Accelerating Drug Discovery: Synthesis of Complex Chemotypes via Multicomponent Reactions

Abstract

The generation of multiple bonds in one reaction step has attracted massive interest in drug discovery and development. Multicomponent reactions (MCRs) offer the advantage of combining three or more reagents in a one-pot fashion to effectively yield a synthetic product. This approach significantly accelerates the synthesis of relevant compounds for biological testing. However, there is a perception that this methodology will only produce simple chemical scaffolds with limited use in medicinal chemistry. In this Microperspective, we want to highlight the value of MCRs toward the synthesis of complex molecules characterized by the presence of quaternary and chiral centers. This paper will cover specific examples showing the impact of this technology toward the discovery of clinical compounds and recent breakthroughs to expand the scope of the reactions toward topologically rich molecular chemotypes.

Drug discovery has experienced a profound evolution in the past decade, with an increased emphasis on challenging therapeutic targets once considered undruggable¹ and new chemical modalities² steadily advancing through clinical studies.³ As a result, we have witnessed an incredible application of new technologies focusing on identifying initial hits for those medicinal chemistry campaigns. The ability to screen large compound libraries like DNA-encoded libraries⁴ and ultra-large libraries,⁵ coupled with innovation on structure-based drug discovery, mass spectrometry,⁶ chemoproteomics, automation,⁷ and artificial intelligence,⁸ has revolutionized the field of drug discovery.

Despite all those advances, one of the main challenges in hit-to-lead campaigns is rapid hit assessment and identification of a chemical series with a dynamic range of biological activity. The early establishment of a structure–activity relationship (SAR) of a specific hit leads to a steady progression to the next discovery phase. Synthetic feasibility⁹ is a critical factor to enable a fast iteration from drug design hypothesis to biological testing and reduce the cycle time of each iteration (Figure 1A). Identifying new technologies to reduce cycle time is critical in the pharmaceutical industry in all phases of research and development. The more modular the hit evaluation effort is, simultaneously exploring the different molecular domains of the initial hit, the shorter the cycle time (Figure 1B).

Figure 1.

(A) Design–synthesize–test–analyze cycle in medicinal chemistry. (B) Representation of the modular approach to explore different R substitutions within a hit.

Some of the most popular reactions in the past decades are amide-bond-forming¹⁰ and cross-coupling reactions¹¹ due to their versatility and reproducibility. However, those reactions generate sp²−sp² bonds, leading to molecular structures with significant developability issues, like low aqueous solubility, poor metabolic stability, and potential off-target effects. The late-stage challenges of “flat” chemical structures¹² and the medicinal chemistry efforts to design compounds with an increased number of sp³ centers have been well documented. The concept of fraction sp³ (F_sp³), defined as the number of sp³-hybridized carbons divided by the total carbon count, has been recently implemented as a critical parameter in drug design to increase the probability of clinical success. Furthermore, an approach to quantify the complexity of a molecule relies on the use of F_sp³ and the presence of chiral carbon centers. There is a growing interest in designing and synthesizing topologically complex molecular compounds to augment the chance to have biological activity.^13,14 Architecturally complex molecules, defined by the number of saturated carbons, might cover larger chemical space, increasing the probability to bind to cryptic binding sites of targeted proteins. Notably, the three-dimensional configuration might lead to enhanced selectivity and fewer off-target effects. The ultimate saturated carbon moiety is a quaternary center. A quaternary center displays four substituents in a tetrahedral fashion, leading to a sterically hindered and often rigid molecular conformation. Those types of molecular complexity have been one of the key appeals of natural products in drug discovery.¹⁵ Recently, there have been reviews highlighting the importance of including quaternary centers in medicinal chemistry,¹⁶ in spite of the poor synthetic feasibility.

Cognizant about the interest in the medicinal chemistry community around designing intricate compounds with a rich three-dimensional configuration in a time-efficient manner, we thought about multicomponent reactions (MCRs). MCRs are defined as reactions where three or more reagents are combined in a one-pot fashion to effectively yield a synthetic product. A critical advantage of MCRs versus traditional methods is the rapid generation of the desired product in the minimal number of steps, providing opportunities for green sustainable chemistry,¹⁷ minimizing purifications, and reducing waste and solvents. In addition, the modular nature of MCRs can play a crucial role in decreasing cycle time and allowing for simultaneous assessment of the different molecular domains (Figure 1). The value of MCRs has been demonstrated in the pharmaceutical industry with their application toward the development of many approved drugs. In this Microperspective, we want to highlight the recent technological advances in MCRs yielding complex molecules with quaternary centers or with at least one chiral center. We describe specific examples of the impact of MCRs on drug discovery and development with marketed approved compounds. In addition, we concisely illustrate important breakthroughs in this synthetic methodology in the past few years toward topologically rich molecules.

Passerini Reaction (Three-Component Reaction)

The Passerini reaction is an isocyanide-based MCR discovered by Mario Passerini and first reported in 1921.^18,19 The three-component reaction comprises isocyanides, a carbonyl-containing compound (e.g., aldehydes/ketones), and carboxylic acids to give α-acyloxyamides. The generally accepted mechanism proceeds via a concerted fashion whereby the carboxylic acid and the carbonyl compound form a hydrogen-bonded complex and react with the isocyanide. Overall, this reaction is an α-addition of the carbonyl component and of the carboxylate to the isocyanide, providing an imidate intermediate which then subsequently undergoes a Mumm rearrangement to yield the α-acyloxyamide Passerini product (4, Scheme 1).¹⁹ The Passerini reaction is a valuable reaction as it provides three points of diversity, enabling rapid production of diverse compound libraries from simple starting materials, obviating the need for synthesis of complex intermediates.²⁰ However, the Passerini reaction is much less exploited than its daughter reaction, the Ugi reaction (discussed in the next section); this is likely due to the hydrolyzable ester functionality of the α-acyloxyamide skeleton (4). Esters formed by the Passerini reaction, as with other esters, are generally metabolically unstable in vivo due to hydrolytic enzymes. The Passerini approach has been successfully applied to peptide macrocyclization to generate depsipeptides.²¹ The amide-to-ester substitution in cyclic peptides has been shown to increase membrane permeability.^22,23

Scheme 1. Passerini Reaction.

In an effort to expand the scope of the Passerini reaction, Brunelli and co-workers produced a library of 43 α-acyloxy carboxamides to evaluate the effects of substitution on the metabolic stability of the resulting ester moiety (Scheme 2).²⁰ Particular focus was given to the carboxylic acids and aldehydes, selecting diverse substrate models from aliphatic to substituted aromatic compounds. Assuming minimal impact of the isocyanide component due to its distance from the ester’s moiety, it was decided not to alter that substitution. Metabolic stability of the molecules toward hydrolysis was assessed in mouse liver microsomes and select compounds in human liver microsomes. In a further study, compounds with best hepatic stability were evaluated in human plasma and under acidic and alkaline conditions, to mimic gastrointestinal tract conditions.

Scheme 2. Passerini Reaction in the Preparation of Hydrolytically Stable α-Acyloxy Carboxamides.

As a result, an ortho,ortho′-disubstituted aromatic ring directly attached to the ester moiety provided hydrolytic stability independent of the chemical nature of the R² group of the aldehyde (Scheme 2). However, when R² was a bulky substituent, an increased hydrolytic stability was observed only in human microsomes, regardless of the nature of the substitution of the carboxylic acid (R³). This research proves the value of the Passerini MCR to prepare metabolically stable α-acyloxy carboxamides in medicinal chemistry.

Recently, Pirali and colleagues²⁴ reported a cutting-edge application of MCRs to new chemical modalities, in particular to proteolysis targeting chimeras (PROTACs).³ They leverage the versatility of the Passerini MCR as a modular synthetic platform to build heterobifunctional protein degraders. As a proof of concept, the approach was applied to the synthesis of putative BRD4-degrading PROTACs, identifying several degraders with high degradation efficiency (Scheme 3). The authors were inspired by the work of Ciulli and co-workers²⁵ optimizing PROTAC cell permeability by replacing an amide with an ester without metabolic stability concerns. Indeed, the Passerini approach seemed an excellent choice to tackle the synthesis of a chiral BRD4-degrading PROTAC containing an ester moiety (12, α-acyloxy amide). Notably, 12 demonstrated high stability in mouse liver microsomes, in concordance with previous research on ester PROTAC derivatives.

Scheme 3. Synthesis of a PROTAC Molecule Using the Passerini Reaction^,

Color code displays the different components to be assembled into the protein degraders.

Key components of the Passerini reaction are shown in the black boxes.

Ugi Reaction (Four-Component Reaction)

The Ugi reaction is a MCR comprising four components: an amine, a ketone or aldehyde, an isocyanide, and a carboxylic acid to synthesize a bis-amide (Scheme 4). The reaction name honors the work by Ivar Karl Ugi, who first described it in 1959.²⁶ The mechanism of the reaction follows a cascade fashion, starting with condensation between an amine and the carbonyl group from an aldehyde or ketone. The resulting imine gets protonated from the carboxylic acid, leading to an activated iminium moiety which reacts with the isocyanide. Reaction with the carboxylate results in an amino-nitrilium derivative that reacts with the carboxylate, followed by the Mumm rearrangement to yield the bis-amide product (17, Scheme 4). The classical four-component Ugi reaction is very prevalent, as it is an uncatalyzed reaction with an intrinsic high atom economy. In addition, the only byproduct formed is a molecule of water, simplifying purification. A key advantage of this MCR is the extremely modular approach, enabling the modification of each of the components in an independent fashion. In general, the chemical yield is high, increasing its merit.²⁷

Scheme 4. Ugi Reaction.

The Agios team took advantage of the four-component Ugi MCR methodology to rapidly explore the SAR around the high-throughput screen (HTS) hit 18 (IDH1 mutant R132H, IC₅₀ = 90 nM, Scheme 5) to identify inhibitors of mutant isocitrate dehydrogenase-1 (IDH1)²⁸ to treat cancer. The medicinal chemists recognized the value of the modular SAR exploration using the Ugi reaction and decided to initially profile the compounds in their racemic form. Strategic modifications of a close analog of 18 to understand the key structural elements included evaluation of the enantiomers of the α-carbon stereocenter (Figure 2). Chiral synthesis of analogs 26 and 27 starting from d- and l-mandelic acid identified compound 26 (S stereochemistry), retaining all the biological activity from the racemate. Furthermore, quaternary substitution at the α-carbon (25) led to a significant decrease (18-fold loss) in biological activity.

Scheme 5. Retrosynthesis of the Initial IDH1 Hit to a Four-Component Ugi Reaction.

Figure 2.

SAR evaluation of the α-carbon stereocenter.

The team continued their drug discovery campaign improving the pharmacokinetic profile. The introduction of a fluorinated cycloalkyl group and proline moiety helped to decrease clearance by preventing oxidative metabolism, resulting in a lead compound, 29 (AGI-14100, Figure 3). While 29 displayed the desired in vitro potency for IDH1 and metabolic stability, it was a robust inducer of CYP3A4. To minimize this issue, a 5-fluoropyridine was incorporated, diminishing the overall lipophilicity of the resulting molecule 30. This systematic SAR evaluation of the initial hit led to the eventual discovery of the clinical candidate AG-120²⁹ (30, Figure 3). During all the phases of SAR exploration, the application of the rapid and modular four-component Ugi reaction was maintained. Ivosidenib (AG-120, 30) was approved for patients suffering from relapsed or refractory acute myeloid leukemia (AML) by the FDA in July 2018.

Figure 3.

SAR evolution of the phenyl-glycine scaffold to clinical candidate AG-120.

One of the main challenges of the Ugi reaction was the development of an enantioselective version. It took almost 60 years to demonstrate that chiral phosphoric acids can catalyze the Ugi reaction, yielding a product with high enantioselectivity.³⁰ It is hypothesized that the chiral phosphoric acid forms a complex with the carboxylic acid, setting the direction for the isocyanide approach to the imine intermediate.

A recent example leverages enantiomerically pure α-hydrazino acids (31) as bifunctional components in a Ugi MCR approach³¹ to provide highly functionalized 1,2-diazetidin-3-one derivatives (Scheme 6). Heterocyclic compounds containing a diazetidin-3-one (or aza-β-lactam) core have been described as potent and selective inhibitors of the serine hydrolase protein phosphatase methylesterase-1 (PME-1). A structurally diverse library with moieties amenable for additional modification was prepared using unprotected α-hydrazino acids (31). An integral part of the successful approach was the identification of hexafluoro-isopropanol (HFIP)³² as a solvent during the optimization of the conditions to generate 1,2-diazetidin-3-ones with ketones.

Scheme 6. Use of Enantiomerically Pure α-Hydrazino Acids in the Ugi MCR.

This efficient approach allows in one step the synthesis of complex molecules incorporating three-dimensionality through quaternary centers that could not be easily accessible otherwise (Figure 4). The introduction of protected functional groups (35) or other functionalities (like esters (36) or nitro groups (37)) may lead to further functionalization.

Figure 4.

Examples of a diverse library generated via Ugi MCR of unprotected α-hydrazino acids.

Strecker Reaction (Three-Component Reaction)

The Strecker reaction is an effective procedure to synthesize an amino acid from ammonia or amines, aldehydes, or ketones and a cyanide. It was the first MCR, reported by Adolph Strecker in 1850.³³ The mechanism is explained as the reaction of the carbonyl moiety with ammonia to yield an imine intermediate. Cyanide nucleophilic addition to the imine generates an α-amino nitrile (40) which is subsequently hydrolyzed to yield the α-amino acid (41, Scheme 7). The traditional reaction provides a racemic mixture of the product; however, introducing asymmetric auxiliaries or chiral catalysts enables stereoselective applications.³⁴

Scheme 7. Strecker Reaction.

The use of the Strecker reaction significantly influenced the discovery of saxagliptin (46, Scheme 8), an orally bioavailable dipeptidyl peptidase IV (DPP-IV) inhibitor approved by the FDA in 2009 for the treatment of type 2 diabetes mellitus.³⁵ The SAR exploration of a β-quaternary N-terminal amino acid-derived series was efficiently accomplished by employing an asymmetric Strecker synthesis (Scheme 8). In particular, the introduction of (R)-2-phenylglycinol as a chiral auxiliary led to the desired diastereomer 44 of an adamantyl amino nitrile derivative. Subsequent hydrolysis of 44 resulted in the corresponding enantiomerically pure amino acid 45, bearing a bulky adamantyl substitution in the α-position. Cleavage of the chiral auxiliary and additional synthetic steps led to the synthesis of saxagliptin. With 4 stereocenters and 2 quaternary carbons, saxagliptin is a quite rigid molecule (3 rotatable bonds) with high fraction sp³ (F_sp³ = 0.89). Preclinically, saxagliptin behaved as a highly efficacious and long-acting inhibitor of DPP-IV, overcoming chemical stability and formulation challenges observed with previous compounds from the same chemical class.

Scheme 8. Auxiliary-Controlled Asymmetric Strecker Reaction in the Synthesis of Saxagliptin (46).

An asymmetric version of the Strecker reaction reported by Jacobsen and co-workers leverages the identification of effective catalysts, allowing for a straightforward approach to enantiomerically pure α-amino nitriles and α-amino acids avoiding the use of chiral auxiliaries.³⁶ Recently, an approach was developed to synthesize N-unprotected α-amino nitriles with a chiral quaternary center maintaining 99% ee.³⁷ The use of isatin-derived N-unsubstituted ketimines (Scheme 9) and a chiral squaramide catalyst (C5) led to the validation of an efficient MCR approach to prepare enantiopure unnatural amino acid derivatives in high yields and enantioselectivity.

Scheme 9. Enantioselective Strecker Reaction of N-Unsubstituted Ketimines.

Bucherer–Bergs Reaction (Three-Component Reaction)

The Bucherer–Bergs reaction is a MCR between aldehydes or ketones, potassium (or sodium) cyanide, and ammonium carbonate which yields 5-substituted or 5,5-disubstituted hydantoins 51 (Scheme 10).³⁸ While 5,5-dimethylhydantoin was first observed by Ciamician and Silber in 1905,³⁹ the MCR is named after Hermann Bergs, the first chemist to report the reaction,⁴⁰ and Hans Theodor Bucherer, who developed conditions and applications of this method.^41−43,38

Scheme 10. Bucherer–Bergs Reaction.

The mechanism of the reaction proceeds by formation of an imine intermediate by condensation of the carbonyl with ammonia. The imine subsequently reacts with the cyanide, forming an amino nitrile. The resultant amino nitrile reacts with CO₂, forming a carbamic acid intermediate, which undergoes cyclization to yield a 5-imino-oxazolidin-2-one, and its subsequent rearrangement, via an isocyanate intermediate, leads to the hydantoin product 51.⁴⁴ However, one important drawback of the reaction is the limited points of diversity, only at the C-5 position.

The Bucherer–Bergs reaction was employed in the discovery of GLPG1972/S201086 (referred to herein as GLPG1972), a compound in phase 2 clinical studies with the potential for disease-modifying osteoarthritis treatment.⁴⁵ Co-developed by Galapagos and Servier, GLPG1972 is a potent and selective disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) inhibitor. Degradation of human aggrecan, a component of cartilage, is impacted by the aggrecanase ADAMTS-5. GLPG1972 was identified after optimization of a hydantoin series following a HTS campaign, with hydantoins being previously reported as zinc-binding groups.^46,47 As the hydantoin moiety was key to the series’ activity, the Bucherer–Bergs reaction proved crucial for rapid progression of this series.

Compound 52 (Scheme 11) was selected as a representative hit from the hydantoin series. The compound displayed a desirable overall profile, with various avenues for series optimization. SAR efforts initially focused on the quaternary center of the hydantoin and the aromatic side chain, ultimately leading to the discovery of GLPG1972 (53, Scheme 11). GLPG1972 displayed high potency against rat and human recombinant ADAMTS-5 and in a mouse cartilage explant assay. Additionally, GLPG1972 possessed an excellent selectivity profile versus a range of metalloproteinases (MMPs and ADAMTS) and good oral plasma exposure in rats and dogs.

Scheme 11. SAR Evolution of the Hydantoin Series to GLPG1972 (53).

The preparation of GLPG1972 comprises four linear steps and one supercritical fluid chromatography (SFC) separation, providing the clinical candidate 53 in an overall yield of 6%. Scheme 12 depicts the portion of the synthetic route that utilizes the Bucherer–Bergs reaction. Synthetically prepared γ-keto ester 54 underwent Bucherer–Bergs reaction to provide the racemic hydantoin 55. Further synthesis and purification provided the enantiomerically pure compound GLPG1972 (53).

Scheme 12. Bucherer–Bergs Reaction in the Synthesis of GLPG1972 (53).

In another example, the Bucherer–Bergs reaction was employed in the preparation and discovery of an interleukin 17A (IL-17A) protein–protein interaction modulator (PPIm) clinical development candidate for potential treatment of autoimmune disorders.⁴⁸ Initial assessment of earlier established ligands revealed that binding to the IL-17A dimer occurs at the interface between the two IL-7A monomers. The research program initially began by analyzing the overlap of these known ligands in the active-site region, leading to a series of benzhydryl-glycine-containing compounds (56, Scheme 13). Initially SAR exploration was undertaken around R¹, as detailed in Scheme 13, and this led to the identification of dimethyl-pyrazole derivative 57 as a key compound with PPIm activity and displaying potential for oral bioavailability. Expansion of the amino acid domain (R² in Scheme 13) led to the discovery of a dicyclopropyl-alanine group, imparting robust activity and metabolic stability. Finally, optimization of the R²/R³ domains was undertaken to further refine molecules, resulting in the identification of PPIm 59 as a clinical development candidate for potential treatment of IL-17A-mediated diseases.

Scheme 13. SAR Exploration to Clinical Candidate 59.

SAR evaluation of the R²-substituted moiety was assisted by the Bucherer–Bergs reaction. The Bucherer–Bergs reaction played a crucial role in the efficient preparation of the amino acid domain and thus the progression of 59 as a development candidate. The synthesis of compound 59, detailing the Bucherer–Bergs reaction contribution to the synthesis, is presented in Scheme 14.

Scheme 14. Bucherer–Bergs Reaction in the Synthesis of Clinical Compound 59.

Betti Reaction (Three-Component Reaction)

The Betti reaction, first uncovered at the beginning of the 20th century by Mario Betti, is a three-component reaction that comprises a phenol compound, an aldehyde, and an amine/ammonia (Scheme 15).⁴⁹ The reaction proceeds after formation of an imine (generated via the amine and aldehyde) which subsequently reacts with the phenol. The reaction has been significantly utilized over the years due to its convenience and the access to a variety of valuable scaffolds. Efforts to improve the reaction have focused on overcoming certain drawbacks of the classical method such as structural variations, reducing reaction times, and increasing yields.

Scheme 15. Betti Reaction.

An α-tertiary amine moiety is an important structural motif that is present in various biologically active natural products and pharmaceuticals.⁵⁰ With a specific focus on obtaining α-triphenylmethylamines, a versatile synthetic route was developed utilizing a Brønsted acid-catalyzed (BA) Betti reaction.⁵¹ Since reactive imine species can be formed in situ from their stable precursors, it was reasoned that a benzophenone-derived iminium species (68, Scheme 16) could act as a highly reactive electrophile for poor nucleophiles, such as phenols, and enable 1,2-addition of aryl rings in a formal Betti reaction. Thus, a BA formal Betti reaction was devised, involving 1,2-addition of phenols to N-acyl benzophenone-ketimines generated in situ from α^N-hydroxy amides (Scheme 16).

Scheme 16. Brønsted Acid-Catalyzed (BA) Formal Betti Reaction.

This strategy enables access to crowded α-triphenylmethylamines, a highly valued bioactive structural motif, introducing chemical diversity through a quaternary center.

To enhance this methodology, investigation of various Brønsted and Lewis acids, catalytic efficiency, solvent influence, temperature, and catalyst/reagent loading was undertaken. This effort resulted in optimal reaction conditions comprising diarylketimine precursor (1.0 equiv), phenol (1.5 equiv), and methanesulfonic acid (10 mol%) in cyclohexane at 80 °C (Scheme 17). Further, the substrate scope, reaction limitations, and synthetic utility were explored. This optimized transformation provides a streamlined synthesis of an array of α-triphenylmethylamines in good to excellent yields, thus paving the way for the preparation of these highly valuable moieties in multiple medicinal chemistry campaigns.

Scheme 17. Optimized Acid-Catalyzed Formal Betti Reaction.

A version of the Betti reaction exploits the identification of chiral phosphoric acid catalysts for the conversion of phenols and N-acyl diarylketimines, generated in situ, to quaternary stereocenters containing three phenyl rings.⁵² The development of this reaction assists in the construction of enantiomerically pure complex structures. The reaction is achieved by the arylation of benzophenone-derived ketimines (Scheme 18).

Scheme 18. Organocatalytic Formal Betti Reaction of N-Acyl Diarylketimines.

The investigation focused on combining 3-phenyl 3-hydroxyisoindolinone (76) with 2,6-dimethylphenol (77) in the presence of various chiral phosphoric acids (Scheme 19). Upon identification of a 9-anthracenyl-substituted chiral phosphoric acid (BA2) as the optimal catalyst, solvent, temperature, additives, and concentration were further investigated. This resulted in optimal reaction conditions for the transformation comprising diarylketimine precursor (1.0 equiv), phenol (5.0 equiv), and catalyst BA2 (10 mol%) in toluene (0.2 M suspension) at 40 °C (Scheme 19).

Scheme 19. Optimized Enantioselective Betti Reaction.

This methodology enables wide substrate scope of phenols and ketimines and the generation of isoindolinone analogs containing a congested quaternary stereocenter with three phenyl rings in high yields, enantioselectivities, and regioselectivities.

In this Microperspective, we have shown examples that demonstrate the vast opportunities that MCRs offer to drug discovery and development. The few selected MCR approaches provide a direct route to complex chemotypes presenting quaternary or chiral centers. The intrinsic modular aspect of this methodology enhanced its versatility and effectiveness to quickly establish meaningful SAR trends for medicinal chemistry efforts. We have highlighted relevant breakthroughs on identifying new reaction conditions using novel chiral catalysts or chiral auxiliaries to prepare compounds with a three-dimensional conformation and sterically crowded stereocenters.

While most of the examples have been focused on small-molecule approaches, some instances covered examples of new chemical modalities like PROTACs and macrocycles. We envision further developments in this technology using automation and machine learning to revolutionize early drug discovery and significantly decrease cycle times to develop a clinical compound.

Glossary

Abbreviations

ADAMTS-5

A disintegrin and metalloproteinase with thrombospondin motifs 5

AML

acute myeloid leukemia

DPP-IV

dipeptidyl peptidase IV

FDA

U.S. Food and Drug Administration

HFIP

hexafluoroisopropanol

HTS

high-throughput screen

IDH1

isocitrate dehydrogenase-1

MCR

multicomponent reaction

MMP

metalloproteinase

PPIm

protein–protein interaction modulator

PROTACs

proteolysis targeting chimeras

SAR

structure–activity relationship

SFC

supercritical fluid chromatography

rt

room temperature

The authors declare no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Enabling Drug Discovery Technologies - Recent Progress”.