Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

Abstract

The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp³-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring-a phenomenon called "pseudorotation". In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure-activity relationship (SAR) of the studied compounds. To aid the reader's approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

Keywords: Anti-inflammatory and analgesic agents; Anticancer and antibacterial agents; Antidiabetics; Central nervous system diseases; Pyrrolidine.

Fig. 1

Comparison of the three-dimensional (3D) shape of the non-aromatic pyrrolidine and cyclopentane rings with the aromatic pyrrole ring. Bond angles, bond lengths, and MMFF94 values were calculated using LigandScout software version 4.4 Expert

Fig. 2

Representative structures of natural alkaloids 1–5

Fig. 3

Exo and endo conformers of trans- and cis-4-fluoroproline 6 and 7, respectively; trans/cis-4-fluoroproline 8 resulting from the superimposition of structures 6 and 7

Fig. 4

Stereospecific pyrrolidine derivatives (R,R)-9, (S,S)-9, 11a,b, 12a,b, 13a,b, and 14

Fig. 5

Structures of retinoic acid-related orphan receptor γ (RORγt) ligands 15 and its RORγt binding conformation (top right) [40] as well as 16

Fig. 6.

1,3-Dipolar cycloadditions to stereoselectively obtain pyrrolidine derivatives

Fig. 7

General synthetic scheme to benzimidazole carboxamides 19a–p. R substituents and poly(adenosine 5′-diphosphate (ADP)-ribose) polymerase (PARPs) inhibition assay of compounds 19a–p. PARP-1 and -2 inhibition (%) were evaluated at 10 nM. Reagents and conditions: a trifluoroacetic acid (TFA), dichloromethane (DCM), 17 h, room temperature (r.t.), yield: 96%

Fig. 8

General synthetic scheme to pyrrolidine sulfonamides 23a–ad. ER Efflux ratio values. K_i values towards hGLYT1 [46]. Reagents and conditions: a TFA (catalyst), DCM, r.t., overnight

Fig. 8

General synthetic scheme to pyrrolidine sulfonamides 23a–ad. ER Efflux ratio values. K_i values towards hGLYT1 [46]. Reagents and conditions: a TFA (catalyst), DCM, r.t., overnight

Fig. 9.

1,3-Dipolar cycloadditions to yield 4-benzylpyrrolidine-3-carboxylic acids 25 and 26, synthesis of cholesterol-conjugated spiro-pyrrolidine/pyrrolizines 28–30, and 3D/2D interaction diagrams of compound 28 with the active site of target receptor protein 1XFF [48]. Reagents and conditions: a TFA (1 M solution in DCM); b isopropyl alcohol (iPrOH), 2 h, under reflux, yields: 76% (28), 67% (29), 63% (30)

Fig. 10.

1,3-Dipolar cycloadditions to yield phenyl/thiophene dispiro indenoquinoxaline pyrrolidine quinolone derivatives 36a–f and 37a–f. Reagents and conditions: a MeOH, under reflux, 2–3 h, yields: 92–98% (36a–f) and 93–96% (37a–f)

Fig. 11

General synthetic scheme to spiro[pyrrolidine-3,3′-oxindoles] 38a–n. Reagents and conditions: a ArCHO, NBS, water/tetrahydrofuran (THF), TFA (cat), 0 °C to r.t., yields: 45–94%

Fig. 12

Blue panel Synthesis of diastereoisomers 41a,b and 42 obtained by reaction of 5,6-O-isopropylidene-d-xylo-hexos-4-ulose 39 with benzylamine hydrochloride and l-phenylalanine methyl ester hydrochloride, respectively. Yellow panel Synthesis of final compounds 43a,b, 44a,b, 45, 46 and 47a,b. Reagents and conditions: a sodium cyanoborohydride (NaBH₃CN), methanol (MeOH); 60 °C, 24–48 h, yields: 37% (41a,b), 44% (42)

Fig. 13

General synthetic scheme to pyrrolidines 51a–f. Reagents and conditions: a sodium triacetoxyborohydride [NaBH(OAc)₃], DCM, − 70 °C to r.t., overnight, yields: 21–45%

Fig. 14

General synthetic schemes to polyhydroxylated pyrrolidines 54 and pyrrolidone 57. Reagents and conditions: a (1) O₃, MeOH, − 78 °C, 40 min; (2) DMS, 40 min, − 78 °C to r.t., not isolated; b [Zn(BH₄)₂], MeOH or DCM, − 20 °C, 2 h, yield: 74%; c TFA (2 equiv), DCM, 1 h, yield: 74%; d TBSCl, imidazole, DMF, 20 h, r.t., yield: 74%; e BH₃. DMS, THF, 4 h, r.t., yield: 60%; f tetra-n-butylammonium fluoride (TBAF), THF, 12 h, r.t., yield: 99%. g triethylamine (TEA), 1,4-dioxane, 5 h, under reflux, yield: 77%

Fig. 15

General synthetic routes to pyrrolidine-2,5-diones 59a–p, 62a–g, and 63a–h. Reagents and conditions: a 180 °C, 1.5 h., yields: 60–82% (59a–p), 70% (61), 54–86 (62a–g)

Fig. 16

General synthetic routes to pyrrolidine-2,5-diones 66a–m and 69a–p. Reagents and conditions: a 180 °C, 1 h, yields: 68% (65), 70% (68, R, R¹ = phenyl), 36% (68, R = methyl, R¹ = ethyl)

Fig. 17

General synthesis of pyrrolidine-2,5-diones 71a–g and 74a–e. Reagents and conditions: a SOCl₂, under reflux, 5–8 h, yields: 83–96%; b OtBU-l-threonine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), chloroform (CHCl₃), r.t., yields: 51.3–63.2%

Fig. 18

General synthetic scheme to pyrrolizine carboxamide derivatives 77–84. Reagents and conditions: a K₂CO₃, acetone, under reflux, 24 h, yields: 68% (77)

Fig. 19

Molecular structures of pyrrolidinyl-carbazole derivatives 85a–p, pyrrolidine-2-carbonitriles 86a–d, Mcl-1 inhibitor 87, and pyrrolidine-1-carboxylates 88a–p

Fig. 20

Molecular structures of pyroglutamic acid derivatives 89a–e and 90 and N-(2′-nitrophenyl)pyrrolidine-2-carboxamides 91a–k

Fig. 21

Molecular structures of pyrrolidine derivatives 92a,b, Schiff bases 93a–o and their reduced counterparts 94a-o, benzenesulfonylpyrrolidines 95a–d, and pyrrolidine-based 3-deoxysphingomyelins 96, 97a,b, 98, 99a,b

Fig. 22

Molecular structures of hybrid benzofuroxan-based pyrrolidine hydroxamates 100a,b and 101a,b, pyrrolidine benzonitriles 102a–c, hybrid pyrrolidine derivatives 103, 104a,b, 105, 106, and pyrrolidine amides 107, 108, 109a,b, 110, 111

Fig. 23

Molecular structures of triazine-pyrrolidine-2-thiones 112a,b and pyrrolidin-2-ones 113a,b, pyrrolidin-2-ones 114a–e, and pyrrolidin-2-ones 115a–o

Fig. 24

Molecular structures of hybrid pyrrolidine-2,5-diones 116a–m, 2-(hydroxymethyl)pyrrolidines 117 and 118, pyrrolidine phosphonates 119,120a,b, and phosphoramidate prodrugs 121,122a,b