RESUMO
To identify effective and low toxicity synergistic antifungal compounds, 24 derivatives of chalcone were synthesized to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. The minimal inhibitory concentration (MIC80) and the fractional inhibitory concentration index (FICI) of the antifungal synergist fluconazole were measured against fluconazole-resistant Candida albicans. This was done via methods established by the clinical and laboratory standards institute (CLSI). Of the synthesized compounds, 2'-hydroxy-4'-methoxychalcone (8) exhibited the most potent in vitro (FICI=0.007) effects. The structure activity relationship of the compounds are then discussed.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Chalconas/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Lack of novel antifungal agents and severe drug resistance has led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with anti-resistant potency are highly desirable. Thus, derivatives of curcumin were synthesized to restore the effectiveness of fluconazole (FLC) against FLC-resistant Candida spp. and structure-activity relationships were then discussed. Some novel derivatives showed promising features as novel antifungal lead compounds. Of them, compound 4 showed good alone or synergistic antifungal activity against FLC-resistant Candida spp. Moreover, compound 4 was proven as a potent inhibitor of Candida albicans biofilm formation and yeast-to-hypha morphological transition whether used alone or in combination with FLC, which was further confirmed by the inhibitory effect on cellular surface hydrophobicity of C. albicans. Compound 4 also inhibits intracellular ATP production of C. albicans and disrupts membrane permeability of C. albicans when used in combination with FLC. The results highlighted the potential of curcumin derivatives to overcome fluconazole-related and biofilm-related drug resistance.
Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Curcumina/análogos & derivados , Fluconazol/farmacologia , Trifosfato de Adenosina/metabolismo , Antifúngicos/síntese química , Antifúngicos/química , Candida/efeitos dos fármacos , Candida/metabolismo , Candida/fisiologia , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Twenty-three monoketone derivatives of curcumin were synthesized to investigate the synergy with fluconazole against fluconazole-resistant Candida spp. The minimal inhibitory concentration (MIC80) and the fractional inhibitory concentration index (FICI) of the antifungal synergist fluconazole were measured against fluconazole-resistant C. albicans, C. tropicalis and C. krusei in vitro. Most of these compounds showed good synergistic activities against C. tropicalis. Among them, compound 9 exhibited significant synergistic activities against Candida spp. SARs were also discussed. In particular, a cell growth test exhibited that a combination of 1 µg ml-1 fluconazole and 64 µg ml-1 or 128 µg ml-1 compound 9 showed the most potent fungicidal effect against C. tropicalis. The synergistic effect may be associated with the changes of the intracellular ATP content and cell membrane permeability. Our results provided a basis for future evaluation and development of these compounds as leads for therapeutics for fluconazole-resistant candidiasis.