The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery stages for a better analog design. Herein in this work, to enable decision making on a project, we have synthesized by employing a Diversity-Oriented Synthetic (DOS) methodology, a small library of molecular fragments endowed with acidic properties. By combining in-silico and experimental methodologies these compounds were chemically characterized and, particularly, with the aim to know their physicochemical properties, the aqueous ionization constants (pKa), partition coefficients logD and logP of each fragment was firstly estimated by using molecular modeling studies and then validated by experimental determinations. A face to face comparison between data and the corresponding carboxylic acid might help medicinal chemists in finding the best replacement to be used. Finally, in the framework of Fragment Based Drug Design (FBDD) the small library of fragments obtained with our approach showed good versatility both in synthetic and physico-chemical properties.

当寻找羧酸的替代品时，药用化学家的工具箱中有很多（生物）等排体。然而，酸替代物的系统评估通常是耗时且昂贵的，而对于更好的类似物设计，在早期发现阶段需要理化性质（logP和logD）以及酸度的预测。在本文中，为了使项目决策可行，我们采用了面向多样性的合成（DOS）方法进行合成，该方法是具有酸性特性​​的小分子片段库。通过结合计算机和实验方法，对这些化合物进行了化学表征，尤其是为了了解其理化性质，首先通过分子建模研究估算了每个片段的水电离常数（pKa），分配系数logD和logP，然后通过实验对其进行了验证。决心。数据和相应的羧酸之间的面对面比较可能会帮助药物化学家找到要使用的最佳替代品。最后，在基于片段的药物设计（FBDD）框架中，使用我们的方法获得的小片段文库在合成和理化性质方面均显示出良好的通用性。