Leukopenia remains a major clinical challenge associated with infectious diseases, oncological therapies, autoimmune disorders, and metabolic and iatrogenic conditions. Insufficient leukopoiesis not only increases susceptibility to infections but also limits the intensity and continuity of anticancer and immunosuppressive treatments. Targeted stimulation of leukopoiesis therefore represents a critical therapeutic strategy in modern biomedicine. This narrative review summarizes pharmacological and biotechnological approaches to leukopoiesis stimulation based on an analysis of peer-reviewed literature from major biomedical databases. Emphasis was placed on molecular mechanisms of action, clinical positioning, and translational potential of leukopoiesis-modulating agents. Current leukopoiesis-stimulating strategies encompass cytokine-based therapies, bone marrow-derived peptides, thymic and microbial immunomodulators, nucleic acid-based agents, plant-derived compounds, and chemically synthesized small molecules. Classical colony-stimulating factors remain the cornerstone of clinical practice; however, their limitations, including adverse effects and restricted spectrum of action, have driven the development of alternative approaches. Emerging strategies increasingly target specific regulatory nodes of hematopoiesis, including bone marrow stromal interactions, transcription factor signaling, chemokine receptor pathways, and immune cell differentiation programs. Advances in the understanding of leukopoiesis regulation have expanded therapeutic opportunities beyond conventional growth factor administration. Pharmacological and biotechnological targeting of leukopoiesis holds promise for improving clinical outcomes in patients with leukopenia of diverse etiologies. Future progress in this field will depend on the integration of mechanistic insights with clinical evidence to enable more selective, effective, and safer leukopoiesis-stimulating therapies.

The study focuses on the synthesis and pharmacological evaluation of novel structural analogs of the anesthetic and antiarrhythmic Kazcaine. Two new derivatives were synthesized by acylation of propylacetylene alcohol 1-(2-ethoxyethyl)-4-oxopiperidine with fluorobenzoyl chlorides. Their complexes with cyclodextrin were obtained for biological screening. The evaluation of the myelostimulating activity of these complexes revealed that one of them, specifically the 3-fluorobenzoyloxy derivative, demonstrated a pronounced myelostimulating effect, particularly with regard to the stimulation of leukopoiesis and thrombopoiesis. The compound, in complex with β-cyclodextrin, showed significant stimulation of leukocyte and platelet proliferation, with a noticeable increase in the total number of leukocytes and improvement in granulocyte and lymphocyte recovery. These results indicate that the synthesized compounds have significant potential for pharmacological use, especially for stimulating hematopoiesis and protecting against myelosuppression. In addition, quantum chemical calculations of the reactions showed that ortho- and meta-fluorobenzoyl chloride have higher reactivity, which is confirmed by the high yields of the products (94% and 89%) obtained as a result of the synthesis.

The significance of the study is due to the problem of the increase in patients with secondary forms of leukopoiesis-depressive diseases. The development of leukopoiesis-stimulating drugs is necessary. These drugs are used in the treatment of cancer patients to prevent the development of febrile neutropenia, to stimulate the immune system in the postoperative period, to restore immune reactivity in environmentally caused secondary immunodeficiency syndrome. The rate of increase in patients with the secondary form of leukopoiesis-depressive syndrome is due to the increased use of cytostatic drugs. Preclinical work was carried out to study new synthetic compounds BIV-241 (dimethyl ((4-methoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phosphonate), BIV-242 (dimethyl ((3-methoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phosphonate), BIV-243 (dimethyl ((2-fluorophenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phosphonate) for leukopoiesis-stimulating activity. The studies were conducted on a cyclophosphamide-induced model of pancytopenia on outbred white rats. Compounds BIV-241 and BIV-242 did not show the desired activity. Compound BIV-243 is of interest for further development, as it had moderate leukopoiesis-, erythrocytopoiesis- and thrombocytopoiesis-stimulating activity.

A series of novel imidazole-containing α-aminophosponate derivatives were synthesized based on 1-(3-aminopropyl)imidazole using the absolute benzene under the one-pot, three-component Kabachnik–Fields reaction. The hematopoiesis-stimulating activity was evaluated for the compounds 7βCD-12βCD. The structure of the obtained compounds was confirmed using nuclear magnetic resonance (NMR) spectroscopy, infrared spectroscopy (IR), and elemental analysis. All tested compounds were β-cyclodextrin inclusion complexes of dialkyl(3-(1H-imidazol-1-yl)propylamino)(fluoro- and trifluoromethylphenyl)methyl)phosphonates to enhance aqueous solubility, improve bioavailability, and modulate the pharmacokinetic profile of the phosphonates. Among the tested derivatives, compounds 7βCD, 8βCD, 10βCD, and 11βCD exhibited low hematopoiesis-stimulating activity, whereas 9βCD and 12βCD demonstrated a moderate stimulatory effect on leukopoiesis. Biological evalution in a cyclophosphamide-induced pancytopenia model revealed that several complexes exhibit hematopoietic properties. Notably, 9βCD and 12βCD moderately stimulated leukopoiesis at a level comparable to methyluracil, significantly restoring the total leukocyte and lymphocyte counts and normalizing the Harkavy index. Despite their positive effects on leukopoiesis, compounds 9βCD and 12βCD showed limited influence on erythropoiesis and thrombopoiesis. In contrast, other derivatives (7βCD, 8βCD, 11βCD) did not exhibit stimulatory activity and, in some cases, even suppressed hematopoietic parameters. Taken together, these findings indicate that complexes of β-cyclodextrin with imidazole-containing α-aminophosphonates - particularly the complex of dimethyl(((3-(1H-imidazol-1-yl)propyl)amino)(4-fluorophenyl)methyl)phosphonate with β-cyclodextrin (9βCD) and complex of dimethyl ((3-(1H-imidazol-1-yl)propylamino)(4-(trifluoromethylphenyl)-methyl)phosphonate with β-cyclodextrin (12βCD) - represent promising scaffolds for the development of novel modulators of hematopoiesis. The observed biological activity may be associated with the presence of electron-withdrawing substituents (fluoro- and trifluoromethyl groups) and the imidazole fragment, which can contribute to intermolecular interactions with biological targets and participate in hydrogen bonding, facilitating binding to enzyme active sites, while the phosphonate moiety provides enhanced metabolic stability. Overall, these holdings suggest the potential of certain phosphonate derivatives, particularly 9βCD and 12βCD, as possible candidates for the further development of immunomodulating agents. Key words: hematopoiesis-stimulating activity; phosphonate derivatives; β-cyclodextrin inclusion complexes of dialkyl ((3-(1H-imidazol-1-yl)propylamino)(fluoro- and trifluoromethylphenyl)methyl)phosphonate.