Synthesis, in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents

Abstract

Dedicated to Prof. Antonio Togni on the occasion of his 65th birthday and retirement New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4-d]pyrimidine scaffold. The docking analyzes have shown that 7piperazine substituted oxazolo[4,5-d]pyrimidines 8a-8c could be potential VEGFR2 inhibitors with high free energy of ligand-protein complex formation (ΔG: À 10.1, À 9.6, À 9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5-d]pyrimidines 8a-8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4-[5-(4-Chlorophenyl)-2-phenyl[1,3] oxazolo[4,5-d]pyrimidin-7-yl]piperazin-1-ium trifluoroacetate (8c) exhibited a slightly higher antiproliferative effect (IC 50 = 0.21 μM) than doxorubicin (IC 50 = 0.36 μM) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC 50 = 1.7 μM) and HCT-116 (IC 50 = 0.24 μM) cells.

Synthesis of some oxazolo[4,5 d]pyrimidine derivatives and evaluation of their antiviral activity and cytotoxicity

“…The synthesis of oxazolo [4,5-d]pyrimidines 1-9 is depicted in Scheme 1 and was carried out by a route described previously. [4][5][6] Available oxazolones I were used as starting substrates. Oxazolo [4,5-d]pyrimidin-7(6H)-ones III were obtained through a simple sequence of the reactions I → II → III (Scheme 1).…”

“…10 The chlorination of these compounds (POCl3 (excess), Me2NPh, 105 -110°C) afforded 7-chlorosubstituted oxazolo [4,5-d]pyrimidines IV. [4][5][6]10 Treatment of compounds IV with the primary or secondary amines, in the presence of triethylamine in dioxane, resulted in high yields of the corresponding 7-aminesubstituted oxazolo [4,5-d]pyrimidines 1-9. The synthesis of oxazolo [4,5-d]pyrimidines V was accomplished in analogy to previously reported compounds.…”

“…Some of oxazolo [4,5-d]pyrimidine derivatives were also shown to exhibit anticancer activity. [4][5][6] Since oxazoleand pyrimidine-based heterocycles, including oxazolo [5,4-d]pyrimidines, have demonstrated antiviral effects, [7][8][9] the synthesis of new compounds that contain oxazolo [4,5-d]pyrimidine fragment was of interest to us and therefore we decided to synthesize them and to evaluate their antiviral activity and toxicity.…”

Intrinsic drug potential of oxazolo[5,4‐d]pyrimidines and oxazolo[4,5‐d]pyrimidines

“…Among them, compounds 1 (Figure 22) displayed the most growth inhibitory and cytotoxic activities against all cancer cell lines. Piperazine-containing oxazolo [4,5d]pyrimidine depicted in Figure 23 has been demonstrated a slightly higher anticancer effect (IC 50 = 0.21 µM) than control drug, doxorubicin (IC 50 = 0.36 µM), on MDA-MB-231 cell line and displayed relatively good results on OVCAR-3 (IC 50 = 1.7 µM) and HCT-116 (IC 50 = 0.24 µM) cells (Velihina et al, 2020).…”

Analysis of Interactions of NHC Type Molecules and NHC-Ag Complexes with VEGFR-2 and DNA: A Molecular Docking Study

“…Molecular docking method is accepted as an essential tool for investigating the interactions between new molecules and biological macromolecules such as DNA, proteins, enzymes [29][30][31][32].…”