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• 22 new compounds with biphenyl imidazole scaffolds were designed and synthesized. • Compound 12m showed better antifungal activity than fluconazole. • The structure-activity relationships of compounds were discussed. • Compound 12m exhibited low inhibition profiles for human cytochrome P450 isoforms. To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans , C. neoformans , A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization. [ABSTRACT FROM AUTHOR]

To further enhance the anti- Aspergillus efficacy of our previously discovered antifungal lead compound 1 , a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans , C. neoformans , A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability. [ABSTRACT FROM AUTHOR]

To further enhance the anti- Aspergillus efficacy of our previously discovered antifungal lead compounds ( 1 ), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans . In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp . Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp. , C. neoformans , A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability. [ABSTRACT FROM AUTHOR]

Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans . The most promising compounds 12f – g and 19a – b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125–2 μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans . Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization. [ABSTRACT FROM AUTHOR]

A series of compounds with benzothiazole and amide-imidazole scaffolds were designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. The antifungal activity of these compounds was evaluated in vitro , and their structure-activity relationships (SARs) were evaluated. The synthesized compounds showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans . The most potent compounds 14o , 14p , and 14r exhibited potent activity, with minimum inhibitory concentration (MIC) values in the range of 0.125–2 μg/mL. Preliminary mechanism studies revealed that the compound 14p might act by inhibiting the CYP51 of Candida albicans . The SARs and binding mode established in this study are useful for further lead optimization. [ABSTRACT FROM AUTHOR]

To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of l -amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i , 14n , 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis , with MIC values in the range of 0.03–0.06 μg/mL, and against A. fumigatus and C. neoformans , with MIC values in the range of 1–2 μg/mL. Notably, Compounds 14i , 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S -configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent. Image 1 • Compounds 14i , 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra. • Compounds 14i , 14n, 14s and 14v showed moderate antifungal activities against fluconazole-resisitent Candida albicans. • l Compound 14v reduced the content of ergosterol in a dose-dependent manner. • l Compounds 14n and 14v were almost nontoxic to mammalian A549 cells. • Compound 14v showed excellent stability in human plasma. [ABSTRACT FROM AUTHOR]

To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[ b ]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03–0.5 μ g/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25–2 μ g/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro , with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study. [Display omitted] • A novel class of 2-(benzo[ b ]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. • Compounds A30 - A34 exhibited excellent broad-spectrum antifungal activities. • Compounds A31 and A33 showed weak inhibitory effect on CYP3A4 and CYP2D6. • Compound A31 showed high metabolic stability in vitro and in vivo. [ABSTRACT FROM AUTHOR]

l -amino alcohol derivatives exhibited high antifungal activity, but the metabolic stability of human liver microsomes in vitro was poor, and the half-life of optimal compound 5 was less than 5 min. To improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of antifungal compounds with a dihydrooxazole scaffold was designed and synthesized. Compounds A33-A38 substituted with 4-phenyl group on dihydrooxazole ring exhibited excellent antifungal activities against C. albicans , C. tropicalis and C. krusei , with MIC values in the range of 0.03–0.25 μ g/mL. In addition, the metabolic stability of compounds A33 and A34 in human liver microsomes in vitro was improved significantly, with the half-life greater than 145 min and the half-life of 59.1 min, respectively. Moreover, pharmacokinetic studies in SD rats showed that A33 exhibited favourable pharmacokinetic properties, with a bioavailability of 77.69%, and half-life (intravenous administration) of 9.35 h, indicating that A33 is worthy of further study. [Display omitted] • A novel class of dihydrooxazole compounds was designed and synthesized. • Compounds A33 - A38 showed excellent antifungal activities. • The metabolic stability of compounds A33 and A34 was improved dramatically. • Compound A33 exhibited favourable pharmacokinetic properties in SD rats. [ABSTRACT FROM AUTHOR]

A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03–1 μ g/mL. Compounds with R1 = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1–8 μ g/mL. Compounds with R1 = H or 2-F (such as 15a , 15o , 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632 , 901 and 904 with MIC values in the range of 0.125–4 μ g/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o , 15z and 15ae were nearly nontoxic to mammalian A549 cells. Image 1 • 32 new compounds of β-Azole-phenylacetone derivatives were designed and synthesized. • Compounds 15a , 15b and 15u - ae exhibited excellent antifungal activities against five susceptible pathogenic strains. • Compound 15o showed moderate antifungal activities against five fluconazole-resistant Candida albicans. • Compound 15ae can reduce the content of ergosterol. • Compounds 15o , 15z , and 15ae were nearly nontoxic to mammalian A549 cells. [ABSTRACT FROM AUTHOR]