Determination of Lipophilicity of Naphthylhydroxamic Acids through Various Methods to Assist Drug Discovery

ABSTRACT Background Lipophilicity is a crucial physicochemical property that affects drug absorption, distribution, and membrane permeability. The potential of three naphthyl hydroxamic acids, N-1-naphthyl-o-ethoxybenzohydroxamic acid ( 1 ), N-1-naphthyl-o-methylbenzohydroxamic acid ( 2 ), and N-1-naphthyl-p-methylbenzohydroxamic acid ( 3 ) was evaluated to determine their potential as drug candidates. Methods Lipophilicity was assessed using four complementary approaches Shake-Flask method, Solvation Descriptors measurements, Reverse-phase high-performance liquid chromatography (RP-HPLC), and Computational techniques . The Shake-Flask method was used to determine partition coefficients ( logP ) in 1-octanol/water and chloroform/water systems. Abraham's solvation equation was used to evaluate solute descriptors, including polarizability, π 2 H , excess molar refraction, R 2 , hydrogen bond donor acidity, Ʃ Ʃ α 2 H , and a hydrogen bond acceptor basicity, Ʃ Ʃ β 2 0 at temperatures of 298, 303, 308, and 313 K. Additionally, the lipophilicity factor, logk w, was evaluated using the RP-HPLC method. A computational study was conducted using various prediction software, including Bioloom database ( logP ), milogP , AlogP , ( ACD/logP ), and Chemdraw ( clogP ). Results For the studied compounds, all the mentioned methods show a comparable trend in lipophilicity. With increasing temperature, the lipophilicity ( logP ) of the three naphthyl hydroxamic acids decreases. Chromatographic retention parameters were well interrelated with calculated lipophilicity descriptors, confirming interactions with biological systems. Conclusion The present study provides a comprehensive understanding of the lipophilicity of the three naphthyl hydroxamic acids (1–3), with logP values in the optimal range of 1–5. However, in the present study, only these three derivatives are investigated, thereby generalizability of the established structure-property relationships is needed for the entire class of hydroxamic acids, so that pharmacological experiments, including cytotoxicity and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies, are required to confirm the therapeutic potential of these compounds. These findings show the potential significance of the three naphthyl hydroxamic acids in drug discovery and design, and confirm the necessity for pharmacological investigation.