Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

Abstract

Spirooxindoles occupy an important place in heterocyclic chemistry. Many natural spirooxindole-containing compounds have been identified as bio-promising agents. Synthetic analogs have also been synthesized utilizing different pathways. The present article summarizes the recent development of both natural and synthetic spirooxindole-containing compounds prepared from isatin or its derivatives reported in the last five years. The spirooxindoles are categorized based on their mentioned biological properties.

Keywords: alkaloids; biological properties; natural product; spirooxindole; synthesis.

Figure 1

Natural C-2 and C-3 spiroindole-containing compounds.

Figure 2

Cipargamin (NITD609), MI-888, MI-219 and SOID-6 representatives of potent biologically active spirooxindoles.

Figure 3

Flueindoline C 1 isolated from the ripe fruits of Flueggea virosa and spiroindoles 2, 3 from Datura metel L. seeds.

Figure 4

Spirooxindole alkaloids 4–7 isolated from the leaves of Malaysian Mitragyna speciosa (Kratom).

Figure 5

Spirooxindoles (2S,3S)-javaniside 8, naucleoxoside A 9, and naucleoxoside B 10 isolated from the stem of Nauclea officinalis.

Figure 6

Monoterpenoid indoles 11–14 isolated from the leaves and stems of Gardneria multiflora.

Figure 7

Spirooxindoles 15–19 isolated from the marine fungus Penicillium janthinellum HK1–6.

Scheme 1

Synthesis of 3-spirocyclopropyl-2-oxindoles 21.

Scheme 2

Synthesis of spiro[indoline-3,4’-pyrans] 27 and 28.

Scheme 3

Synthesis of spiro[indoline-3,2’-[1,3,4]oxadiazols] 30.

Scheme 4

Synthesis of spiro-β-lactam-oxindoles 31.

Scheme 5

Synthesis of spiro[indoline-3,3’-pyrazoline]-2-ones 33 and spiro[indoline-3,4’-pyrimidin]-2-ones 34.

Scheme 6

Synthesis of spiro[indoline-3,4’-pyrimidin]-2-ones 34.

Scheme 7

Synthesis of spiro[indoline-3,3’-pyrrolidines] 40–42.

Scheme 8

Synthesis of spirooxindolopyrrolidines 47 and 48.

Scheme 9

Synthesis of spiro[indoline-3,4’-[1,3]dithiines] 50.

Scheme 10

Synthesis of spiro[indoline-3,2’-thiazolidine]-2,4’-dione 52.

Scheme 11

Synthesis of spiro[indoline-3,2’-thiazolidines] 54.

Scheme 12

Synthesis of Isoniazid-spirooxindoles 56.

Scheme 13

Synthesis of dispiro[indoline-3,2’-pyrrolidine-3’,3″-piperidines] 58.

Scheme 14

Synthesis of spiro[[ 1,2,3]triazolo[4,5-b]pyridine-7,3’-indolines] 60.

Figure 8

MDM2-p53 inhibitors entered in human clinical trials.

Scheme 15

Synthesis of spirooxindole derivative 63.

Scheme 16

Synthesis of spiropyrazoline-oxindole 66 and 67.

Scheme 17

Synthesis of spirooxindoles 69.

Scheme 18

Synthesis of spirooxindoles 70.

Scheme 19

Synthesis of nitroisoxazole-containing spirooxindoles 71.

Scheme 20

Synthesis of dispirooxindoles 73.

Scheme 21

Synthesis of spiro[indoline-3,2′-naphthalenes] 74.

Scheme 22

Synthesis of spirooxindoles 77.

Scheme 23

Synthesis of spiro[chroman-2,3’-indoline] 78 and spiro[indoline-3,3’-pyrazols] 81.

Scheme 24

Synthesis of spiroindole-pyrrolidines 82.

Scheme 25

Synthesis of spiro[indole-3,5′-isoxazoles] 84.

Scheme 26

Synthesis of spiroindoles 86 and 3,3′-bis(1H-indole)methanes 87.

Scheme 27

Synthesis of spiro[indoline -3,2′-pyrrolidins] 89.

Scheme 28

Synthesis of thiazolo-pyrrolidine-spirooxoindoles 91.

Scheme 29

Synthesis of spirooxindole-pyrrolo-carbazole 93.

Scheme 30

Synthesis of spiro[indoline-pyrrolizin]-ones 95.

Scheme 31

Synthesis of spirooxindoles 97.

Scheme 32

Synthesis of spirocyclopropaneoxindoles 99.

Scheme 33

Synthesis of spiro[chromeno[4,3-b]chromene-7,3′-indolines] 100 and spiro[indeno[2′,1′:5,6]pyrano[3,2-c]chromene-7,3′-indolines] 101.

Scheme 34

Synthesis of spiro[acridine-9,3′-indolines]-1,2′,8-triones 102.

Scheme 35

Synthesis of spirooxindoles 104, 105, and 106.

Scheme 36

Synthesis of spiro[indoline-2,5′-[4′,5′]dihydrothiazoles] 109.

Scheme 37

Synthesis of spirooxindoles 113.

Scheme 38

Synthesis of spiro[indoline-3,3′-pyrrolidines] 114.

Figure 9

Artemisinin, antimalarial drug.

Scheme 39

Synthesis of spiro[indoline-3,2′- [1,3,4]oxadiazol]-2-ones 117.

Scheme 40

Synthesis of Spiro[indoline-3,2′-quinolins] 121 and spiro[indoline-3,5′-pyrano[3,2-c]quinolins] 122.

Scheme 41

Synthesis of spirooxindoles 124a, 124b.

Scheme 42

Synthesis of Spirooxindoles 126.

Scheme 43

Synthesis of spirooxindoles 129 and 130.

Scheme 44

Synthesis of spirooxindoles 130.

Figure 10

Spiro[indoline-3,2′-quinolins] 121 of promising anti-leishmanial properties.

Scheme 45

Synthesis of spirooxindoles 131.