Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives

Abstract

Artemisinin (ART) and its derivatives artesunate (AS), dihydroartemisinin (DHA) are a group of drugs containing a sesquiterpene lactone used to treat malaria. Previously, AS was shown to not have antibacterial activity but to significantly increase the antibacterial activities of β-lactam antibiotics against E. coli. Herein, molecular docking experiments showed that ART, AS and DHA could dock into AcrB very well, especially DHA and AS; both DHA and AS had the same docking pose. The affinity between AS and AcrB seemed weaker than that of DHA, while the succinate tail of AS, which was like a "bug", could extend in the binding pocket very well. Imitating the parent nucleus of DHA and the succinate tail of AS, twenty-one DHA derivatives 4a-u were designed and synthesized. Among them, seventeen were new compounds. The synergistic effects against E. coli AG100A/pET28a-AcrB showed among the new structures 4k, 4l, 4m, 4n, and 4r exhibited significant synergism with β-lactam antibiotics although they had no direct antibacterial activities themelves. The bacterial growth assay showed that only 4k in combination with ampicillin or cefuroxime could totally inhibit bacterial growth from 0 to 12 h, demonstrating that 4k had the best antibacterial enhancement effect. In conclusion, our results provided a new idea and several candidate compounds for antibacterial activity enhancers against multidrug resistant E. coli.

Design of New Antibacterial Enhancers Based on AcrB’s Structure and the Evaluation of Their Antibacterial Enhancement Activity

“…Till now, the main known AcrB inhibitors are PAβN, NMP, D13-9001, and MBX2319 reported by others, and AS and DHA7 reported by the present study [8,9,10]. However, these inhibitors such as PAβN had much more serious toxicity or lower activities; so new antibacterial enhancers should be developed.…”

“…Eighteen artemisinin (ART) derivatives have been derived from a previous work so far [10]. DHA7 was selected as the molecular template (Figure 1A).…”

“…Previous works verified that AS and DHA7 had antibacterial enhancement activity while ART and DHA did not have such activity [9,10]. Therefore, molecular docking was first performed on ART and three ART derivatives including DHA, AS, and DHA7 to identify a possible binding pocket for their potency.…”

“…Our previous studies reported the antibacterial enhancement activity of AS and its derivative DHA7 for the first time [9,10]. Although DHA7 had better activity than AS, it was still only effective against standard E. coli strains rather than clinical strains and had poor aqueous solubility as AS.…”

“…Based on the results of molecular docking experiments, a new antibiotic enhancer named as dihydroartemisinine 7 (DHA7) was developed by removing the carbonyl group and replacing the carboxyl group with imidazole in the succinate tail of AS. DHA7 has better antibacterial enhancement activity of β-lactam antibiotics than AS does [10]. This experiment proved that the strategy of changing the chemical structure of the succinate tail of AS to obtain a better active compound targeting AcrB was feasible.…”