A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide

Abstract

Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and 1H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.

The role of halofuginone in fibrosis: more to be explored?

“…If halofuginone were found to be successful with minimal unwanted side effects in a clinical trial addressing a cell-or tissue-specific fibrotic indication, then it might be considered as an anti-fibrotic therapy for other indications as well. Additionally, as Zhang et al [164] explained, linear synthesis of halofuginone hydrobromide can be achieved now, but only its anti-coccidial activity has been evaluated and verified so far. Therefore, if halofuginone can be specifically designed for the inhibition or promotion of some signaling pathway that plays a vital role in alleviating or even reversing fibrosis on the basis of Zhang and colleagues' methods [164], then fibrosis may not be such a challenging problem in the near future.…”

“…Additionally, as Zhang et al [164] explained, linear synthesis of halofuginone hydrobromide can be achieved now, but only its anti-coccidial activity has been evaluated and verified so far. Therefore, if halofuginone can be specifically designed for the inhibition or promotion of some signaling pathway that plays a vital role in alleviating or even reversing fibrosis on the basis of Zhang and colleagues' methods [164], then fibrosis may not be such a challenging problem in the near future. In conclusion, the outlook for the use of halofuginone against numerous fibrotic diseases appears bright, but many questions remain that must absolutely be explored further.…”