Design, synthesis, and biological evaluation of 2-phenylthiazole CYP51 inhibitors.

Fungal pathogens have emerged as one of the most significant threats to global public health. Invasive fungal infections, characterized by high morbidity and mortality rates, have become one of the most severe diseases, posing a substantial threat to human health. In this study, a rational drug design strategy was employed, targeting lanosterol 14α-demethylase (CYP51). Using SCZ-14, a CYP51 inhibitor with moderate antifungal activity, as the lead compound, 27 novel 2-phenylthiazole derivatives were designed and synthesized through two rounds of structural optimization. Among these compounds, compound B9 exhibited potent inhibitory activity against seven common clinically susceptible fungal strains and moderate activity against six fluconazole-resistant fungi strains, and it demonstrated low cytotoxicity. In addition, the preferred compound B9 had good drug-like properties according to the prediction software. In addition, molecular dynamics studies were conducted on compound B9. All the results of the above research show that the target compound B9 is valuable for further study.