Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Abstract

The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

Reductive Functionalization of Amides in Synthesis and for Modification of Bioactive Compounds

“…The reductive functionalization of amides opens a simple route to the installation of moieties, which could mimic carbonyl function and be amide bioisosteres. The thoughtful choice of replacement gives a high probability of more efficient candidates or significant improvement of marketed drugs (Kumari et al, 2020 ).…”

Chemoselective Amide‐Forming Ligation Between Acylsilanes and Hydroxylamines Under Aqueous Conditions

“…Amide bond formation is among the most extensively employed reactions in chemical industries and academic settings [1] due to the prevalence of this functional group in numerous life‐saving pharmaceutical products, [1, 2a] peptides, [2b] biological conjugates, [2c,d] agrochemicals [2e] and materials such as polymers, [2f,g] MOFs [2h] and hydrogels [2i] . Recent cheminformatics analysis of around 420 000 bioactive molecules from the ChEMBL database has identified the amide bond as the most occurring functional group in 40.3 % of all molecules [3] .…”

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

“…The synthesis of amides is among the most important reactions in organic chemistry and biochemistry because of the widespread occurrence of amides in pharmaceuticals, peptides, biologically active compounds, industrial polymers, detergents, and lubricants [ 1 , 2 , 3 , 4 , 5 , 6 ]. Consequently, many different physical [ 7 ] and chemical protocols have been developed for the synthesis of amides by dehydro-condensation of a carboxylic acid and an amine [ 8 , 9 , 10 , 11 , 12 , 13 ]. Catalytic routes for the preparation of amides have also been reported with the intent to increase atom efficiency of the process [ 2 , 14 ].…”