Investigation of Experimental and In Silico Physicochemical Propertiesof Thiazole-Pyridinium Anti-Acetylcholinesterase Derivatives withPotential Anti-Alzheimer’s Activity

Background: Physicochemical properties play important role in fundamental issues like absorption and distribution of pharmaceuticals to the target tissue. This is particularly importantfor drugs acting in central nervous system (CNS). In this study, physicochemical properties of previously synthesized thiazole-pyridinium derivatives with anti-acetylcholinesterase activity and possible anti-Alzheimer effect were studied. Methods: Partition coefficient (n-octanol/water) and chromatographic Rf values for the studied compounds were determined using shake flask and high performance thin layer chromatography(HPTLC) methods, respectively. Different druglikeness properties of the compounds were also calculated using available software and web-servers. Results: The experimentally determined logarithm of partition coefficients (log P) for the studied compounds were in the range of -1.00 to -0.38. The Rf values for the studied compounds under the applied chromatographic condition ranged between 0.38 to 0.58. Moreover, calculated physicochemical properties, and druglikeness scores of the studied thiazole-pyridiniumderivatives and matching piperidine analogues were predicted. Furthermore, some ADMETfeatures of studied compounds like toxicity and metabolism by CYP450 (2C9, 2D6, 3A4, 1A2and 2C19) enzymes were predicted. Conclusion: The ranges of experimental and calculated LogP values for the studied thiazolepyridinumswere close. However, the determined Rf values showed relatively better correlation to the predicted LogP values indicating the suitability of used chromatographic method for comparing the lipophilicity of the positively charged pyridinium derivatives. The studied compounds were predicted to pass GI membrane and reach the CNS where they can exert their effects. In silico studies indicate that the piperidine counterparts of the studied thiazolepyridiniumsmay represent anti-Alzheimer agents with improved druglikeness properties.