The minireview surveys the modification of native nucleosides as a result of which huge libraries of nucleoside analogs of various structures were synthesized. Particular attention is paid to the synthesis of the so-called prodrug forms of nucleoside analogs which ensure their penetration into the cell and metabolism to active 5'-triphosphate derivatives. All the best known antiviral cyclic nucleoside analogs approved for the treatment of HIV infections, hepatitis B, C, and influenza since the 1960s, as well as those in various stages of clinical trials in recent years, are listed. Nucleoside analogs that have shown the ability to inhibit the replication of SARS-CoV and MERS-CoV are discussed, including remdesivir, approved by the FDA for emergency use in the fight against COVID-19.

Conjugates of antitubercular drug Isoniazid (hydrazide of isonicotinic acid), nicotinic and alpha-picolinic acid hydrazides and glycoside steviolbioside from the plant Stevia rebaudiana as well as the product of its acid hydrolysis, diterpenoid isosteviol, were synthesized. Besides, isosteviol hydrazide and hydrazone derivatives as well as conjugates containing two isosteviol moieties connected by dihydrazide linker were also obtained. Both initial compounds and their synthetic derivatives inhibit the growth of Mycobacterium tuberculosis (H37Rv in vitro). The minimum concentration at which the growth of M. tuberculosis was inhibited by 100% (MIC) for stevioside and steviolbioside equals 7.5 and 3.8 microg/mL, respectively. MIC values for conjugates of the hydrazides of pyridine carbonic acids and steviolbioside as well as isosteviol are in the ranges 5-10 and 10-20 microg/mL, respectively. Maximum inhibitory effect against M. tuberculosis showed the conjugates of isosteviol and adipic acid dihydrazide (MIC values ranged from 1.7 to 3.1 microg/mL). Antitubercular activity of the compounds studied is higher than the activity of antitubercular drug Pyrizanamide (MIC = 12.5-20 microg/mL) but lower than the activity of antitubercular drug Isoniazid (MIC = 0.02-0.04 microg/mL).

Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-triO -acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC 50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC 50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC 50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).

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Macrocycles with one and more ent-beyerane skeletons were prepared by the reaction of 16,19-dihydroxyent-beyerane with several dibasic carboxylic acid chlorides. The structures of the synthesized compounds, namely, the number of ent-beyerane skeletons in the macrocycle, depended on the length of the polymethylene chain in the acid chloride. The molecular structures of two of the synthesized macrocycles were established by x-ray crystal structures.The number of publications on the synthesis of macrocyclic compounds has risen dramatically in the last 20 years. The interest in them is due to their ability to act as host molecules, often exhibiting highly selective molecular recognition of guests (ions) [1-3]. Native macrocycles isolated from plants or marine organisms were also described in the literature [4][5][6][7]. However, these compounds have little practical value despite their biological activity because they are isolated in minimal quantities from natural sources. In this respect synthetic macrocycles obtained from biologically active metabolites isolated from natural sources in tangible quantities are much more promising. Several such compounds are known, for example, synthetic macrocycles based on bile acids [8] and mono-[9, 10] and diterpenoids [11][12][13][14]. It is noteworthy that the first macrocycles containing two diterpenoid skeletons were obtained as side products from the synthesis of compounds in which two isosteviol (16-oxo-ent-beyeran-19-oic acid) diterpenoid molecules (1) were joined by diester and anhydride spacers [14]. In order to synthesize macrocycles based on this diterpenoid, we used a more rational approach, the so-called acid-chloride approach, which consisted of the reaction of fully reduced isosteviol, diol 2, with dibasic carboxylic acid chlorides. As it turned out, the structures of the products depended on that of the starting acid chloride, namely, on the length of the hydrocarbon chain between the C(O)Cl groups.The reaction of 2 (16,19-dihydroxy-ent-beyerane) with malonic acid dichloride gave in 9% yield a product with a molecular ion that corresponded to the mass of macrocycle 3. According to PMR data this macrocycle was not a pure compound but a mixture of the head-to-head 3a and head-to-tail 3b isomers. This was indicated by the presence of not a single multiplet