Design and Discovery of Pyrazolo[1,5- a]pyrimidinyl Oxazoline as a Promising Antifungal Model

Our previous work demonstrated the values of 2-(2-oxazolinyl)aniline (NHPhOx) in achieving scaffold-distinct Antifungal amides. Herein, amide-free Antifungal leads are disclosed, featuring the replacement of N-phenylamide by pyrazolo[1,5-a]pyrimidine. Pyrazolo[1,5-a]pyrimidine oxazolines and analogs were designed and synthesized via N-distribution inspired hybridization of pharmaceutically important pyrazolo[1,5-a]pyrimidine and oxazolines. In vitro evaluation showed that compound D10 stands out as a novel Antifungal candidate against agriculturally important Colletotrichum capsici and Pyricularia oryzae. Specifically, this candidate (EC₅₀ value of 1.6 μM) is more promising against C. capsici, which is 1.6- and 3.5-fold more potent than carbendazim and azoxystrobin, respectively. At a concentration of 100 μM, it achieved 58% preventative and 60% curative efficacy against C. capsici in pepper fruits, which are marginally better than the positive control carbendazim. Mechanistic investigations confirmed that it could disrupt the cell membrane integrity of C. capsici. The biosafety assessment showed that no adverse effects of this candidate were observed for rice and earthworms.

antifungal activity; lead optimization; oxazoline; pyrazolo[1,5-a]pyrimidine; scaffold hopping.