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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.

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Acylation products of 2-aryl-5-hydrazino-4-X-1,3-oxazoles [X = C(O)OAlk, P(O)(OAlk) 2 ], when heated in acetic acid or ethanol, undergo recyclization and transform into the derivatives of 1,3,4-oxadiazol-2-ylglycine or its phosphonyl analog. A similar rearrangement also occurs in the reactions of 2-alkyl(aryl)-5-hydrazino-1,3-oxazole-4-carbonitriles with carboxylic acid chlorides in pyridine, but it is accompanied by additional cyclization involving the amide residue and nitrile group, yielding 2-(5-amino-1,3-oxazol-4-yl)-1,3,4-oxadiazole derivatives.A systematic study of the reactions of b,b-disubstituted enamides I3III with hydrazine hydrate, initiated recently [133] and continued in this work, showed that the possible applications of this polycondensation are fairly wide, and it is indispensable for preparative synthesis of 5-hydrazino-1,3-oxazole derivatives IV3 VI containing in 4-position various electron-withdrawing groups: C(O)OAlk, P(O)(OAlk) 2 , and C=N. The 1 H NMR and IR spectra of these products are consistent with their suggested structures (Table 1). Transformations I 6 IV, II 6 V, and III 6 VI are similar to the extensively studied cyclocondensations of enamides I3III with primary and secondary amines (see references in [4]). Therefore, there is no doubt that compounds IV3VI are, indeed, the 5-hydrazino-1,3-oxazole derivatives differently reacting with carboxylic acid chlorides in the presence of bases. The reaction pathway essentially depends on the structure of electron-withdrawing substituents in 4-position of the heteroring and on the acylation conditions. In particular, acylation of the hydrazino group in alkyl esters of 2-aryl-5-hydrazino-1,3-oxazole-4-carboxylic acids IV and their phosphonyl analogs V in acetonitrile in the presence of an equimolar amount of triethylamine mainly occurs at the nitrogen atom more remote from the oxazole ring. The reaction yields b-acylation products VII and VIII containing the HtNHNHCO fragment, as indicated by the 1 H NMR spectra (Table 1).At the same time, 2-aryl-5-hydrazino-1,3-oxazole-4-carbonitriles VI structurally related to IV and V react with carboxylic acid chlorides in the presence of triethylamine quite differently, yielding mainly the a-acylation products HtN(COR 2 )NH 2 whose structure was unambiguously proved by spectral and chemical methods [2]. The acylation pathway of substrates VI changes if the acylation with carboxylic acid chlorides is performed in pyridine. The b-acylation products IX formed in the first step are difficult to isolate pure, because they readily undergo further transformations (see scheme). However, we were able to isolate one of these compounds (X = CN, R 1 = R 2 = 4-CH 3 C 6 H 4 ) and to record its 1 H NMR spectrum. The spectrum contained two broadened singlets at 10.43 and 10.93 ppm, assignable to two different N3H protons in the HtNHNHCO group.The structural similarity of b-acylation products VII3IX was proved not only by spectroscopy, but also by the fact that, in contrast to the isomeric a-acylation products, compoun...

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Previously unknown methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates have been synthesized. Their reactions with amines and amidines have yielded the corresponding sulfonamides and 6H,7H-[1,3]oxazolo-[5,4-d]pyrimidin-7-ones.

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Synthesis of a series of 2-(dichloromethyl)pyrazolo [1,5-a][1,3,5]triazines and evaluation in vitro of their anticancer activity against a panel of 60 cell lines derived from nine cancer types, namely leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer. Methods. Organic synthesis; biological tests; spectral methods; statistical methods. Results. In vitro screening of the anticancer activity showed that 5 of 26 tested compounds can effectively inhibit the growth of certain cancer cell lines. Conclusions. New type of N-(2,2-dichloro-1-cyanoethenyl)carboxamides heterocyclization with 1H-pyrazol-5-amines led to the formation of 2-(dichloromethyl)pyrazolo [1,5-a][1,3,5]triazines. Some of these compounds inhibit growth of certain cancer cell lines.