Phosphodiesterase Inhibition and Immunotropic Activity of Dipyridamole Dynamic Derivatives

Introduction. Many pharmacological properties of dipyridamole (DIP) are associated with its ability to inhibit phosphodiesterases (PDEs). Actually, DIP has interesting properties like antiviral for influenza, SARS-2 COVID-19, and herpesviruses. Our research aimed to design and synthesize the dynamic combinatorial DIP derivatives with more pronounced inhibiting properties in relation to PDE and to carry out the HPLC analysis of the resulting combinatorial derivatives of DIP. This study is aimed at investigating the effect of the dynamic derivative of dipyridamole (DDD) on intestinal dysbiosis syndrome in mice caused by streptomycin against the background of cyclophosphamide-induced cellular immunodeficiency. Materials and methods. For the synthesis of a dynamic combinatorial derivative of dipyridamole, we used a molecular dynamic method for drug design and combinatorial acylation of dipyridamole by succinic and acetic anhydride in different molar ranges of acylation agents. Combinatorial derivatives were analyzed using gradient HPLC with a UV detector. Also, derivatives established the inhibition ability for phosphodiesterase by the spectrophotometric method. Also, we used an in vivo mouse model with immunodeficiency caused by cyclophosphamide for pharmacological study. Results and discussion. Molecular modeling suggests that 18 different dipyridamole derivatives can self-assemble into a stable supramolecular structure with lower total energy. Specific combinatorial molar ratios of the synthesis components were necessary to create a new supramolecular compound with enhanced pharmacological properties. The inhibition of phosphodiesterase in such a dynamic combinatorial derivative already appeared at a concentration of 0.05 μM. In mice with colitis caused by streptomycin treatment, the administration of DDD per os resulted in an antidiarrheal effect and prevention of the animals' weight loss. Given the cyclophosphamide-induced immunosuppression and streptomycin-associated diarrhea, immunity was completely restored only under the action of DDD. Conclusions. The most effective dipyridamole derivative for phosphodiesterase inhibition was formed only if the number of different derivatives in solution was maximum and consisted of all 18 molecules. With other quantities of modifiers, there was no qualitative change in the inhibitory activity of the combinatorial mixture against phosphodiesterase. According to all parameters, DDD has been proven to be more effective than the pure dipyridamole reference product.