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This review summarizes and analyzes published medicinal chemistry data regarding physiologically active 2-arylbenzothiazoles – a promising class of antiproliferative agents and potential diagnostic agents for Alzheimer’s disease. The data have been examined in the light of SAR approach to the properties of 2-arylbenzothiazoles and substances bioactivation mechanisms using labeled radiopharmaceuticals. The most promising leaders-in-class for which clinical trials have been recommended or conducted have been highlighted. Synthetic methods for the preparation of 2-arylbenzothiazoles as precursors of new-generation drugs have been analyzed in detail. Various methods for the preparation of fluorine-containing 2-arylbenzothiazoles, including synthetic pathway to antiproliferative drugs PMX 610, 5-F 203, and Phortress have been described. 2-Arylbenzothiazoles future application in biology and medicine has been discussed.

4,5-Bis(butoxy)-2-nitrobenzaldehyde and 4,5-bis(tert-butoxycarbonyloxy)-2-nitrobenzaldehyde, as well as their fluorine-18 labeled derivatives (the half-life of F18 is T 1/2 = 110 min) were synthesized for use as precursors in the synthesis of fluorine-18 labeled catecholamines and 6-[18F]fluoro-l-DOPA ((S)-3-[4,5-dihydroxy-2-[18F]fluorophenyl]-2-aminopropionic acid), important radiopharmaceutical agents (RPAs) for positron emission tomography. An advantageous feature of the newly obtained substituted nitrobenzaldehydes is the presence of labile protective groups which can be removed without using aggressive chemicals and severe conditions, which is of fundamental importance for automation of the RPA synthesis in modern synthesis apparatus. A high and stable radiofluorination yield achieved under the optimum fluorination conditions (Kryptofix 222 [K/K2.2.2.]+[18F–], DMF, 140 °C, 10 min) using 4,5-bis(butoxy)-2-nitrobenzaldehyde as a substrate (83±6%, the number of experiments was n = 15) makes this compound a precursor of choice for the radioactive synthesis.

2-Aryl- and 2-furyl-4-carboxy-1,3-thiazolidines were synthesized. Their spectral properties were studied, and conformational analysis was performed. It was shown that they exist in solution as an equilibrium of neutral and zwitter-ion forms. The influence of the nature of substitutents and of their location in a benzene ring of thiazolidines as ligands of rhodium complexes on acetophenone hydrosilylation with diphenylsilane was examined. Thiazolidines containing donor substituents in the para-position of the benzene ring were found to be the most effective; maximal asymmetrical induction (55% ee) was reached in the presence of 2-(4-methoxyphenyl)-4-carboxy-1,3-thiazolidine.

Synthesis was carried out of the new mixed-ligand square-planar platinum(II)complexes {Pt(R2SO)[(-)-S-NOBIN]Cl2}, where (-)-S-NOBIN was S-2-amino-2′-hydroxy-1,1′-binaphthyl (R = Me, Et). The complexes are of interest as catalysts for asymmetrical synthesis. The detailed analysis of NMR, UV, and CD spectra of these compounds was performed. These complexes were established to be a mixture of the corresponding cis- and trans-isomers.

A preparative method of synthesis of optically pure S-2-amino-2′-hydroxy-1,1′-binaphthyl (S-Nobin), the precoursor in the synthesis of other asymmetric 1,1-binaphthyls applied as the ligands at the creation of the catalysts of asymmetric synthesis, is modified. The UV and CD spectra of this compound were studied in detail and essential dependence of spectral information on the solvent nature was shown.

Glycosylation of 5-phenylpyrano[2,3-d:6,5-d′]dipyrimidine-4,6-diones through the corresponding di-O-trimethylsilyl derivative with excess 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose gives a mixture of 3-mono-and 3,7-bis(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-5-phenylpyrano[2,3-d:6,5-d′]dipyrimidines; in the reaction with equimolar amounts of the reactants, only the monoriboside is formed. Isomeric N,N′-disubstituted pyranodipyrimidines, as well as mixtures of their mono-and disubstituted derivatives can be separated by fractional crystallization. The alkylation of pyrano[2,3-d:6,5-d′]dipyrimidine-4,6-dione and its 5-phenyl-substituted derivative with 2-oxabutane-1,4-diyl diacetate provides an efficient procedure for the synthesis of acyclic analogs of glycosides based on pyrano[2,3-d:6,5-d′]dipyrimidines.

5-Fluoro-4-hydroxy-2-methoxypyrimidine exists in a solution as two oxo tautomers with the conjugated and isolated double bonds in the ring. The latter tautomer has a zwitterionic structure, and it dominates in water and trifluoroethanol. 5-Fluoro-4-hydroxy-2-methoxypyrimidine in acidic medium gives rise to an equilibrium mixture of two protonated forms at a ratio of about ∼1:1. The zwitterionic structure of 4-hydroxypyrimidines is stabilized if the solvent is capable for specific solvation via hydrogen bonding.

Methylation of 5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(3H)-dione and its 5-phenyl analog with dimethyl sulfate in the presence of LiOH in aqueous solution gives rise to the corresponding 3,7-dimethyl derivatives. The same isomers are formed by methylation of 5-phenyl-5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(3H)-dione with methyl iodide in the presence of K2CO3 in N,N-dimethylacetamide. However, with ethyl bromide, propyl iodide, or butyl bromide instead of methyl iodide, mixtures of 3,7- and 1,7-dialkyl-5-phenyl-5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6-diones were obtained.

The reaction of 2,4,6-tris(trimethylsiloxy)pyrimidine with 2-oxabutane-1,4-diyl diacetate in methylene chloride in methylene chloride in the presence of SnCl4 proceeds regioselectively to form 1-[(2-acetoxyethoxy)methyl]barbituric acid. The latter is readily deacetylated to a free acyclic analog of N-ribosides of barbituric acid. 1-[(2-Acetoxy- and 2-hydroxyethoxy)methyl]barbituric acids easily react with aromatic and heterocyclic aldehydes in water and organic solvents, forming 5-ylidenebarbituric acids. The structure of the products was proved by 1H NMR and UV spectroscopy. Certain of the products exhibit a moderate antimicrobial and antiviral activity.

13C NMR spectroscopy was used to study the stereoselectivity of glycosylation of phenols with the α and β anomers of penta-O-acetyl-D-glucopyranose, penta-O-trifluoroacetyl-D-glucopyranose, and 2,3,4,6-tetra-O-acetyl-1-O-trifluoroacetyl-D-glucopyranose in the presence of boron trifluoride etherate at varied temperature, time, and catalyst amount. The boron trifluoride etherate-catalyzed reaction of penta-O-acetyl-β-D-glucopyranose and 2,3,4,6-tetra-O-acetyl-1-O-trifluoroacetyl-β-D-glucopyranose with phenols occurs with a high stereocontrol to give, depending on conditions, predominantly 1,2-cis- or 1,2-trans-arylglycosides. This reaction can be used for preparative synthesis of the α- and β-anomeric forms of glycosides of a wide range of phenols.

5′-O-Benzoyl-3′-(tetrazole-2”-yl)-3′-deoxythymidine and its 5”-substituted derivatives were obtained by the reaction of 5′-O-benzoyl-2,3′-anhydrothymidine with triethylammonium salts of either tetrazole or 5-substituted tetrazoles. Debenzoylation of these compounds yielded 3′-(tetrazole-2”-yl)-3′-deoxythymidine and its 5”-derivatives. Structures of two of them were confirmed by X-ray analysis. Both 3′-(tetrazole-2”-yl)-3′-deoxythymidine and 3′-(5”-methyltetrazole-2”-yl)-3′-deoxythymidine have anti-conformation with respect to the glycosidic bond, and 2′-endo-3′-exo-conformation of the sugar residue with gauche + orientation relative to the C4′-C5′ bond. 3′-(Tetrazole-2”-yl)-3′-deoxythymidine 5′-triphosphate exhibited poor termination substrate properties towards avian myeloblastosis virus reverse transcriptase and did not serve as a substrate for other employed DNA polymerases.

Peaks of molecular ions that generally have the maximum intensity are observed in the mass spectra of most of the investigated 5- and 6-substituted uracils and 5-substituted orotic acids and their deutero analogs and methylated derivatives. The principal pathway of the fragmentation of the molecular ions is retrodiene fragmentation with the formation of [O=C(4)C(5)R5C(6)R(6)N(1)R1]+ (F1) ions. The stabilities of the latter depend on the nature and position of the substituents attached to the C(5) and C(6) atoms. The fragmentation of the F1 ions can be realized via four principal pathways (B-E) with the detachment of N-CR6 (B), O=C=CR5 (C), CO (D), and R6 (E) fragments. The most general pathway for the fragmentation of 5-substituted uracils is pathway C, whereas the most general pathway for 6-substituted uracils is pathway E. In the spectra of 5-substituted orotic acids the intensities of the molecular-ion peaks are high (∼100%) only in the case of electron-donor R5 and decrease sharply with an increase in the electron-acceptor strength of the substituent. The principal pathways of fragmentation of the molecular ions are decarboxylation (F) and retrodiene fragmentation (A), the contribution of which is appreciably smaller. The M-CO2 ions formed after decarboxylation undergo fragmentation via a scheme similar to that observed for 5-substituted uracils.

The solid and the argon-matrix isolated samples of 6-fluorothymine, 1-methyl-6-fluorothymine, 1,3-dimethyl-6-fluorothymine and 3-methylfluorothymine are studied at low temperatures by i.r. spectroscopy. The spectra obtained are interpreted using the calculation of planar normal vibration frequencies. The electronegative fluorine atom in the 6-position is shown to have a strong influence on the normal vibration frequency changes of crystalline and isolated thymine. NH ⋯ F hydrogen bonds are evidenced to exist in crystalline samples.

5''-Derivatives of 3'-(tetrazole-2''-yl)-3'-deoxythymidines were synthesized by interaction of 5'-benzoyl-2',3'-anhydrothymidine with tetrazole or its 5-derivatives followed by debenzoylation. Structures of two of them, 3'-(tetrazole-2''-yl)-3'-deoxythymidine and 3'-(5''-methyltetrazole-2''-yl)-3'-deoxythymidine, elucidated by X-ray analysis, revealed anti conformation of thymine about the glycosidic bond and 2'-endo-3'-exo-conformation of the sugar residue with gauche+ orientation with respect to C4'-C5'-bond. 3'-(Tetrazole-2''-yl)-3'-deoxythymidine 5'-triphosphate demonstrated poor substrate properties for the avian myeloblastosis virus reverse transcriptase and none for several other DNA polymerases.

5-Arylazo and 5-arylideneamino-2,4,6-triaminopyrimidines and their 6-hydroxy analogs were obtained by azo coupling of 2,4,6-triamino- and 2,4-diamino-6-hydroxypyrimidines with aryldiazonium salts, and also by the reaction of benzaldehydes with 2,4,5,6-tetraamino- and 2,4,5-triamino-6-hydroxypyrimidines, respectively. According to spectral data, in solvents with different polarity, these compounds exist preferentially in the triamino- or diaminohydroxy form. The main paths of the mass spectrometric fragmentation of the compounds studied have been determined.

The reaction of 2, 4, 5-triamino-6-hydroxypyrimidine with phosphorus pentasulfide in quinoline has yielded 2, 4, 5-triamino-6-mercaptopyrimidine. 8-Hydroxymethyl derivatives of guanine and thioguanine have been synthesized by the acylation of 2, 4, 5-triamino-6-hydroxypyrimidine and the corresponding 6-mercapto compound with glycolic acid or ethyl glycolate, with subsequent treatment of the resulting 5-hydroxyacetylamino derivatives with aqueous alkali.

The synthesis of β-(8-guanyl)propionic acid and its chloride, methyl ester, bis(2′-hydroxyethyl)amide, and bis(2′-chloroethyl)amide has been effected. The latter readily rearranges under certain conditions into 2′-chloroethylaminoethyl β-(8-guanyl)propionate.

Condensation of 5,6-diaminouracil with ethyl cyanoacetate yields xanthine-8-acetonitrile which is hydrolyzed by alkalis to xanthine-8-acetic acid. Also synthesized were its ethyl ester, acid chloride, and bis(2′-hydroxyethyl)amide.