Synthesis and Biological Activities of Pyrazino[1,2- a]indole and Pyrazino[1,2- a]indol-1-one Derivatives

Abstract

This review concerns the synthesis and biological activities of pyrazino[1,2-a]indoles and pyrazino[1,2-a]indol-1-ones reported since 1997 and the discovery of biological activity of pyrazinoindole derivatives. In the first part, we first presented the synthetic routes that have been reported from a methodological point of view to access the pyrazinoindole unit according to cyclization reactions using or not using metal catalysts. Then, syntheses and neuropsychiatric, auto-immune, anti-infectious and anti-cancer properties of pyrazinoindoles were detailed. In the second part, we first reported the main accesses to pyrazinoindol-1-one substrates according to Michael reactions, metal-catalyzed and metal-free cyclization reactions. The syntheses and anti-cancer, anti-infectious, anti-allergenic and neuropsychiatric properties of pyrazinoindolones were next described and discussed.

Keywords: biological activity; catalysis; cyclization; pyrazinoindole; pyrazinoindolone.

Figure 1

Targets of this review and selection of biologically active tetrahydro-pyrazino[1,2-a]indoles 1a, 2a and dihydro-pyrazino[1,2-a]indol-1-ones 3a, 4a.

Scheme 1

Synthesis of pyrazinoindoles.

Scheme 2

Synthesis of 1,2,3,4-tetrahydro-pyrazinoindoles.

Scheme 3

Synthesis of tetrahydro-pyrazinoindoles 36 and their binding data at the 5HT_2C receptor subtype.

Figure 2

Tetrahydro-pyrazinoindoles 37 and their binding data at I₂ and α-adrenergic receptors.

Scheme 4

Synthesis of tetrahydro-pyrazinoindoles 1 and 39.

Scheme 5

Synthesis of tetrahydro-pyrazinoindole 41 and human S1P₁ cAMP EC₅₀ values of derivatives 42a–d.

Scheme 6

Synthesis of tetrahydro-pyrazinoindoles 2, 46a–c and effect in cAMP assay in hA₁CHO cells.

Scheme 7

Synthesis and anti-cancer properties of a selection of pyrazinoindoles 49a–c.

Scheme 8

Synthesis of pyrazinoindoles 51 and their IC₅₀ values against three human cancer cell lines.

Scheme 9

Synthesis of pyrazinoindolones 54a,b.

Scheme 10

Synthesis of pyrazinoindolones 61 and selected examples.

Scheme 11

Synthesis of pyrazinoindolones 63 and selected examples.

Scheme 12

Synthesis of pyrazinoindolones 65 and 66 and selected examples.

Scheme 13

Synthesis of pyrazinoindolones 68 and selected examples.

Scheme 14

Synthesis of pyrazinoindolones 70 and selected examples.

Scheme 15

Synthesis of pyrazinoindolones 73 and selected examples.

Scheme 16

Synthesis of optically active pyrazinoindolones 34a,b.

Scheme 17

Synthesis of pyrazinoindolone 78a–d.

Scheme 18

Synthesis of pyrazinoindolones 80 and selected examples.

Scheme 19

Synthesis of pyrazinoindolones 83 as MAPK2 inhibitors.

Scheme 20

Synthesis and evaluation of pyrazinoindolones 85 as anti-cancer agents.

Scheme 21

Synthesis and evaluation of optically active 3-substituted pyrazinoindolones 88.

Scheme 22

Synthesis and evaluation of optically active pyrazinoindolone 48.

Scheme 23

Synthesis and cytotoxic properties of symmetrical and unsymmetrical diketopiperazines 95 and 95.

Scheme 24

Secondary metabolites 96–98 from the marine fungus Neosartorya pseudofischeri.

Scheme 25

Synthesis and evaluation of a selection of hydroxyimides 102 as antiviral compounds.

Scheme 26

Synthesis of a dengue inhibitor 3.

Scheme 27

Synthesis of 108a,b as 5-HT_1A and 5-HT₂ ligands.

Scheme 28

Synthesis of pyrazinoindolones 4, 112, and affinity over histamine H3 receptor subtype.

Figure 3

Overview of tetrahydro-pyrazino[1,2-a]indoles having biological properties.

Figure 4

Overview of pyrazino[1,2-a]indol-1-ones having biological properties.