Determination of Acidity Constant (pKa), Lipophilic Partition (LogP) and Distribution Coefficients (LogD) Values of Some 3-(2-Phenylethyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione-5-Acetic Acid Derivatives

Invasive fungal infections pose a significant threat to human health, emphasizing the urgent need for new and effective antifungal agents. 3,5-Disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives have shown promising antifungal activity. This study focused on characterizing the physicochemical properties, specifically the acidity constant (pKa), lipophilic partition coefficient (logP), and distribution coefficient (logD), of four 3-(2-phenylethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione-5-acetic acid derivatives (EP1, EP2, EP3, and EP4) with varying α-carbon substituents. pKa values were determined using two independent methods: parallel factor analysis (PARAFAC) of UV spectroscopic data and reversed-phase high-performance liquid chromatography (RP-HPLC). Lipophilicity was assessed by measuring logD values using the shake-flask method with n-octanol, and logP values were calculated based on the determined pKa and logD values. The pKa values determined by both PARAFAC and RP-HPLC showed a good correlation. The α-carbon substituent significantly influenced pKa, with electron-withdrawing substituents resulting in lower pKa values, consistent with inductive effects. The logD-pH profiles exhibited typical bell-shaped curves, with logP values at pH 5.5 ranging from -0.38 to 3.00. EP1, EP2, and EP4 displayed lipophilic characteristics, while EP3 showed higher hydrophilicity. This study provides the first reported pKa, logP, and logD values for these novel thiadiazine derivatives. The findings emphasize the influence of structural modifications on physicochemical properties, which are critical for drug absorption, distribution, and target interaction. These data provide a valuable basis for elucidation of the structure-activity relationship and formulation optimization of these antifungal agents.