Four types of adamantane-containing compounds were designed by modifying molecules with proven activity against resistant influenza A viral strains or mutated M2 channel of the virion envelope. Three series were obtained, excluding 5'-methyl-5'H-spiro[adamantane-2,4'-thiazol]-2'-amine, since no intramolecular cyclization of 1-tert-butyl-3-(2-vinyladamantan-2-yl)thiourea occurred in the reaction with HBr or bromine. 2,7-Diazaspiro[3.5]nonane comprising derivatives of adamantane and new series of rimantadine amides have manifested high cytotoxicity, while acceptable selectivity was observed for ester analogues of the latter, and three novel esters demonstrated potent antiviral activity (IC50 = 1.5-12.6 mu M vs. 67 mu M for rimantadine) against the rimantadine-resistant influenza virus A/PR/8/34.

Pyridine-containing amides of rimantadine (1-(1-adamantyl)ethylamine) were synthesized by the amidation of rimantadine hydrochloride by the corresponding acids in the NEt3—N,N′-dicyclohexylcarbodiimide (DCC)—4-(N,N-dimethylamino)pyridine (DMAP) system as the analogues of previously described antiviral compounds 1-adamantylmethyl-5-aminoisoxazole-3-carboxylate and N-[5-(thien-2-yl)isoxazol-3-yl]methyladamantane-1-amine. The spectrum of antiviral activity against the rimantadine-resistant A/PR/8/34 strain of influenza A virus, tick-borne encephalitis virus (TBEV) strain Absettarov (European subtype), yellow fever virus (YFV) vaccine strain 17D, and West Nile virus (WNV) strain Strix nebulosa-12 was studied. The structure—activity relationships were discussed. Synthesized compounds efficiently inhibited the reproduction of TBEV and WNV. N-[1-(Adamantan-1-yl)ethyl]picolinamide efficiently inhibited the reproduction of enveloped viruses with both type I (influenza) and type II (flaviviruses) fusion proteins. The antiviral activity against the rimantadine-resistant influenza virus A/PR/8/34 and a low cytotoxicity (high selectivity index) were revealed for N-[1-(adamantan-1-yl)ethyl]-isonicotinamide.

The synthesis of homodimeric bis-esters of abiraterone (an inhibitor of androgens synthesis used for treatment of prostate cancer) as a novel depot form of the drug intended for parenteral administration has been undertaken. The conjugate with succinic linker has been synthesized, while only mono-esters of malic and citric acid were obtained. The target ‘twin’ demonstrated excellent characteristics in preliminary biotests, proving the concept of long-lasting depot-prodrug.

Esters of podophyllotoxin and epipodophyllotoxin with 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butanoic and (4 R )- N -( tert -butoxycarbonyl)-1,3-thiazolidine-4-carboxylic acids were synthesized. The obtained esters are less lipophilic analogs of the known podophyllotoxin esters. Two new compounds were found to demonstrate selective cytotoxicity against cancer cells in the mixed culture of lung carcinoma cells (A549) and noncancerous lung fibroblasts (VA13). Podophyllotoxin ester with (4 R )-1,3-thiazolidine-4-carboxylic acid moiety was also synthesized. This compound like its pyrrolidine analog was found to be nonselective but in contrast two orders of magnitude less active. Selectivity against cancer cells in combination with acceptable lipophilicity of the podophyllotoxin and epipodophyllotoxin esters bearing the tert -butoxycarbonylthiazolidine moiety makes these compounds promising for further in vitro and in vivo evaluation.

Structural optimization of butyrylcholinesterase inhibitors, 5-bromomethyl- and 5-iodomethyl-N,N-disubstituted 2-aminothiazolines, led to a series of their annulated bicyclic analogues, obtained by intramolecular cyclization of cycloalkenylthioureas. The most active compound in this series, cyclohepta[d]thiazol-2-amine, is a mixed-type butyryl-cholinesterase inhibitor with IC50 = 130 nm, highly selective compared to acetylcholinesterase and non-toxic at 100 μm concentrations.

A series of podophyllotoxin and epipodophyllotoxin esters with methylisoxazole fragments containing a halogen atom or a nitro group at position 4 of the heterocycle was synthesized. The starting isoxazolecarboxylic acids were obtained by bromination, iodination, or nitration of 5-methylisoxazole-3-carboxylic acid, which then were converted to the target esters by esterification in the DCC/DMAP or EDC/DMAP system. The results of molecular docking of podophyllotoxin and epipodophyllotoxin esters with the iodine-containing isoxazole derivatives predicted their ability to bind to tubulin and topoisomerase II, respectively, and do not exclude the possibility of the formation of halogen bonds with target proteins. The primary bioscreening showed that all compounds obtained at a concentration of 100 nmol L-1 caused a decrease in the number of A549 and VA13 cells by 40-60% after 72 h of treatment.

The present minireview concerns the application of cyclic isothiourea moiety (with endocyclic sulfur atom) in drug design and includes the examples of bioisosteric replacement, conformational restriction, etc. The synthetic procedures leading to the target structures of cyclic isothioureas and their bicyclic derivatives are also discussed. The review gives multiple useful examples for the chemists searching novel heterocyclic compounds with neuroprotective, antihypotensive, antiproliferative, antiobestic, and analgetic properties.

Bicyclic isothioureas of N-(4-methoxyphenyl)-2-aminocycloalkane[d]thiazole type were obtained using intramolecular electrophilic cyclization of N-(cycloalk-2-enyl)-N′-(4-methoxyphenyl)thioureas. Isothiourea fused with sevenmembered ring caused noticeable changes of the morphology of human lung carcinoma cells A549, but without affecting their microtubule net.

Two novel C(7)-derivatives of natural anticancer agent colchicine were designed with the purpose to study their ability to induce tubulin clustering in cancer cells. The compounds were synthesized via amidation of N-deacetylcolchicine and Steglich esterification. The conjugate of colchicine with the guanosine derivative possesses moderate cytotoxicity to these cells (EC50 = 13.7 µmol L−1) inducing the depolymerization of microtubules of human lung carcinoma A549 cells but does not stimulate the formation of tubulin clusters. The colchicine conjugate with the biphenyl moiety causes a strong tubulin clustering comparable to that of anticancer agent tubuloclustin. This effect was observed for the first time for the colchicine derivative bearing no substituent at the acetyl group capable of forming hydrogen bonds with target protein.

Reactions of 1-[(endo-bicyclo[3.3.1]non-6-en-3-yl)methyl]-3-tert-butylthiourea with I2/ButOOH and I2/K2CO3 afforded 4-azatricyclo[4.3.1.13,8]undecane based products via intramolecular cyclization, as determined by X-ray analysis and NMR spectroscopy.

A convenient synthetic pathway to bridged isothioureas via cyclization of tert-butyl-substituted cyclohex-3-en-1-ylthiourea by the action of bromine has been developed. The effective use of tert-butyl protective group was demonstrated, and the crystal structure of synthesized (3aRS,7SR,7aRS)-7-bromo-3a,4, 5,6,7,7a-hexahydro-1,3-benzothiazol-2-amine hydrobromide was determined by X-ray analysis. (1RS,5SR)-2-Thia-4-aza-bicyclo[3.3.1]non-3-en-3-amine as a strong inducible nitric oxide synthase inhibitor in vitro surprisingly caused additional hypotension in LPS-induced acute endotoxic shock model while its C8-hydroxy-derivative displayed prominent and durable vasoconstrictive effect.

Synthesis of analogs of tubuloclustin ( N -(7-adamant-2-yloxy-7-oxoheptanoyl)- N -deacetylcolchicine ( 1 )) with the colchicine fragment replaced with 2-methoxyestradiol scaffold attached via phenolic hydroxy group was described. Esters 3a–c exhibit moderate cytotoxicity (EC 50 = 5–6 μmol L –1 ) and exert a weak effect on the microtubule network in A549 human lung carcinoma cells similar to the clustering effect of tubuloclustin and its derivatives. Conjugates 6a–c and 7a–c with the phenolic ester bond are low stable and compounds 7a–c are inactive to the microtubules of A549 cells, while compounds 6a–c cause an unusual effect of curling of the microtubules.

In a search of nitric oxide synthase inhibitors with prolonged vasoconstrictive activity, a series of lipophilic cyclohexafused 2-amino-2-thiazolines was obtained via cyclization of tert-butyl- or benzoyl-substituted N-(cyclohex-2-en-1-yl)thioureas. The crystal structure of intermediate N-[(3aRS,7aSR)-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazol-2-yl]benzamide hydrobromide was determined by X-ray analysis. One compound was found to cause pronounced and prolonged vasoconstrictive effect after single injection to the Wystar rats with lipopolysaccharide induced acute endotoxic (vasodilatation) shock.

In an attempt to synthesize 4-thia-6-azatricyclo[5.3.1.13,9]dodecan-5-imine as putative antihypotensive agent with prolonged effect, a reaction of 1-[(1RS,3SR,5SR)-bicyclo[3.3.1]non-6-en-3-yl]-3-tert-butylthiourea in the presence of bromine was undertaken. The intramolecular cyclization however was accompanied by precursive oxidation of thiourea to urea fragment and proceeded via nitrogen atom yielding the bridged tricyclic urea derivative as determined by X-ray analysis and liquid chromatography–mass spectrometry technique. The compounds obtained in the present study belong to a novel and unusual structural type of bridged tricyclic ureas.

Two pairs of bicyclo[3.3.1]nonane derivatives with 2-methoxyphenol moiety were synthesized as non-steroidal 2-methoxyestradiol mimetics demonstrating noticeable cytotoxicity to human lung carcinoma cell line A549. Compounds with 2-methoxyphenol annulated with bicyclo[3.3.1]nonane fragment were obtained using BF3-assisted oxirane opening in 5- (4-benzyloxy-3-methoxyphenyl)-1-oxaspiro [2.5] octanes with simultaneous intramolecular cyclization and reduction as the key step. endo-7-Hydroxybicyclo[3.3.1]nonane-exo-3-carboxylic acid was converted into two esters containing 2-methoxyphenol fragment in either acid or alcohol part of the molecule.

Tubuloclustin [N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine], a highly cytotoxic anti-tubulin compound is known for its ability to promote microtubule disassembly followed by the formation of tubulin clusters of unique morphology. Three series of antimitotic agents related to tubuloclustin were designed and synthesized in order to enhance the molecular diversity of “tubuloclustin-like” family of compounds. The series of compounds with modified adamantane moiety was highly potent in cytotoxic effect on human lung carcinoma A549 cells (EC50 = 6–400 nM) and was active in affecting the microtubule arrays and induction of strong tubulin clusterization. In two other sets of compounds, the colchicine moiety of tubuloclustin was replaced by podophyllotoxin or combretastatin A-4. All combretastatin A-4 derivatives displayed noticeable cytotoxic activity (\(\hbox {EC}50=0.8{-}1.6\,\upmu \hbox {M}\)) but their effect on microtubules depended on the position of the linker attachment. Podophyllotoxin derivatives were also toxic to A549 cells (\(\hbox {EC}50=0.38{-}0.50\,\upmu \hbox {M}\)) and caused both microtubule depolymerization and some tubulin clustering. The data obtained gave additional evidence that the whole panel of C7-colchicine, podophyllotoxin and combretastatin derivatives could manifest clustering effect, and the strength of this effect correlated with cytotoxic activity of the compounds.

Adamantaneacetic and adamantanecarboxylic acid esters containing 3-hydroxy-4-methoxybenzyl, 3,4,5-trimethoxybenzyl, or 5-(hydroxymethyl)-2-methoxyphenyl groups were synthesized as unusual analogs of natural antitumor and anti-tubulin agents combretastatin A-4 and 2-methoxyestradiol. The compounds were found to possess noticeable cytotoxicity to epithelial human carcinoma cell line A549 (EC 50 = 4.3—81 μmol L –1 ). An ability to cause complete depolymerization of microtubule network of A549 cells was demonstrated for 5-(hydroxymethyl)-2-methoxyphenyl adamantan-1-ylacetate ( 6a ) at a concentration of 100 μmol L –1 . Ester 6a belongs to a new structural type, which is unusual for the ligands of the tubulin colchicine domain, and is an interesting lead compound for further structural optimization.