RESUMEN
Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were designed and synthesized in an effort to obtain antifungals with potent, broad-spectrum activity that are less susceptible to resistance. Most of these compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.125 µg/mL to 0.5 µg/mL. Use of recombinant Saccharomyces cerevisiae strains showed compounds 7 and 10 overcame the overexpression and resistant-related mutations in ERG11 of S. cerevisae and several pathogenic Candida spp. Despite being substrates of the C. albicans and Candida auris Cdr1 drug efflux pumps, compounds 7 and 10 showed moderate potency against five fluconazole (FCZ)-resistant fungi with MIC values from 2.0 µg/mL to 16.0 µg/mL. Growth kinetics confirmed compounds 7 and 10 had much stronger fungistatic activity than FCZ. For C. albicans, compounds 7 and 10 inhibited the yeast-to-hyphae transition, biofilm formation and destroyed mature biofilm more effectively than FCZ. Preliminary mechanism of action studies showed compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption. Further investigation of these novel triazole derivatives is also warranted by their predicted ADMET properties and low cytotoxicity.
Asunto(s)
Antifúngicos , Candida , Pruebas de Sensibilidad Microbiana , Pirazoles , Triazoles , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Relación Estructura-Actividad , Candida/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Cryptococcus neoformans/efectos de los fármacos , Humanos , Farmacorresistencia Fúngica/efectos de los fármacos , Saccharomyces cerevisiae/efectos de los fármacos , Candida albicans/efectos de los fármacosRESUMEN
Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 µg/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.
Asunto(s)
Antifúngicos , Candida albicans , Cryptococcus neoformans , Pruebas de Sensibilidad Microbiana , Tetrazoles , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/uso terapéutico , Tetrazoles/farmacología , Tetrazoles/química , Tetrazoles/síntesis química , Tetrazoles/farmacocinética , Tetrazoles/uso terapéutico , Animales , Humanos , Candida albicans/efectos de los fármacos , Ratones , Cryptococcus neoformans/efectos de los fármacos , Relación Estructura-Actividad , Aspergillus fumigatus/efectos de los fármacos , Descubrimiento de Drogas , Farmacorresistencia Fúngica/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismoRESUMEN
Invasive fungal infections pose a serious threat to public health and are associated with high mortality and incidence rates. The development of novel antifungal agents is urgently needed. Based on hit-to-lead optimization, a series of 2,4,6-trisubstituted triazine hydrazone compounds were designed, synthesized, and biological evaluation was performed, leading to the identification of compound 28 with excellent in vitro synergy (FICI range: 0.094-0.38) and improved monotherapy potency against fluconazole-resistant Candida albicans and Candida auris (MIC range: 1.0-16.0 µg/mL). Moreover, 28 exhibited broad-spectrum antifungal activity against multiple pathogenic strains. Furthermore, 28 could inhibit hyphal and biofilm formation, which may be related to its ability to disrupt the fungal cell wall. Additionally, 28 significantly reduced the CFU in a mouse model of disseminated infection with candidiasis at a dose of 10 mg/kg. Overall, the triazine-based hydrazone compound 28 with low cytotoxicity, hemolysis, and favorable ADME/T characteristics represents a promising lead to further investigation.
Asunto(s)
Antifúngicos , Candidiasis , Animales , Ratones , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Fluconazol/farmacología , Candida albicans , Candidiasis/tratamiento farmacológico , Candidiasis/microbiologíaRESUMEN
Here we designed and synthesized 58 deferasirox derivatives with the aim of discovering novel antifungal agents. Most compounds exhibited moderate to excellent in vitro antifungal activities against Cryptococcus neoformans H99 with MIC values ranging from 0.25 µg/mL to 16 µg/mL, including ten compounds with MIC values less than 1 µg/mL that were further screened against an additional six pathogenic fungi. This class of compounds showed high potency against Candida glabrata with MIC values ranging from <0.125 µg/mL to 1 µg/mL. We identified that compound 54 has high potency against 14 strains of Candida glabrata spp. and Cryptococcus spp. with MIC values ranging from <0.125 µg/mL to 1 µg/mL. In addition, compound 54 significantly reduced the CFU in a mouse model of disseminated infection with Cryptococcus neoformans H99 at a dose of 10 mg/kg, which is comparable to FLC. Further investigations on compound 54 are currently in progress.
Asunto(s)
Criptococosis , Cryptococcus neoformans , Ratones , Animales , Antifúngicos/farmacología , Deferasirox/farmacología , Pruebas de Sensibilidad Microbiana , Criptococosis/tratamiento farmacológicoRESUMEN
A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of ≤0.125 µg/mL-4.0 µg/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.
Asunto(s)
Antifúngicos , Triazoles , Humanos , Antifúngicos/química , Triazoles/química , Simulación del Acoplamiento Molecular , Fluconazol/farmacología , Candida albicans , Relación Estructura-Actividad , Pruebas de Sensibilidad MicrobianaRESUMEN
Previous work led to the rational design, synthesis and testing of novel antifungal triazole analogues bearing alkynyl-methoxyl side chains. Tests of in vitro antifungal activity showed Candida albicans SC5314 and Candida glabrata 537 gave MIC values of ≤0.125 µg/mL for most of the compounds. Among these, compounds 16, 18, and 29 displayed broad-spectrum antifungal activity against seven human pathogenic fungal species, two fluconazole-resistant C. albicans isolates and two multi-drug resistant Candida auris isolates. Moreover, 0.5 µg/mL of 16, 18, and 29 was more effective than 2 µg/mL of fluconazole at inhibiting fungal growth of the strains tested. The most active compound (16) completely inhibited the growth of C. albicans SC5314 at 16 µg/mL for 24 h, affected biofilm formation and destroyed the mature biofilm at 64 µg/mL. Several Saccharomyces cerevisiae strains, overexpressing recombinant Cyp51s or drug efflux pumps, indicated 16, 18, and 29 targeted Cyp51 without being significantly affected by a common active site mutation, but were susceptible to target overexpression and efflux by both MFS and ABC transporters. GC-MS analysis demonstrated that 16, 18, and 29 interfered with the C. albicans ergosterol biosynthesis pathway by inhibition at Cyp51. Molecular docking studies elucidated the binding modes of 18 with Cyp51. The compounds showed low cytotoxicity, low hemolytic activity and favorable ADMT properties. Importantly, compound 16 showed potent in vivo antifungal efficacy in the G. mellonella infection model. Taken together, this study presents more effective, broad-spectrum, low toxicity triazole analogues that can contribute to the development of novel antifungal agents and help overcome antifungal resistance.
Asunto(s)
Antifúngicos , Triazoles , Humanos , Antifúngicos/farmacología , Triazoles/farmacología , Fluconazol/farmacología , Simulación del Acoplamiento Molecular , Pruebas de Sensibilidad Microbiana , Candida albicans , Farmacorresistencia Fúngica , Saccharomyces cerevisiaeRESUMEN
The clinical prevalence of antifungal drug resistance has been increasing over recent years, resulting in the failure of treatments. In an attempt to overcome this critical problem, we sought novel synergistic enhancers to restore the effectiveness of fluconazole against resistant Candida albicans. Based on the structural optimization of hit compound 8 from our in-house library, a series of novel 1,3,5-triazines derivatives was designed, synthesized, and biologically evaluated for synergistic activity in combination with fluconazole. Among them, compounds 10a-o, which contain thiosemicarbazides side chains, exhibited excellent in vitro synergistic antifungal potency (MIC80 = 0.125-2.0 µg/mL, FICI range from 0.127 to 0.25). Interestingly, compound 10l exhibited moderate C. albicans activity as monotherapy with an MIC80 value of 4.0 µg/mL, and also on several Cryptococcus strains (MIC80 ranging from ≤ 0.125-0.5 µg/mL) and C. glabrata (MIC80 ≤ 0.125 µg/mL). These effects were fungal-selective, with much lower levels of cytotoxicity towards human umbilical vein endothelial cells. Here, we report a series of thiosemicarbazides containing 1,3,5-triazines derivatives as potent synergists with fluconazole, and have preliminarily validated compound 10l as a promising antifungal lead for further investigation.
RESUMEN
In order to develop new triazole derivatives, we optimized the lead compound a6 by structural modifications to obtain a series of (2R,3R)-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compounds 5-36. Most of the target compounds exhibited excellent in vitro antifungal activity against Candida albicans 10231 and Candida glabrata 537 with MIC ≤ 0.125 µg/mL. Of particular note, compounds 6, 22, 28, 30 and 36 were highly active against Candida neoformans 32609 with MIC ≤ 0.125 µg/mL and showed broad-spectrum antifungal activity including against fluconazole-resistant Candida auris 891. In addition, compounds 6 and 22 demonstrated inhibitory effects on filamentation in the azole-resistant C. albicans isolate. Moreover, compounds 6 and 22 were minimally toxic to HUVECs and possessed weak inhibitory effects on the human CYP3A4 and CYP2D6. SARs and docking study further indicated that ortho-substituted groups in the terminal phenyl ring can promote the compounds to improve their antifungal activity.
Asunto(s)
Antifúngicos , Triazoles , Humanos , Antifúngicos/química , Triazoles/química , Pruebas de Sensibilidad Microbiana , Fluconazol/farmacología , Candida albicans , Relación Estructura-ActividadRESUMEN
A series of triazole derivatives containing phenylethynyl pyrazole moiety as side chain were designed, synthesized, and most of them exhibited good in vitro antifungal activities. Especially, compounds 5k and 6c showed excellent in vitro activities against C. albicans (MIC = 0.125, 0.0625 µg/mL), C. neoformans (MIC = 0.125, 0.0625 µg/mL), and A. fumigatus (MIC = 8.0, 4.0 µg/mL). Compound 6c also exerted superior activity to compound 5k and fluconazole in inhibiting hyphae growth of C. albicans and inhibiting drug-resistant strains of C. albicans, and it could reduce fungal burdens in mice kidney at a dosage of 1.0 mg/kg. An in vivo efficacy evaluation indicated that 6c could effectively protect mice models from C. albicans infection at doses of 0.5, 1.0, and 2.0 mg/kg. These results suggested that compound 6c deserves further investigation.