The Design and Application of Bioisosteres in Drug Design

Abstract

Bioisosterism, the design of structural motifs that emulate established functionality to effect a biological response, has evolved into a powerful design principle in medicinal chemistry and drug discovery that can be implemented to address issues associated with intrinsic potency and/or a range of developability challenges. While bioisosterism has its origins in the concept of isosterism, which was invoked to explain the similarity of physicochemical properties between molecules with analogous size and shape, the contemporary interpretation of bioisosterism extends well beyond this simple definition to encompass relationships that reflect a recapitulation of biological properties by molecules that can be structurally quite disparate. This article provides a synopsis of established and emerging bioisosteric relationships that are discussed in the context of applications to solving problems in drug discovery and development. Bioisosteres that are described range from the replacement of hydrogen atoms by deuterium or fluorine to more esoteric higher order bioisosteres that convene intricate arrays of functionality. These are considered nonclassical in nature and offer functional mimesis of a range of simple and complex functionalities encompassing exchangeable groups, cyclic/noncyclic substructures capable of mimicking rings, and extends to include drug–water and drug–metal complexes.

Peroxide-Initiated Hydrophosphinylation of gem-Difluoroalkenes

“…The gem-difluoroalkene, bearing an electrophilic character at the terminal difluorinated carbon atom, 10 represents an attractive electrophile for nucleophilic addition. However, nucleophilic addition reactions of gem-difluoroalkenes with a wide variety of nucleophiles that proceed under basic conditions typically generate anionic intermediates that decompose through β−F elimination to deliver monofluorinated products, 11−14 2B), 15 with the exception of specialized gem-difluoroenol ether substates that are set up to undergo a [2,3] rearrangement to deliver α,α-difluorodiphenylphosphine oxides (Figure 2C). 16 In contrast, the addition of P-based radicals into gemdifluoroalkenes avoids the pitfalls of nucleophilic addition/ elimination sequences (Figure 2D).…”

Accelerated Synthesis of Bicyclo[1.1.1]pentylamines: A High-Throughput Approach

“…As a consequence, arylamines are recurrent scaffolds in medicinal chemistry optimizations, despite they are often being considered structural alerts due to their genotoxic potential and propensity to form reactive metabolites . In an attempt to enhance safety and decrease attrition related to aniline-derived toxicity, a plausible strategy consists of searching for new bioisosteric replacements . Among nonclassical bioisosteres, bicyclo[1.1.1]­pentane (BCP) has gained interest over the past decade as an effective sp 3 -rich phenyl mimic .…”