The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pK_a is significantly lower than the basic pK_a. Through concordance of measured and calculated pK_a and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpK_a. These nonclassical zwitterions are characterized by a weak acidic and basic pK_a and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

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非经典两性离子作为设计原理，在不影响渗透性的情况下降低亲脂性

生物活性分子的电离影响许多 ADME 相关的物理化学性质，特别是溶解度、亲脂性和渗透性。两性电解质同时含有酸性和碱性基团，与普通两性电解质和两性离子不同。一篇有影响力的评论指出，只有当酸性 p Ka显着低于碱性 p Ka时_{，两性离子才存在。通过测量}和计算的 p Ka与 log P的一致性，我们表明，尽管_Δp Ka较低或为负，但几种市售药物和天然产物仍会发生两性离子行为。这些非经典两性离子的特征是弱酸性和碱性 pKa以及通过扩展芳香系统的共轭，通常包括通过分子内氢键形成的假环_。与大多数经典两性离子相比，非经典两性离子可以表现出优异的渗透性。由于渗透性和亲脂性通常是相关的，低亲脂性和高渗透性的结合使得非经典两性离子成为药物化学中有吸引力的设计原则。