Institute of Bioorganic Chemistry and Petrochemistry V.P. Kukhar

A scalable synthesis of trans-1,2-fluoroalkyl-substituted cyclopentane building blocks was developed. The approach relies on orthogonal late-stage functionalization of a common precursor – monoester of trans-1,2-cyclopentanecarboxylic acid. Fluoromethyl-substituted derivatives were accessed via exhaustive reduction of the COOH group, activation of the resulting primary alcohol as a triflate, and nucleophilic substitution with fluoride. Meanwhile, difluoro- and trifluoromethyl groups were introduced through deoxofluorination of the corresponding aldehyde or carboxylic acid. The resulting fluorinated esters were efficiently diversified into a broad range of building blocks relevant to medicinal chemistry, including carboxylic acids, primary amines, azides, alcohols, and sulfonyl chlorides. In addition to the synthetic developments, the effect of the fluoroalkyl substituent (CH2F, CHF2, CF3) on physicochemical properties of the cyclopentane derivatives was established by measuring pKₐ and LogP values of model derivatives.

A method of C-H functionalization of the N-protected alkyl 1,2,3-triazole-4-carboxylates with various C-, P- and S-electrophiles using an in situ generated turbo-Hauser base, has been developed. The resulting compounds underwent N- and O-deprotection giving rise to the corresponding NH-5-substituted 1,2,3-triazole-4-carboxylates, which possess multiple sites for further functionalization.

The development of acetylcholinesterase (AChE) inhibitors remains a promising research direction in drug discovery for Alzheimer's disease. A series of eighteen pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized as novel tacrine-like AChE inhibitors. Sixteen compounds inhibited AChE in the micromolar range. Among them, 4-(dimethylamino)-7,8-dimethylpyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin-6(7H)-one (22) exhibited the highest inhibitory activity against the enzyme with an IC50 value of 0.22 ± 0.02 µM, showing mixed-type inhibition. In silico studies showed that 22 occupies the catalytic anionic site of hAChE and forms strong π–π stacking interactions with Trp86, similar to those of tacrine. This study demonstrates the potential use of methyl-substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidines in the development of potent AChE inhibitors.

Multigram synthesis and physicocochemical characterization of (oxa)azaspiro[2. n ]alkane derivatives – promising scaffolds for drug discovery – are reported.

A synthetic approach has been developed for the preparation of new bioisosteres of homoproline, namely α-hydroxyphosphonic acids. At the key stages of the synthesis, the phosphorylation of carbonyl derivatives of (S)- and (R)-proline via the Abramov reaction was employed. The resulting α-hydroxyphosphonic acids are promising compounds with, potential biologicalactivity and may serve as valuable candidates for the development of new pharmaceuticals and physiologically active compounds

A practical and scalableprotocol for the deoxyfluorination ofhydroxyalkyl-substituted aryl- and alkenylboronates was developed.The optimized conditions (combining Deoxo-Fluor with TEA·3HFas the reagents and substrate preconversion to trifluoroborate salts)enabled efficient transformation across a wide range of (homo)­benzylicand allylic alcohols while tolerating protected carboxyl and aminogroups. The resulting fluorinated boronates performed well as versatilebuilding blocks in oxidation and Suzuki cross-coupling reactions.Furthermore, a telescoped one-pot strategy allowed direct utilizationof crude fluorinated intermediates, enabling access to complex molecularframeworks containing alcohol, carbonyl, and ester functionalities,typically intolerant to late-stage fluorination conditions. This methodologyoffers a general and efficient route for the incorporation of monofluorinatedaliphatic fragments into structures that are relevant for medicinalchemistry and materials science.

Abstract Ten 5-(arylsulfanyl), 5-(arylsulfinyl), and 5-(arylsulfonyl) derivatives of 1,3-oxazol-4-ylphosphonates and 1,3-oxazole-4-carbonitriles were synthesized and characterized using IR, 1H NMR, 13C NMR, 31P NMR spectroscopy, elemental analysis, and mass spectrometry. Their anticancer activity was assessed against NCI-60 human tumor cell lines using a single-dose assay. Diethyl [2-phenyl-5-(phenylsulfonyl)-1,3-oxazol-4-yl]phosphonate, diethyl [5-(4-chlorophenylsulfonyl)-2-(4-methylphenyl)-1,3-oxazol-4-yl]phosphonate, and 5-(4-methylphenylsulfonyl)-2-phenyl-1,3-oxazole-4-carbonitrile, which demonstrated the highest anticancer activity, were selected for five-dose screening. The two phosphonates showed selectivity (SIr > 3 by TGI and LC50) against most leukemia lines, while the 1,3-oxazole-4-carbonitrile derivative was selective against renal (63%), colon (57%), and breast cancer (50%). One compound demonstrated selectivity against the entire leukemia subpanel. A comparison analysis revealed that no standard drug exhibited a high degree of similarity to compounds across all potency vectors. This suggests that the molecular mechanisms may be unique. Possible targets such as cannabinoid receptor 2, adenosine A3 receptor, and cyclin-dependent kinase 2 have been proposed based on in silico studies. The parameters of druglikeness predicted by the ADMET analysis were within the rational range for all compounds. The two phosphonates are expected to be preferable for the development of antileukemia agents, while 5-(4-methylphenylsulfonyl)-2-phenyl-1,3-oxazole-4-carbonitrile is considered promising for agents targeting renal, colon, and breast cancers.