthetic Route of C16H22N2O4 This article mentions the following:
The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic mols. of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, sym. bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (Ki = 2-4 μM). The putative mode of inhibition is discussed according to mol. modeling supported by in vitro tests. In the experiment, the researchers used many compounds, for example, 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (cas: 162046-66-4Synthetic Route of C16H22N2O4).
4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (cas: 162046-66-4) belongs to piperazine derivatives. Piperazine was first introduced as an anthelmintic in 1953. Piperazine compounds mediate their anthelmintic action by generally paralyzing parasites, allowing the host body to easily remove or expel the invading organism. Although many piperazine derivatives occur naturally, piperazine itself can be synthesized by reacting alcoholic ammonia with 1,2-dichloroethane, by the action of sodium and ethylene glycol on ethylene diamine hydrochloride, or by reduction of pyrazine with sodium in ethanol.Synthetic Route of C16H22N2O4
Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics