Lipophilicity assessment of some isoniazid derivatives active against Mycobacterium tuberculosis
2020
Santos, M. Soledade C.S. | Matos, Ana Marta | Reis, Marina | Martins, Filomena
Micelle-water partition coefficients, log Kₚ₍NₐDS/w₎, and octanol-water partition coefficients,log Pₒ/w, for 9 isoniazid derivatives, previously assessed as active against Mycobacterium tuberculosis, were determined using derivative spectrophotometry and the shake flask method in buffer systems at adequate pH values and ionic strength (0.1 M).Most of the compounds conform to a linear dependence between log Kₚ₍NₐDS/w₎ and log Pₒ/w demonstrating that lipophilicity is predominantly determined by hydrophobic, non-specific, interactions. A regression slope, lower than 1 (0.81), signals partition of neutral compounds towards micellar media as less favorable than towards octanol.The 2 most hydrophobic compounds show negative deviations from the correlation line, which were reasoned in terms of size effects. Steric packing constraints in the micellar palisade, explain the decreased affinity of the bulkier compounds towards micellar media. This effect is partially compensated in the case of the N’-C₁₀ INH derivative, due to a larger positive entropic contribution for the transfer process from the aqueous towards the micellar phase due to a “better fit” within the micellar hydrocarbon core.To the best of our knowledge, the systematic comparison of lipophilicity scales, sensitive to different molecular interactions, has never been used before, within a family of closely related compounds. The experimental data obtained provided relevant insights and foresee specific interactions of compound N’-C₁₀ INH with biological membranes which support previous molecular dynamic simulations and bioactivity evaluation studies.
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