Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC₅₀ value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.

The protein kinase Pkc1 of Candida albicans (CaPkc1), one of the key proteins involved in MAPK pathway, is described as a regulator of cell wall integrity during growth, morphogenesis, and response to cell wall stress. The ()-cercosporamide is an antifungal natural product isolated from the phytopathogen fungus Cercosporidium henningsii. This phytoxin was found to inhibit selectively CaPkc1 and constitutes an interesting model for the design of novel antifungal molecules. In this research, 4,7,9-trihydroxy[1]benzofuro[3,2-d]pyrimidine-6-carboxamide (13) derived from ()-cercosporamide was synthesized via a seven-step procedure by well-known reactions and evaluation of cytotoxicity and inhibition of CaPkc1. The bioassay showed CaPkc1 inhibitory activity 87 higher and cytotoxicity 100 times less than the reference, ()-cercosporamide.

Treatment of fungal infections is very difficult because of the limited therapeutic arsenal and the emergence of resistance to the two major antifungal classes: azoles and echinocandins. Consequently, finding new targets and new therapeutic strategies is a priority. The protein kinase Pkc1 of Candida albicans (CaPkc1), one of the key proteins involved in MAPK pathways, is described as a regulator of cell wall integrity during growth, morphogenesis, and response to cell wall stress. Therefore, the discovery of CaPkc1 inhibitory molecules can open up new and promising prospects in the development of new antifungal drugs that inhibit CaPkc1. In this study, we evaluated the CaPkc1 inhibitory activity of three benzofuro[3,2-d]pyrimidine derivatives at three different concentrations of 50 µM, 100 µM, and 150 µM. A concentration of 100 μM was optimal for CaPkc1 inhibitory activity with all three benzofuro[3,2-d]pyrimidine derivatives. Keywords: Benzofuro[3,2-d]pyrimidine, CaPkc1, Candida albicans, antifungal activity.