The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review

Abstract

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

Keywords: benzoylpiperidine; benzoylpiperidine-based small molecules; bioisostere; diagnostic agents; drug design; medicinal chemistry; phenyl(piperidin-4-yl)methanone; privileged structure; therapeutic agents.

Figure 1

The benzoylpiperidine fragment (phenyl(piperdin-4-yl)methanone, in the red square) and the structures of two representative 5-HT_2A antagonists, ketanserin (1) and altanserin (2), with the benzoylpiperidine fragment highlighted in red.

Figure 2

General classification of benzoylpiperidine-based small molecules as therapeutics and diagnostics.

Figure 3

Percentages of therapeutic and diagnostic benzoylpiperidine-based molecules herein reported.

Figure 4

Main commercially available precursors for the synthesis of the benzoylpiperidine fragment (highlighted in red). Reagents and conditions: (a) nucleophilic substitutions with tosylates, N-alkylations with alkylhalides, or amidic condensations with carboxylic acids; (b) Ac₂O, pyridine, 140 °C, 2 h; (c) i. SOCl₂, dry 1,2-DCE. Sixty °C, 4 h, ii. properly substituted aromatic system, AlCl₃, dry 1,2-DCE, 90 °C, overnight; (d) (Boc)₂O, 1N NaOH, 1,4-dioxane, acetonitrile, H₂O; (e) N,O-dimethylhydroxylamine hydrochloride, HBTU, DIPEA, DMF; (f) aromatic organometallic reagent such as a Grignard reagent or organolithium reagent; (g) Et₃N, BzCl, dry DCM, rt, 20 h; (h) NaOH, aqueous EtOH (70%), rt, 18 h; (i) i. (COCl)₂, dry DCM, rt, 15 h; ii. bromobenzene, AlCl₃, 90 °C, 6.5 h; (j) PCC, CH₂Cl₂; (k) ArMgBr or ArLi, THF; (l) Dess-Martin periodinane; (m) 4N HCl in 1,4-dioxane.

Figure 5

Benzoylpiperidine-based reversible MAGL inhibitors (the benzoylpiperidine fragment is highlighted in red, the benzoyl moiety is in the magenta dashed square and the phenylamidic moiety is in the blue dashed square).

Figure 6

Design and structure of Tankyrases inhibitors as potential anti-cancer agents. IC₅₀ values were evaluated in the HEK293 SuperTopFlash (STF) reporter gene assay. The benzoylpiperidine fragment is highlighted in red.

Figure 7

Structure of 29 Complex I inhibitor (benzoylpiperidine highlighted in red).

Figure 8

Structure of compounds 30–33 developed by Guillaumet et al. [33] possessing a benzoylpiperidine fragment (in red).

Figure 9

Structure of the 5-HT_2A ligands 36,37 possessing a benzoylpiperidine fragment (in red).

Figure 10

Optimization of 5-HT_2A ligands 35 and 43 and structure of compounds 44–46. Benzoylpiperidine fragment is highlighted in red.

Figure 11

Structure of the 5-HT_2A ligand 52 possessing a benzoylpiperidine fragment (in red).

Figure 12

Structure of the 5-HT_2A selective antagonists 2, (+)-54, 53, and the developed ligand 55 possessing a benzoylpiperidine fragment (in red).

Figure 13

Structure of the 5-HT_2A dimeric ligands 56–62 possessing a benzoylpiperidine fragment (in red).

Figure 14

Structure of the dual 5-HT₇^/5-HT_2A ligands 63,64 possessing a benzoylpiperidine fragment (in red).

Figure 15

Design and structure of 5-HT_2A/mGlu₂ dimeric ligands 66–72 possessing a benzoylpiperidine fragment (in red).

Figure 16

Structure of 73, general structure 74, and GlyT1 inhibitor 75 possessing a substituted benzoylpiperidine fragment (in red).

Figure 17

Structure of the most active σ₁ inhibitor 76 developed by Wang et al. [18], possessing a benzoylpiperidine fragment (in red).

Figure 18

Design and structure of σ₁ inhibitor 78 developed by Prof. Efange’s research group possessing a benzoylpiperidine fragment (in red). The common fundamental chemical features of compounds 77 and 78 are highlighted in magenta, blue and green dashed squares.

Figure 19

Design and structure of Donezepil (79) and the AChEI 80 possessing a benzoylpiperidine fragment (in red).

Figure 20

Structure of compound 81 and of neuroprotective agents 82–84 possessing a benzoylpiperidine fragment (in red). Percentage refers to cell viability when compounds are tested at a 0.1 µM concentration.

Figure 21

Structure of Mtb inhibitors 85, 86. The benzoylpiperidine fragment is highlighted in red.

Figure 22

General structure of nitroimidazopyridazine antiparasitics 87 and structure of 88 (benzoylpiperidine fragment in red).

Figure 23

Structure of the most active SCD-1 inhibitor 89 developed by the research group of Ohsumi, possessing a benzoylpiperidine fragment (in red).

Figure 24

Structures of AMPK activators 90–91b. EC₅₀ values refer to AMPK activation in HepG2 cells. The benzoylpiperidine fragment is highlighted in red.

Figure 25

hERG K⁺ ligands possessing a benzoylpiperidine fragment (in red).

Figure 26

Structure of the most representative factor Xa inhibitors 98 and 99 identified by Jones et al. [26,135] possessing a benzoylpiperidine fragment (in red).

Figure 27

Structure of the most representative β2-adrenoceptor ligand 100 identified by Tasler et al. [141], possessing a benzoylpiperidine fragment (in red). ^a hβ2-adrenergic affinity in binding assays. ^b hβ2-adrenergic antagonistic effect in functional assays.

Figure 28

Structures of the VAChT ligands as PET radiotracers identified by Tu et al. [51] possessing a benzoylpiperidine fragment (in red). * K_i value refers to the minus isomer.

Figure 29

Structure of benzoylpiperidine (fragment highlighted in red) VAChT ligands as a diagnostic developed by Barthel et al. [27].

Figure 30

Structures of the 5-HT_2A ligand Setoperone (120). The benzoylpiperidine fragment is highlighted in red.

Figure 31

Structures of the benzoylpiperidines 121–128 identified by Fu et al. [28] as 5-HT_2A ligands for PET or SPECT brain imaging. The benzoylpiperidine fragment is highlighted in red.