We have designed and synthesized a series of bioinspired pyrano[2,3-f]coumarin-based Calanolide A analogs with anti-HIV activity. The design of these new calanolide analogs involved incorporating nitrogen heterocycles or aromatic groups in lieu of ring C, effectively mimicking and preserving their bioactive properties. Three directions for the synthesis were explored: reaction of 5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one with (i) 1,2,4-triazines, (ii) sulfonylation followed by Suzuki cross-coupling with (het)aryl boronic acids, and (iii) aminomethylation by Mannich reaction. Antiviral assay of the synthesized compounds showed that compound 4 has moderate activity against HIV-1 on enzymes and poor activity on the cell model. A molecular docking study demonstrates a good correlation between in silico and in vitro HIV-1 reverse transcriptase (RT) activity of the compounds when docked to the nonnucleoside RT inhibitor binding site, and alternative binding modes of the considered analogs of Calanolide A were established.

The strategy of the nucleophilic substitution of hydrogen (S_N^H) was first applied for the metal-free C-H/C-H coupling reactions of 4H-imidazole 3-oxides with indoles. As a result, a series of novel bifunctional azaheterocyclic derivatives were obtained in yields up to 95%. In silico experiments on the molecular docking were performed to evaluate the binding possibility of the synthesized small azaheterocyclic molecules to the selected biotargets (BACE1, BChE, CK1δ, AChE) associated with the pathogenesis of neurodegenerative diseases. To assess the cytotoxicity for the synthesized compounds, a series of in vitro experiments were also carried out on healthy human embryo kidney cells (HEK-293). The leading compound bearing both 5-phenyl-4H-imidazole and 1-methyl-1H-indole moieties was defined as the prospective molecule possessing the lowest cytotoxicity (IC₅₀ > 300 µM on HEK-293) and the highest binding energy in the protein–ligand complex (AChE, −13.57 kcal/mol). The developed compounds could be of particular interest in medicinal chemistry, particularly in the targeted design of small-molecule candidates for the treatment of neurodegenerative disorders.

Azolo[1,5-a]pyrimidine is one of the most promising scaffold in the development of potent anticancer agents. However, the structural motifs in such development are often limited to 5,7-substituted azolo[1,5-a]pyrimidines due to the well-known synthesis route and existing drugs (e.g., Dinaciclib) on their basis. To expand the understanding of rare substituent combinations in this research field, a new series of 7-amino-5-aryl-6-cyanoazolo[1,5-a]pyrimidines with various azole moieties were synthesized and studied on A172, Rd, Hos and HEK293 cell lines. The obtained derivatives were further modified by acylation to introduce an additional pharmacophore moiety. During the study of anticancer activity, compounds with a pronounced cytotoxic effect were found. The analysis of activity against the embryonal rhabdomyosarcoma (Rd) cell line suggested a mechanism of cytotoxic action causing a significant decrease in mitochondrial potential in neoplastic cells.