The aim of this work was to prepare new heterodimeric molecules containing pharmacophoric fragments of 3-cyanoquinoline/3-aminothieno[2,3-b]pyridine/3-aminothieno[2,3-b]quinoline on one side and phenothiazine on the other. The products were synthesized via selective S-alkylation of readily available 2-thioxo-3-cyanopyridines or -quinolines with N-(chloroacetyl)phenothiazines, followed by base-promoted Thorpe–Ziegler isomerization of the resulting N-[(3-cyanopyridin-2-ylthio)acetyl]phenothiazines. We found that both the S-alkylation and the Thorpe–Ziegler cyclization reactions, when conducted with KOH under heating, were accompanied to a significant extent by a side reaction involving the elimination of phenothiazine. Optimization of the conditions (0–5 °C, anhydrous N,N-dimethylacetamide and NaH or t-BuONa as non-nucleophilic bases) minimized the side reaction and increased the yields of the target heterodimers. The structures of the products were confirmed by IR spectroscopy, ¹H, and ¹³C DEPTQ NMR studies. It was demonstrated that the synthesized 3-aminothieno[2,3-b]pyridines can be acylated with chloroacetyl chloride in hot chloroform. The resulting chloroacetamide derivative reacts with potassium thiocyanate in DMF to form the corresponding 2-iminothiazolidin-4-one; in this process, phenothiazine elimination does not occur, and the Gruner–Gewald rearrangement product was not observed. The structural features and spectral characteristics of the synthesized 2-iminothiazolidin-4-one derivative were investigated by quantum chemical methods at the B3LYP-D4/def2-TZVP level. A range of drug-relevant properties was also evaluated using in silico methods, and ADMET parameters were calculated. A molecular docking study identified a number of potential protein targets for the new heterodimers, indicating the promise of these compounds for the development of novel antitumor agents.

The reaction of 3-aminothieno[2,3- b ]pyridin-2-carboxamides with acetone in the presence of catalytic amounts of TsOH under reflux afforded a series of new 2,2-dimethyl-2,3-dihydropyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4(1 H )-ones in 88–95% yields. Possible protein targets for the new compounds were identified by molecular docking studies. 2,2-Dimethyl-3-(2-methylphenyl)-9-(4-methoxyphenyl)-7-phenyl-2,3-dihydropyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4(1 H )-one exhibits antidote effect against 2,4-dichlorophenoxyacetic acid in a laboratory experiment.

The reaction of 3-amino-4-aryl-2-acyl-6-phenylthieno[2,3-b]pyridines with chloroacetyl chloride in toluene yielded the corresponding chloroacetamides. The latter underwent a cascade rearrangement upon treatment with KSCN in an acetone–EtOH mixture to form previously undescribed ethyl esters of (pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-2-ylthio)acetic acids. Under similar conditions, 4-(4-methoxyphenyl)-6-phenyl-3-(chloroacetamido)thieno[2,3-b]pyridine-2-carbonitrile produced only the isomerization product of the intermediately formed thiocyanatoacetamide—3-(2-imino-4-oxothiazolidin-3-yl)-4-(4-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-carbonitrile.

Previously undescribed nicotinonitrile–coumarin hybrids, namely 2-{[2-oxo-2-(2-oxo-2H-chromen-3-yl)ethyl]thio}pyridine-3-carbonitriles and -quinoline-3-carbonitriles, were synthesized via the reaction of 2-thioxo-1,2-dihydropyridine-3-carbonitriles with 3-(bromoacetyl)coumarin or 3-(bromoacetyl)benzo[f]coumarin in the presence of sodium propylate. Under laboratory conditions on sunflower seedlings, some of the prepared compounds exhibited a pronounced antidote effect against the herbicide 2,4-D, as well as moderate growth-stimulating activity.