FRAGMENT BASED DRUG DESIGN AND DIVERSITY-ORIENTED SYNTHESIS OF CARBOXYLIC ACID ISOSTERES
Authors Ferri M, Alunno M, Greco F A, Mammoli A, Saluti G, Carotti A, Sardella R, Macchiarulo A, Camaioni E, Liscio P
Abstract 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.
Publish Date 2020
Volume 28 (22)
ISSN 1464-3391
DOI doi.org/10.1016/j.bmc.2020.115731
URL https://www.sciencedirect.com/science/article/pii/S0968089620305617?via%3Dihub
Journal Bioorganic & Medicinal Chemistry
Pages art. n. 115731
PMID 33007550