Design,synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans / 药学实践杂志

Objective 3,4-Methylenedioxyphenethylamine and caffeic acid derivatives have been proven previously in our group to produce activity against drug resistant fungi synergistic with fluconazole (FCZ).The two pharmacophores were cou-pled by amino acids as linkers in this project in order to design and synthesize the novel compounds and investigate the activity against drug resistant fungi in vitro.Methods 3,4-Methylenedioxyphenethylamine initially reacted with Boc-protected amino acids,following deprotection and coupling reaction with caffeic acid,to get nine title compounds.All title compounds as well as four intermediates were subjected to antifungal activity screening for fluconazole resistant Candida albicans in vitro.Results Nine title compounds showed synergistic antifungal activity for drug resistant Candida albicans with fluconazole at a concentra-tion range of 0.5-2.0μg/ml.Among them,compounds 3b,3f,3g and 3i showed the higher activity with the same MIC80 value of 0.5 μg/ml,which is comparable to those of the control compounds 7b and 5.Conclusion Linking 3,4-methylenedioxyphen-ethylamine and caffeic acid with piperidine-4-carboxylic acid (3b),valine (3g),leucine (3f) and isoleucine (3i) led to novel compounds with high synergistic antifungal activity against drug resistant Candida albicans combined with fluconazole.

Derivatization of berberine based on its synergistic antifungal activity with fluconazole against fluconazole-resistant Candida albicans / 药学学报

Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.

Derivatization of berberine based on its synergistic antifungal activity with fluconazole against fluconazole-resistant Candida albicans / 药学学报

Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.