Benzofuro[3,2-d]pyrimidines inspired from cercosporamide CaPkc1 inhibitor: Synthesis and evaluation of fluconazole susceptibility restoration

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

“…Modification of the combination of the copper source (CuI), base (Cs 2 CO 3 , NaH), and additional ligand (N,N-dimethylglycine) did not improve the completion of the reaction. Interestingly, the same reaction carried out from phenols 3 [16] and 4, without carboxamide substitution, afforded the desired diaryl ethers 7 and 8 in good yields (73% and 78%, respectively). This result indicated that the reaction is more sensitive to the electronic-withdrawing effect of the carboxamide and the steric hindrance in the ortho position of the phenol than to the bulky benzyl-protecting groups.…”

“…Indeed, benzofuran derivatives exhibited promising antiproliferative activity against two human non-small cell lung cancer (NSCLC) cell lines [15]. More recently, benzofuro [3,2-d]pyrimidines proved to be interesting agents in antifungal chemotherapy by restoring the susceptibility of resistant strains to azole treatment [16].…”

“…Before obtaining the diazonium salt, the advantage of this approach relates to the nitro function that promotes the access to diaryl ethers 5-8 during the initial SNAr reaction between 1iodo-2-nitrobenzene and phenolic derivatives 1-4 (Scheme 1). The standard copper-catalyzed Ullmann diaryl ether synthesis [45,46] was first performed in the presence of the previously synthesized phenol derivative 1 [16] and its dimethyl analogue 2, obtained in the same conditions from commercially available 3,5-dimethoxyphenol 4. This route could allow the introduction of the carboxamide function before the heterocyclization step.…”

Synthesis of 4,7,9-Trihydroxy[1]benzofuro[3,2-d]pyrimidine-6-carboxamide: Evaluation of Cytotoxicity and Inhibition of Protein Kinase C (CaPkc1)

“…Mp � 300-301°C. IR (cm (2-carbamoyl-6-cyano-3,5-dimethoxyphenoxy) acetate (11). To a solution of 3-cyano-2-hydroxy-4,6dimethoxybenzamide (10) (222 mg, 1.00 mmol) in N,Ndimethylformamide (2 mL) was added sodium hydride 60% (48 mg, 1.20 mmol) at room temperature.…”

“…In addition, research results suggest dihydroxybenzofurancarboxamide ring as the pharmacophore of the molecule, justifying the strategy for the design of new tricyclic compounds [10]. Regarding this, our expertise in the synthesis of pyrimidine-fused heterocycles as biological agents targeting kinases was used for the design of the new compounds, constituting the third ring of the benzofuro [3,2-d]pyrimidine derivatives described [11]. In this study, we designed and synthesized a new compound 13, which remained the dihydroxybenzofuran-carboxamide ring (part A, excluding asymmetric carbon), replacing part B with pyrimidine ring (Figure 1) targeting CaPkc1.…”