Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broadspectrum antifungal agents

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 mu g/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25-2 mu 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of novel derivatives were designed and synthesized, and compounds A30-A34 exhibited excellent broad-spectrum antifungal activity with low minimum inhibitory concentrations against various fungi. Compounds A31 and A33 showed high metabolic stability in vitro and weak inhibitory effects on liver microsomal enzymes. Compound A31 demonstrated favorable pharmacokinetic properties in SD rats.