Late-stage modification of bioactive compounds: Improving druggability through efficient molecular editing

Abstract

Synthetic chemistry plays an indispensable role in drug discovery, contributing to hit compounds identification, lead compounds optimization, candidate drugs preparation, and so on. As Nobel Prize laureate James Black emphasized, "the most fruitful basis for the discovery of a new drug is to start with an old drug"¹. Late-stage modification or functionalization of drugs, natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse elements into bioactive compounds promptly. Such modifications alter the chemical space and physiochemical properties of these compounds, ultimately influencing their potency and druggability. To enrich a toolbox of chemical modification methods for drug discovery, this review focuses on the incorporation of halogen, oxygen, and nitrogen-the ubiquitous elements in pharmacophore components of the marketed drugs-through late-stage modification in recent two decades, and discusses the state and challenges faced in these fields. We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functionalized molecules. Ultimately, we hope this review would serve as a valuable resource, facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.

Keywords: Drug space; Halogenation; Late-stage modification; Nitrogenation; Oxygenation; Synthetic chemistry.

Graphical abstract

Figure 1

Influences after introducing ‘X’, ‘O’, and ‘N’ into bioactive compounds. Therefore, LSM has been a convenient and powerful strategy for incorporating ‘X’, ‘O’, and ‘N’ into bioactive compounds. This review would explore the role of LSM in the generation of new molecules from the insight of pharmaceutical science. Specifically, late-stage halogenation, oxygenation, and nitrogenation strategies will be expounded along the logic of conversion of functional groups.

Scheme 1

Directed fluorination of arenes.

Scheme 2

Non-directed fluorination of arenes.

Scheme 3

Direct fluorination of alkanes.

Scheme 4

Fluorination of benzyl and allyl C–H bonds.

Scheme 5

Conversion of C‒X to C–F.

Scheme 6

Conversion of C–O to C–F.

Scheme 7

Other fluorination strategies.

Scheme 8

Chlorination of arenes.

Scheme 9

Chlorination of alkanes.

Scheme 10

Bromination of arenes.

Scheme 11

Other bromination reactions.

Scheme 12

Hydroxylation of arenes.

Scheme 13

Hydroxylation of alkanes.

Scheme 14

Other hydroxylation reactions.

Scheme 15

C(sp³)‒H bonds oxidation of bioactive compounds.

Scheme 16

Peroxidation of bioactive compounds.

Scheme 17

Oxygenation through carbon–carbon/carbon = carbon bonds cleavage.

Scheme 18

Transition-metal-catalyzed arenes C–H bond activation.

Scheme 19

Direct C–H bond amination via electrochemistry and photochemistry strategies.

Scheme 20

Direct C–H amination by electrophilic aminating reagents.

Scheme 21

Primary amination of prepared aryl reagents.

Scheme 22

Cross-coupling of aryl halides for primary anilines formation.

Scheme 23

Late-stage nucleophilic primary amination.

Scheme 24

Late-stage dealkylating C–C bond amination.

Scheme 25

Late-stage amide formation from carboxylic acids.

Scheme 26

Late-stage stepwise amide synthesis by Beckmann rearrangement.

Scheme 27

One-pot amide synthesis and Beckmann rearrangement in natural product derivatization.

Scheme 28

Schmidt-type amide synthesis.

Scheme 29

Late-stage introduction of triazole and tetrazole in drug discovery.

Scheme 30

Late-stage introduction of triazole and tetrazole.

Scheme 31

Late-stage skeleton N atom introduction.

Scheme 32

Direct synthesis of oxo nitriles via N,O-incorporation.

Scheme 33

Direct synthesis of β-azido alcohols via N,O-incorporation.