Design and discovery of boronic acid drugs

Abstract

Research related to boronic acids, from synthetic development to materials to drug discovery, has skyrocketed in the past 20 years. In terms of drug discovery, the incorporation of boronic acids into medicinal chemistry endeavours has seen a steady increase in recent years. In fact, the Food and Drug Administration (FDA) and Health Canada have thus far approved five boronic acid drugs, three of which were approved in the past four years, and several others are in clinical trials. Boronic acids have several desirable properties that has led to their increased use, including potentially enhancing potency of drugs and/or improving their pharmacokinetics profile. This review explores discovery processes of boronic acid drugs. It begins with a brief scope of boron in natural products and in current drugs, followed by an investigation into the various rationalizations for boronic acid incorporation and the synthetic developments that focused on facilitating their addition into organic compounds. We hope that the knowledge we have assembled in this literature review will encourage medicinal chemists to consider the potential benefits of incorporating boronic acids into their future drug discovery endeavours. Contents 1. Introduction 2. Occurrence of boron in nature. Boron in bacteria. Boron in plants. Importance in mammalian systems3. Scope of boronic acid drugs 3.1. Approved boron-containing drugs 3.2. Boron-containing drugs under investigation 3.3. Over-the-counter boron-containing drugs and supplements 3.4. Boron-containing compounds in drug discovery 3.4.1. Anti-cancer boron-containing compounds 3.4.2. Anti-viral boron-containing compounds 3.4.3. Other anti-infective boron-containing compounds 3.4.4. Other therapeutic applications of boron-containing compounds 3.

Recent progress in self-healing polymers and hydrogels based on reversible dynamic B–O bonds: boronic/boronate esters, borax, and benzoxaborole

“…Recently, the incorporation of boronic acids into medicinal chemistry has steadily increased because the boronic acid moiety does not readily come off from organic compounds in physiological systems. 83,84 In biomedical applications, the curing efficiency and mechanical properties of boronic acid-based self-healing materials can decrease in physiological systems because B-O bonds are unstable in aqueous systems. The pH of the system affects the equilibrium of boronic acid/esters in aqueous systems.…”

Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

“…In general, the ability of boronic acids to change their hybridization state between sp2 (trigonal) and sp3 (tetrahedral) forms in aqueous environments makes them good mimetics of the transition state for enzymes using amides, esters or lactams as substrates. [107] This feature and the improved pharmacokinetics profile of the corresponding derivatives are attractive properties that have been exploited in drug development and resulted in several approved drugs. Good examples are bortezomid (Velcade, FDA approved in 2005) [108] and ixazomid (Ninlaro, FDA approved in 2015), [109] which are proteasome inhibitors used for the treatment of myeloma, and tavaborole (Kerydin, FDA approved in 2014), [110] which is a Leucyl-tRNA synthetase inhibitor employed for the treatment of onychomycosis (a fungal infection).…”

Vibrational Studies of Monomer, Dimer and Trimer Structures of 4-Carboxy Phenylboronic Acid

“…The discovery process of boronic acids also relies on the approach. For instance, substrate mimicry or peptidomimetics design, rational design via computational methods, or use as bioisosteres to substitute for certain functional groups can be given as examples [1][2][3][4][5][6][7][8].…”