A review on recent developments of indole-containing antiviral agents

Abstract

Indole represents one of the most important privileged scaffolds in drug discovery. Indole derivatives have the unique property of mimicking the structure of peptides and to bind reversibly to enzymes, which provide tremendous opportunities to discover novel drugs with different modes of action. There are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. There are also an amazing number of approved indole-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. This review focused on the recent development of indole derivatives as antiviral agents with the following objectives: 1) To present one of the most comprehensive listings of indole antiviral agents, drugs on market or compounds in clinical trials; 2) To focus on recent developments of indole compounds (including natural products) and their antiviral activities, summarize the structure property, hoping to inspire new and even more creative approaches; 3) To offer perspectives on how indole scaffolds as a privileged structure might be exploited in the future.

Keywords: Antiviral activity; Entry and fusion inhibitor; Indole; Integrase inhibitor; Natural product; Polymerase inhibitor; Protease inhibitor; Reverse transcriptase inhibitor.

Graphical abstract

Fig. 1

Structures of indole-containing natural products and drugs.

Fig. 2

Structures of indole-containing commercial and on-study antiviral drugs.

Fig. 3

Optimization route of macrocyclic indole from MK-3281 to TMC647055.

Fig. 4

Structures of Arbidol derivatives.

Fig. 5

Optimization route for BMS-378806.

Fig. 6

Indole-containing inhibitors employed in 3D QSAR study.

Fig. 7

Indole-containing structures with gp41-binding activity.

Fig. 8

Optimization route of Sulfonylindolecarboxamide as NNRTI.

Fig. 9

Optimization route of novel IAS derivatives as NNRTIs.

Fig. 10

Optimization route of novel 3-indole sulfonamides as potent NNRTIs.

Fig. 11

Structures of indole-containing NNRTIs.

Fig. 12

Optimization route of novel IAS derivatives as NNRTIs.

Fig. 13

Chiral IAS derivatives as NNRTIs.

Fig. 14

Novel IAS derivatives as NNRTIs.

Fig. 15

Optimization and binding of IAS derivatives as NNRTIs.

Fig. 16

Cyclopropyl indole derivatives as NNRTIs.

Fig. 17

Cyanovinyl (CV) indole derivatives as NNRTIs.

Fig. 18

Chiral indole-based trifluoropropanoates as NNRTIs.

Fig. 19

Butterfly-shaped indole compounds as NNRTIs.

Fig. 20

N-arylindoles as integrase inhibitors.

Fig. 21

Diketo acid (DKA) derivatives as integrase inhibitors.

Fig. 22

Optimization of DKA derivatives as integrase inhibitors.

Fig. 23

Rational modifications of DKA derivatives as integrase inhibitors.

Fig. 24

Magnesium(II) complexes of DKA derivatives as novel integrase inhibitors.

Fig. 25

DKA derivatives as dual integrase inhibitors.

Fig. 26

Non-peptidyl DKA derivatives as integrase inhibitors.

Fig. 27

Indole-carboxylate molecules as Protease (PR) inhibitors.

Fig. 28

Novel indole-based derivatives as protease inhibitors.

Fig. 29

Compounds with indole scaffolds as polymerase inhibitors.

Fig. 30

Indole-N-acetamides as polymerase inhibitors.

Fig. 31

Structures of antiviral Sattazolin, Drymaritin and Caulerpin.

Fig. 32

Structures of antiviral indole alkaloids from root of Isatis indigotica.

Fig. 33

Structures of antiviral Harmaline, Dragmacidin and Dragmacidin F.

Fig. 34

Structures of antiviral Coscinamides and Chlondriamides.

Fig. 35

Structures of antiviral Trigonoliimines.

Fig. 36

Structures of antiviral pentacyclic indolocarbazoles.

Fig. 37

Structures of antiviral indole alkaloids from Cladosporium sp. PJX-41.

Fig. 38

Structures of antiviral Eudistomins, Topsentin and Bromotopsentin.

Fig. 39

Structures of CPI-2081a and CPI-2081b.