Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

Abstract

The concept of bioisosterism and the implementation of bioisosteric replacement is fundamental to medicinal chemistry. The exploration of bioisosteres is often used to probe key structural features of candidate pharmacophores and enhance pharmacokinetic properties. As the understanding of bioisosterism has evolved, capabilities to undertake more ambitious bioisosteric replacements have emerged. Scaffold hopping is a broadly used term in the literature referring to a variety of different bioisosteric replacement strategies, ranging from simple heterocyclic replacements to topological structural overhauls. In this work, we have highlighted recent applications of scaffold hopping in the central nervous system drug discovery space. While we have highlighted the benefits of using scaffold hopping approaches in central nervous system drug discovery, these are also widely applicable to other medicinal chemistry fields. We also recommend a shift toward the use of more refined and meaningful terminology within the realm of scaffold hopping.

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

“…Incorporation of two or more pharmacophores of bioactive scaffolds based on molecular hybridization has been one of the most successful strategies for the discovery of new pesticides and drugs. − For example, flubeneteram, a novel commercial SDHI fungicide approved recently (Figure ), was discovered through pharmacophore-linked fragment virtual screening (PFVS) by the Yang group, − which could be considered as a combination of pyrazole-4-carboxamide and diphenyl ether bioactive scaffolds based on the molecular hybridization strategy. Scaffold hopping, another widely exploited design approach, offers the opportunity to modify known lead compounds to afford novel structures with high potency, low toxicity, and enhanced physicochemical properties. − In this work, in search of novel SDHIs, flubeneteram was used as lead compounds, and we attempted to replace the diphenyl ether scaffold of flubeneteram with extended phenyl diether and aliphatic ether by scaffold hopping (Figure ). A series of novel pyrazole-4-carboxamide derivatives bearing an extended ether group were designed and synthesized by a simple synthetic method (Figure ).…”

Mode of Action of Novel Pyrazoloquinazoline on Diamondback Moth (Plutella xylostella) Ligand-Gated Chloride Channels

“…Pyrazoloquinazoline 5a was the representative compound (Figure ), which showed high insecticidal activity against P. xylostella. − While compounds synthesized by scaffold hopping usually possessed the same target as the original compound, − the mechanism of 5a action on insects has not been well elucidated. The γ-aminobutyric acid (GABA) receptor (GABAR) together with the glutamate-gated chloride channel (GluCl) had been identified as the primary molecular targets of fipronil, , and the mutations at 2′ and 6′ positions of the GABAR subunit of resistance to dieldrin (RDL) were associated with fipronil resistance. − However, our bioassay results verified there was no cross-resistance between 5a and fipronil (Table ), which implied that 5a molecularly targets P.…”

Imidazolone as an Amide Bioisostere in the Development of β-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors

“…The amide functionality is of great interest to medicinal chemists and is ubiquitously seen in peptides and nonpeptidic small molecules due to its ability to participate in hydrogen-bonding interactions with protein residues. Replacing it with a variety of bioisosteres provides a rewarding strategy in lead optimization as the amide bond often suffers from metabolic instability and results in physicochemical and pharmacokinetic complications such as poor solubility or permeability. , There are a number of reports exploiting 3-aminooxetane, fluoroalkene, − CF 3 -ethylamine, and sulfonamide among other functional groups to replace amide scaffolds in the medicinal chemistry literature (Figure ). Perhaps heterocycles represent the most appreciated and frequently employed amide bioisosteres. − Heterocyclic groups are highly diverse in terms of the ring size and heteroatom spatial distribution, with aromatic heterocycles most often exemplified.…”

“…Replacing it with a variety of bioisosteres provides a rewarding strategy in lead optimization as the amide bond often suffers from metabolic instability and results in physicochemical and pharmacokinetic complications such as poor solubility or permeability. 5,6 There are a number of reports exploiting 3-aminooxetane, 7 fluoroalkene, 8−10 CF 3 -ethylamine, 11 and sulfonamide 12 among other functional groups to replace amide scaffolds in the medicinal chemistry literature (Figure 1). Perhaps heterocycles represent the most appreciated and frequently employed amide bioisosteres.…”