Despite numerous studies, high sensitivity of the brain nerve cells to vitamin B1 (thiamine) deficiency could not be explained solely by the co-enzymatic role of thiamine diphosphate. The molecular mechanisms of a high neurotropicity of thiamine have not yet been finally deciphered. Therefore, it is important to elucidate the relationship between the structure and the biological activity of thiamine and its derivatives. This study was conducted to evaluate the molecular structural features of thiamine and related compounds responsible for their ability to bind to nerve cells. In vitro and in silico methodological approaches were used. The interaction of thiamine and other compounds with isolated plasma membrane synaptosomes (PMS) was studied by a radioligand method using the carbon-labeled [thiazolium-2-14C] thiamine. The PMS preparations were obtained from the rat brain by differential centrifugation in a sucrose density gradient. The effect of thiamine derivatives on the viability of isolated thymocytes and neuroblastoma line N1E115 cells was evaluated by the MTT test. Physicochemical parameters of the tested compounds were calculated using Molinspiration software. ADMET properties were predicted using the pkCSM online server. Thiamine-related compounds with a thiazolium ring and with an unsubstituted hydroxyethyl group were found to be promising neuroactive agents. Modification of the aminopyrimidine part in the thiamine molecule provides different degrees of competitiveness of the compound with respect to thiamine. Among the compounds tested, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT) was identified as the best thiamine antagonist. The ability of DMHT to suppress cell viability in vitro was evaluated. Further DMHT studies are expected to provide knowledge for the development of modulators of thiamine-dependent processes in the nerve cells.
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