Boron in Drug Discovery

Abstract

The pursuit of novel therapeutics demands a systematic, rational approach to drug design, prioritizing high potency, selectivity, and precise in vivo drug delivery. This work comprises two studies delving into boron-based compound synthesis and their potential in drug discovery.

Chapter 2 explores boron-based P2X7 receptor antagonists, vital in immune responses, inflammation, and cell death. It aimed to expand the antagonist library with boron, discovering compounds like 89 (IC50 = 388 ± 68) with high nanomolar range potencies. The study emphasized structural rigidity for effective P2X7 inhibition and highlighted the role of three-dimensional contacts at the receptor site, facilitated by adamantane and closo-carboranes.

Chapter 3 employed a fragment-based drug discovery (FBDD) approach to identify boron-based antiviral compounds targeting SARS-CoV-2. Preliminary in vitro evaluations revealed two promising hit fragments, CA87 (nido-carborane; EC50 = 100 µM) and BA34 (ortho-boronic acid; EC50 = 3.13 µM). Assessments against SARS-CoV-2 variants highlighted BA34 isomers' selectivity, notably BA32 (para-substituted phenyl boronic acid), with exceptional delta variant inhibition (EC50 = 6 nM). Expanding the FBDD library yielded 15 additional fragments, aiding structure-activity relationship (SAR) studies. Three potent leads emerged: OX11 (EC50 = 200 nM), BA52 (EC50 = 7.41 nM), and BA49 (EC50 = 390 nM). Unique insights into fragment binding, involving parent compound BA34, revealed direct interaction with the virus spike protein, differentiating it from current COVID-19 agents.

In conclusion, this study underscores boron-based compounds' therapeutic potential, offering distinct advantages in drug design. These findings illuminate the design and optimization of boron-containing compounds across various therapeutic applications, including COVID-19 treatment.