A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC₅₀ = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

Background:: A number of studies demonstrate the efficacy of ribavirin against various cancer types in in vitro and in vivo models. However, ribavirin induces the development of multiple side effects, suggesting a high demand for ribavirin analogues with improved therapeutic indexes. Objective:: This study was focused on the analysis of ribavirin, its aglycon 1,2,4-triazole-3-carboxamide, and several of its derivatives activities in blood cancer cells in vitro. Methods:: Four 1,2,4-triazole-3-carboxamide derivatives were designed and synthesized. Antiproliferative effects were evaluated in chronic myeloid leukemia cells К562 and acute lymphoblastic leukemia cells CCRF-SB as well as in the cells of whole blood mononuclear fraction of healthy volunteers by cell counting using the trypan blue exclusion method. Cell cycle distribution and apoptosis under the influence of the compounds were analyzed by flow cytometry with PI staining, and then apoptosis data were confirmed by Western blot analysis for PARP1 and caspase-3 cleavage. Results:: We demonstrated the significant antiproliferative effect of 5-(tetrahydropyran-2-yl)-1,2,4-triazole-3- carboxamide and 1-(tetrahydropyran-2-yl)-1,2,4-triazol-3-carboxamide in leukemia cell lines in vitro in comparison to non-transformed monocytes, providing the rationale for further studies of 1,2,4-triazole-3-carboxamide derivatives as anti-leukemia drugs. Conclusion:: These results implied that the 1,2,4-triazole-3-carboxamide derivatives exhibited their antiproliferative activities by induction of cell cycle arrest. Consequently, 5-(tetrahydropyran-2-yl)-1,2,4-triazole-3-carboxamide and 1-(tetrahydrofuran-2-yl)-1,2,4-triazol-3-carboxamide may present antimetabolites with potential anticancer efficacy.

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin’s aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments.

Glucocorticoids (GCs) are routinely used to treat hematological malignancies; however, long-term treatment with GCs can lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRAs) with reduced side effects may act as a superior alternative to GCs. More than 30 SEGRAs have been described so far, yet none of them reached clinical trials for anti-cancer treatment. In the present work, we propose a novel approach to increase the number of potential SEGRAs by obtaining derivatives of synephrine, a molecule of natural origin. We synthesized 26 novel compounds from the class of synephrine derivatives and characterized them by HRMS, and ¹H and ¹³C NMR. We evaluated in vitro anti-cancer effects in leukemia K562 and lymphoma Granta cells using the MTT assay and studied their potential affinity for the glucocorticoid receptor (GR) in silico using the molecular docking approach. The novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico exhibited cytotoxic activity against K562 and Granta cells after 24 h of treatment at the concentration of approximately 13 µM which correlated with its highest MolDock Score. The other compound with high GR affinity, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2), demonstrated cytotoxicity in both cell lines at concentrations of 50–70 µM. Overall, our results may provide a solid rationale for developing and further investigating synephrine derivatives as SEGRAs with anti-cancer activity.

Objectives. A key step in the synthesis of natural nucleoside analogs is the formation of a glycosidic bond between the carbohydrate fragment and the heterocyclic base. Glycosylation methods differ in terms of regio- and stereoselectivity. A promising method for the highly specific synthesis of new pharmacologically active compounds involves an enzymatic reaction catalyzed by genetically engineered nucleoside phosphorylases. This study is devoted to the synthesis of a library of analogs of nucleoside heterocyclic bases—5-oxymethyl-1,2,4-triazole- 3-carboxamides—in order to investigate the substrate specificity of genetically engineered nucleoside phosphorylases.Methods. A method of cyclization of acylamidrazones obtained from the single synthetic precursor β-N-tert-butyloxycarbonyl-oxalamidrazone was used to parallel-synthesize new 5-alkoxy/ aryloxymethyl-1,2,4-triazole-3-carboxamides. Silica gel column chromatography was used to isolate and purify the synthesized compounds. A complex of physicochemical analysis methods (nuclear magnetic resonance spectroscopy, chromatography, and mass spectrometry) confirmed the structure of the compounds obtained in the work.Results. 5-alkoxy/aryloxymethyl-1,2,4-triazole-3-carboxamides were obtained to study the substrate specificity of genetically engineered nucleoside phosphorylases. The possibility of obtaining new nucleoside analogs by the chemico-enzymatic method was demonstrated on the basis of preliminary assessment results.Conclusions. The physicochemical characteristics of a series of novel 5-alkoxy/aryloxymethyl- 1,2,4-triazole-3-carboxamides were studied along with their potential to act as substrates for the transglycosylation reaction catalyzed by nucleoside phosphorylases.