Chemistry of trisindolines: natural occurrence, synthesis and bioactivity

First Ambar Wati ^a, Mardi Santoso *^a, Ziad Moussa *^b, Sri Fatmawati ^a, Arif Fadlan ^a and Zaher M. A. Judeh *^c
aDepartment of Chemistry, Institut Teknologi Sepuluh Nopember, Kampus ITS, Sukolilo, Surabaya, 60111, Indonesia
^bDepartment of Chemistry, College of Science, United Arab Emirates University, P. O. Box 15551, Al Ain, United Arab Emirates
^cSchool of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, N1.2–B1-14, Singapore, 637459, Singapore. E-mail: Zaher@ntu.edu.sg

First published on 21st July 2021

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First Ambar Wati

First Ambar Wati is a doctoral student in the Department of Chemistry, Institut Teknologi Sepuluh Nopember (ITS), Surabaya, Indonesia. She completed her undergraduate study in Chemistry at the same institute in 2016. Her research interests include organic synthesis and medicinal chemistry. Currently, she is screening several natural products as antidiabetic, anticancer, and antitubercular candidates at the laboratory of Natural Product and Synthetic Chemistry (NPSC) at ITS.

Mardi Santoso

Dr. Mardi Santoso undertook undergraduate program in chemistry at Institut Teknologi Sepuluh Nopember, Indonesia; and master leading to PhD program in organic chemistry, School of Chemistry, The University of New South Wales, Australia. He worked for one year as a Postdoctoral Research Fellow at unit for organic chemistry, Department of Biosciences at Novum, Karolinska Institute, Sweden. Dr Mardi is currently a Professor of Organic Chemistry at Institut Teknologi Sepuluh Nopember. His main research interests include organic synthesis, essential oils, and plant extracts.

Ziad Moussa

Dr. Ziad Moussa undertook undergraduate and postgraduate studies in chemistry at the University of Calgary (BSc 1998, PhD 2003). His PhD research was conducted under the supervision of Professor Thomas Back and focused on the synthesis and evaluation of some novel selenium-based chiral auxiliaries and glutathione peroxidase mimetics. Following postdoctoral research at Texas A&M University (2003–2006) in the laboratories of Professor Daniel Romo, Ziad joined the department of chemistry at Taibah University as an Assistant Professor (2006–2018). Currently, he is an Associate Professor of organic chemistry at United Arab Emirates University (UAEU). His main research interests include the development of synthetic methodologies and the synthesis and characterization of novel bioactive organic and heterocyclic molecules.

Sri Fatmawati

Dr. Sri Fatmawati is an Assistant Professor in the Department of Chemistry, Institut Teknologi Sepuluh Nopember (ITS), Indonesia. She received her BS in Chemistry from ITS (2002). Both MSc and PhD in Bioresources and Bioenvironmental Sciences were obtained from Kyushu University, Japan (2006 and 2011). She performed postdoctoral studies at the Kyushu University, Japan (2012–2013) and LEMAR, IUEM, Brest France (2015–2016). Her research group develops new drug candidates from natural products. Her group also develops compounds of medicinal value and study the mechanism of action of drug molecules.

Arif Fadlan

Dr. Arif Fadlan is an Assistant Professor in the Department of Chemistry, Institut Teknologi Sepuluh Nopember (ITS) Surabaya, Indonesia. He obtained his BS and MS degree from ITS, and his DSc (Materials Science) (2018) degree from Nara Institute of Science and Technology (NAIST), Japan. His current research interests include small molecule and sugar-modified active compounds, essential oils, and pharmacology properties of neglected but promising-plant extracts.

Zaher M. A. Judeh

Dr. Zaher Judeh undertook his undergraduate studies in chemistry at the University of Pune (BSc 1992), and completed his postgraduate studies at the University of Mumbai (MSc 1994) in India and the University of New South Wales (PhD 2000), Australia. Dr Zaher is an Associate Professor of organic chemistry at Nanyang Technological University and has been there since 2004. His main research interests include the development of synthetic methodologies and the total synthesis of natural products.

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1. Introduction

Heterocyclic compounds are ubiquitous in nature and possess many bioactivities, making them targets for drug development, health supplements and as highly functional materials. According to the Food and Drug Administration (FDA), 59% of the drug molecules are heterocyclic compounds containing at least one nitrogen atom.¹ One such compound is the indole 1 (Fig. 1) scaffold with a bicyclic structure incorporating a benzene ring fused to a pyrrole ring.² It is among the top ten nitrogen heterocyclic scaffolds used for constructing drug molecules.¹ Examples of indole-based drugs include indomethacin, indoxole, and pindolol. Several good reviews covering the chemistry and bioactivity of indoles have been published.^3–5

Trisindolines are compounds containing two indole units connected to the 1H-indol-2,3-dione 2 (also known as isatin) unit either at its C-3 position to form 3,3-di(3-indolyl)-2-indolone 3 or at its C-2 position to form a 2,2-di(3-indolyl)-3-indolone 4 regioisomeric structure (Fig. 1). Since their first discovery,⁶ trisindolines have attracted considerable attention due to their wide biological activities including anticancer,^7–9 antimicrobial,¹⁰ antimycobacterial,¹¹ antifungal,¹⁰ anticonvulsant,¹⁰ α-glucosidase inhibition,¹² and spermicidal¹³ activities. The 3,3-di(3-indolyl)-2-indolone 3 isomer is far more interesting than the 2,2-di(3-indolyl)-3-indolone 4 isomer due to its higher potency and potential as a drug lead compound.⁶ It is worth noting that the widely occurring 1H-indol-2,3-dione 2 (isatin) framework is an indole ring bearing two carbonyl groups at C-2 and C-3 (Fig. 1).^14,15 Isatin forms a core structure of several biologically active molecules and commercial drugs including Sunitinib, Nintedanib, and Semaxanib.^15,16 The chemistry and bioactivity of isatins have also been covered in several reviews.^15,17

To date, no reviews have been published about trisindolines. Hence, this comprehensive review covers the period of 1980–2020 and focuses on the natural occurrence, synthesis, and bioactivities of trisindolines. It highlights the scope, advantages, and limitations of various syntheses of trisindolines. It gives a comprehensive account of the activities reported for trisindolines with a special focus on the structure–activity relationship (SAR) where possible. The review is also meant to be a one-stop reference work for researchers interested in the development of trisindolines as lead drug candidates. Since trisindolines have two isomeric structures, 3,3-di(3-indolyl)-2-indolone 3, and 2,2-di(3-indolyl)-3-indolone 4, we will limit our discussion to the more common and more biologically active 3,3-di(3-indolyl)-2-indolone 3.

2. Natural occurrence of trisindolines

Trisindolines were isolated from several natural sources including bacteria, sponges and plants. Trisindoline 3 was firstly isolated from cultured marine bacterium Vibrio sp. obtained from the Okinawan marine sponge Hyrtios altum.⁶ Trisindolines 3 and 4 were also isolated from the marine sponge Discodermia calyx.¹⁸ Aeromonas sp., a marine-derived bacterium strain CB101, afforded trisindolines 3 and 4 from its ethyl acetate extract.¹⁹ Veluri et al. (2003) isolated trisindoline 3 and 4 from the ethyl acetate extracts of cultured Vibrio parahaemolyticus Bio249's mycelium.²⁰ Trisindoline 4 was also isolated from the marine bacterium Vibrio parahaemolyticus found in the mucus of stressed fish Ostracion cubicus species.²¹ Wang et al. (2014) also isolated trisindoline 3 from the ethyl acetate extract of the deep-sea bacterium Shewanella piezotolerans WP3.²² Trisindoline 3 and its analogues (5-bromo-3,3-di(1H-indol-3-yl)indolin-2-one 5 and 6-bromo-3,3-di(1H-indol-3-yl)indolin-2-one 6) were isolated from the red-sea sponge Callyspongia siphonella (Fig. 2).²³ Fractionation of the indigo metabolites obtained from the extracts of a recombinant E. coli gave trisindoline 3.⁹ Besides sponges and bacteria, the extracts from plant Isatis costata, Brassicaseae species, also afforded trisindoline 3.^24,25 These diverse natural sources gave small amounts of trisindolines. To investigate the bioactivities of trisindolines, practical synthetic routes were developed to obtain them in reasonable amounts and diversify their structures to test their structure–activity relationship (SAR).

3. Synthesis of trisindolines

Trisindolines were synthesized (vide infra) following several routes. Efficient synthesis of trisindolines depends on the catalyst used, reaction conditions and the reactivity of the indoles and isatins which primarily depends on the position and type (electron donating group or electron withdrawing group) of the substituents on these rings. Additionally, the NH substituents on indoles and isatins rings also impact the efficiency of the reaction. The following sections will highlight these synthetic routes in detail.

The synthetic routes based on acid-catalyzed reaction are the most researched and most efficient with respect to yield, selectivity and reaction time.¹³ Trisindolines have also been synthesized in protic solvents and in the complete absence of acid catalysts. Acid-catalyzed indolylation of isatin proceeds through a Friedel–Crafts electrophilic aromatic substitution mechanism. Although the indole itself undergoes faster electrophilic aromatic substitution than benzene, a catalyst is usually required for the indolylation to proceed and give reasonable yields.²⁶ The indolylation is made efficient by increasing the nucleophilicity of the indole ring via appropriately-positioned substituents and by acid-catalyzed activation of the C-3 carbonyl of isatin.²⁷. Mechanistically, the reaction involves two steps where 3-hydroxy-3-indolyl-2-indolone 7 is formed first and then is converted to 3,3-di(3-indolyl)-2-indolone 3 following the addition of a second equivalent of indole 1 (Scheme 1 and 2). Strong acid catalysts directly afford 3,3-diindolyl-2-oxindole 3.²⁶

The proposed general mechanism of acid-catalyzed formation of trisindoline 3 through reaction between isatin 2 and indole 1 is shown in Scheme 2. Formation of 3,3-di(3-indolyl)-2-indolone 3 proceeds through a pathway in which the C-3 position of isatin 2 is activated to give intermediate 8 which undergoes nucleophilic attack by the indole 1 to generate 9. Deprotonation of the tertiary alcohol 9 to 3-hydroxy-3-(1H-indol-3-yl)indolin-2-one 7 is followed by protonation to form 10. Dehydration of 10 generates α,β-unsaturated iminium ion 11 which is followed by addition of a second molecule of indole 1 and re-aromatization of 12, affording trisindoline 3.

Since many common symmetrical and unsymmetrical trisindolines have been prepared by different routes, we categorized them in Table 1 and 2 and assigned them numbers for easy reference throughout this review. In symmetrical trisindolines, the isatin unit bears the same indole moieties. However, in unsymmetrical trisindolines, the isatin unit bears different indole moieties.

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In the below sections, the grouping of the catalysts under different headings is not very strict and is meant for easy reference. This is because some catalysts can fall under several groupings.

3.1 Synthesis of trisindolines from isatin as a coupling partner

Trisindolines can be synthesized from several coupling partners, the most notable of which is indole 1 and isatin 2. Several reagents and catalysts that promote the coupling process are discussed in the next sub-sections.

3.2 Synthesis of trisindolines from isatin-imine as coupling partner

3.3 Synthesis of trisindolines from 3,3-dibromoxindole as coupling partner

Reaction of 3,3-dibromoxindole 215 with indole, catalyzed by silver carbonate at 25 °C for 1.5 h gave trisindoline 3 in 65% yield. Following the same procedure, reaction of 3,3-dibromoxindole 215 with other indoles gave the corresponding trisindolines 15, 172 and 173. 3,3-Dibromoxindole 215 was prepared in 72% yield by refluxing indoline-2-one 216 and copper(II) bromide in ethyl acetate for 3 h (Scheme 46).⁶

3.4 Synthesis of trisindolines from trimerization reactions of indoles

Tabatabaeian et al. (2009) synthesized trisindolines 3, 19, 88 and 167 in 65–80% yields by self-condensation reaction of indoles in the presence of hydrogen peroxide and RuCl₃·nH₂O (5 mol%) as catalyst in methanol at 50 °C within 80–150 minutes (Scheme 47). Deactivated indoles 5-cyanoindole and 5-bromoindole reacted slower and gave lower yields compared with activated (N-methylindole) and unsubstituted indoles. However, 3-methylindole and 2-methylindole were unreactive.⁸²

Trisindoline 3 was prepared by the reaction of indole in the presence of AgNO₃ (20 mol%), acid catalyst additive and TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical) as additive, in pyridine under open air at 65 °C for 48 h. For comparison, compound 3 was obtained in 45%, 56%, 23% yields respectively using methanesulfonic acid or p-toluenesulfonic acid or acetic acid as catalysts (Scheme 48).¹¹³

4. Bioactivity of trisindolines

4.1 Anticancer activity

Trisindoline 3 was reported to have anticancer activity against colorectal adenocarcinoma (HCT15) and uterine sarcoma (MES-SA). Trisindoline 3 displayed stronger toxicity against both multidrug resistant cell lines HCT15/CL02 and MES-SA/DX5 and exhibited IC₅₀ values of 5.11 ± 0.44 μM and 5.50 ± 0.53 μM, respectively, compared to etoposide which is used for treating ovarian and testicular cancers.⁹ Trisindoline 3 displayed IC₅₀ of 18.4 μM against A-549 cell lines (lung cancer cells) while its isomer, 2,2-di(3-indolyl)-3-indolone 4, was less potent with IC₅₀ value of 69.7 μM.¹⁹ In other research, trisindoline 3 showed stronger toxicity against A-549 cell lines with IC₅₀ values of 8.6 μM⁸ and 1.23 ± 0.030 μM.⁷ Trisindoline 3 was also investigated for its anticancer activity against SK-N-SH cell lines (neuroblastoma) and gave IC₅₀ of 11.3 μM⁸ and 0.90 ± 0.06 μM (IC₅₀ of doxorubicin as drug standard was 0.97 ± 0.03 μM).⁷ Furthermore, trisindoline 3 exhibited IC₅₀ value of 5.70 μg mL⁻¹ against HL-60 (human promyelocytic leukemia cell line) and 6.85 μg mL⁻¹ against Bel-7402 (human hepatocellular carcinoma cell line), and was more potent than indoles isolated from Shewanella piezotolerans (Table 5).²² Natural brominated trisindolines 5 and 6 showed promising activity against cancer cell lines HT-29 (human colon), OVCAR-3 (human ovarian), and MM.1S (multiple myeloma) (Fig. 8).²³

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Kamal et al. assayed the bioactivity of trisindolines 3, 15–17, 30, 32, 42, 60, 61, 101, 124 and 144–148 against lung cancer cell lines (A549), central nerve system cancer cell lines (SK-N-SH), breast cancer cell lines (MCF-7), liver cancer cell lines (Hep G-2), and prostate cancer cell lines (DU-145). Trisindolines 16 and 145 with methoxy substituent at C-5 and C-6 showed lower IC₅₀ of 2.2 μM and 1.2 μM, respectively, against DU-145. In comparison, trisindoline 15 with Br on C-5 gave IC₅₀ value of 3.6 μM. Trisindoline 146 showed high potency with IC₅₀ value of 7.5 μM against MCF-7 cancer cells. 5-Fluoro-3,3-di(1H-indol-3-yl)indolin-2-one 32 also showed anticancer potency against Hep G-2 while other analogues either showed higher IC₅₀ or were inactive. Trisindoline 101 showed the best IC₅₀ against SK-N-SH. In addition to its activity against DU-145, trisindoline 145 displayed IC₅₀ value of 7.8 μM against A549 cell lines, and this value was similar to the ones exhibited by trisindolines 146 and 124. Overall, the introduction of a methoxy moiety on the indole framework in any position positively enhanced the anticancer activity.⁸

Trisindolines 3, 15, 17, 22, 30, 31, 42, 54, 55, 86 and 106–110 were examined against MDA-MB 231 (breast), SK-N-SH (neuroblastoma), A549 (lung), and MRC-5 (normal human lung cell) cell lines. Trisindolines 31, 86, 108–110 with 5-chloroisatins were not potent against A549 and SK-N-SH. However, the combination of 5-chloroisatin with 5-bromoindole as in trisindoline 86 gave IC₅₀ of 1.04 μM against SK-N-SH cancer cell line. Isatins and indoles bearing electron withdrawing group (except 5-chloro) and/or with methyl on C-2 showed promising activity with IC₅₀ of 0.75–1.23 μM against lung cancer cells (A549) and 0.90–0.99 μM against neuroblastoma cancer cells (SK-N-SH). In the case of lung cancer, they have significantly lower IC₅₀ value compared to doxorubicin with IC₅₀ of 15.07 μM. However, doxorubicin possessed IC₅₀ of 0.97 μM towards neuroblastoma cancer cell lines. The combinations of isatins and indoles bearing EWG (except CO₂Me) or trisindolines with EWG (except halogen) on indoles and chloro on isatin, inhibited the viability of MDA-MB 231 cells and exhibited IC₅₀ value of 9.95–10.05 μM (IC₅₀ of doxorubicin is 8.14 μM). The introduction of 2-phenylindole decreased the activity against three cancer cell lines (MDA-MB 231, SK-N-SH, A549). Trisindolines 15 and 42 were potent during the inhibition of the above cancer cell lines. Interestingly, trisindolines 3, 15, 17, 22, 30, 31, 42, 54, 55, 86 and 106–110 were not toxic to the normal cell (MRC-5) although some were not active as anticancer agents.⁷ A simplified structure–activity relationship (SAR) of trisindolines toward anticancer activity can be seen in Fig. 9.

4.2 Antimicrobial activity

Trisindoline 3 showed antibacterial activity against E. coli, B. subtilis, S. aureus at 10 μg per disk with inhibition zone of 16, 17, and 10 mm respectively.⁶ Trisindoline 3, unlike its analogues, possessed better activity against Gram-negative bacteria compared to Gram-positive bacteria. Trisindolines 172 with 5-carboxylic acid indole and 173 with 4-hydroxyindole did not show any inhibitions while trisindoline 15 with 5-bromoindole exhibited weak activity (at the concentration of 30 μg per disk) against E. coli.⁶

Trisindoline 3 was found to have excellent antibacterial activity against B. cereus, displaying inhibition zone of 20 mm at 10 μg per paper.¹⁸ The antimicrobial activity of trisindoline 3 and N-benzyl-substituted trisindoline 25 was assayed by disc diffusion method using 6 mm paper discs. Compounds 3 and 25 were found to possess inhibition zones of 25 mm and 26 mm against B. subtilis respectively, while chloramphenicol and gentamycin (antibiotics) showed inhibition zones of 26 mm and 28 mm respectively. Trisindolines 5, 31 and 27 with halogen or nitro groups on the isatin moiety caused 11–18 mm inhibition zone, while trisindolines 17, 57 and 29 with methyl group on the nitrogen did not show inhibition zones. Compounds that were active against B. subtilis, also possessed antimicrobial activity against S. aureus, but with lower inhibition zone of 12–16 mm than that of gentamycin with 20 mm inhibition zone. All the substituted trisindolines 3, 5, 17, 25, 27, 29, 31 and 57 were not active against E. coli and P. aeruginosa.⁵⁹

Trisindolines 14 with 5-bromo and N-benzyl moieties on isatin showed promising antibacterial activity against S. aureus with inhibition zone of 23 mm and MIC of 1.25 μg mL⁻¹. Trisindoline 5 without the N-benzyl moiety on isatin and trisindoline 161 with 2-methyl on the indole unit exhibited lower activity with inhibition zones of 12 mm (MIC of 10 μg mL⁻¹) and 19 mm (MIC of 2.5 μg mL⁻¹), respectively. However, trisindolines 5, 14 and 161 were inactive against E. coli and P. aeruginosa.⁹⁵

Trisindolines 125–137 inhibited E. coli and S. aureus successfully. Trisindoline 135 with N-benzyl group in the isatin and N-propargyl group in indole rings emerged as the most active against E. coli with 17 mm inhibition zone as well as the most active against S. aureus with 15 mm inhibition zone. Trisindolines 125–134, 136 and 137 showed zone of inhibitions of 10–15 mm against E. coli and 10–15 mm against S. aureus. Trisindolines 129, 133 and 137 were the most potent with 15 mm inhibition zone against S. aureus. Under the same conditions, Amikacin exhibited 18- and 17 mm zone of inhibition for E. coli and S. aureus, respectively.¹⁰ The presence of substituents on the nitrogen of isatin or indole seems to contribute positively to the antibacterial activity against E. coli.

The antibacterial activity of trisindolines 5 and 6 was examined against S. aureus, B. subtilis, E. coli, and P. aeruginosa by disc diffusion method (Table 6).²³ Trisindoline 5 possessed wider inhibition zone against S. aureus (17.5 ± 0.8 mm) and B. subtilis (18 ± 0.1 mm) than trisindoline 6, and both were weaker than amikacin. However, trisindolines 5 and 6 showed better inhibition against S. aureus and B. subtilis than gentamicin. Trisindoline 5 with the 5-bromine on isatin is more potent than 6 having 6-bromine. However, both compounds were inactive against Gram-negative bacteria (E. coli, and P. aeruginosa).¹⁹ The structure–activity relationship (SAR) of the trisindolines as antibacterial agents is seen in Fig. 10.

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4.3 Antimycobacterial activity

The potency of trisindoline 3 and its analogues 13 and 14 as antitubercular agents was examined using the resazurin microtiter assay (REMA) method.¹¹ Trisindoline 3 was inactive (MIC > 25 μg mL⁻¹) while trisindolines 13 and 14 inhibited the growth of Mycobacterium tuberculosis H₃₇Rv with MIC values of 12.5 and <6.25 μg mL⁻¹, respectively. Rifampicin reference showed MIC of <6.25 μg mL⁻¹ under the same conditions.¹¹

4.4 Antifungal activity

Trisindolines 3, 5, 17, 25, 27, 29, 31 and 57 were found inactive against Candida albicans by the disc diffusion method.⁵⁹ Compounds 5, 14 and 161 were assayed in vitro using USP 29-NF25 cylinder plate assay against Candida albicans, and none of them were active as antifungal agents.⁹⁵ Surprisingly, trisindolines 125–137 displayed inhibitions against Candida albicans by cup plate method. Compounds 126 and 137 showed the best inhibition (15 mm zone of inhibition) while ketonazole as standard antifungal agent showed 16 mm inhibition zone. Other analogues 125 and 127–136 displayed 10–14 mm inhibition zone. The presence of methoxy group on C-5 of the indole increased the activity against Candida albicans.¹⁰ The inactivity of trisindolines to inhibit the growth of C. albicans was presumably caused by the absence of substituents on the nitrogen atom in either isatin or indole.

4.5 Anticonvulsant activity

A series of trisindolines 125–137 were tested in vivo to examine their anticonvulsant activity by observing seizure in rat.¹⁰ All the tested compounds 125–137 were active at a dose of 20 mg kg⁻¹ and halted convulsion. Compounds 127, 128, 130, 133, 136, 137 markedly showed excellent activities with extensor time of 31.60–31.80 s while standard drug phenytoin's extensor time was 43.00 ± 0.40 s (Table 7). The presence of N-propargyl on indole or isatin moieties as well as N-allyl moiety reduced the time of tonic extensor remarkably. Methyl substituent on C-2 of the indole increased the activity. Trisindoline 125 was less promising as anticonvulsant since it possessed longer extensor time than phenytoin.¹⁰

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4.6 α-Glucosidase inhibition activity

Trisindolines 3, 5, 17, 31, 33 and 45–53 inhibited α-glucosidase activities and possessed significantly lower IC₅₀ values than commercial drug acarbose (Fig. 11).¹² The presence of bromo substituent on isatin ring enhanced the activity. Trisindoles with N-benzyl and N-substituted benzyl isatins were more active than N-alkyl analogues. Trisindoline 3 displayed the lowest inhibition activity and yet was superior to acarbose (Fig. 11).

4.7 Spermicidal activity

Trisindoline 3 and its analogues 15–17, 22 and 105 were investigated for their effects on sperm mobility (Table 8). The minimum effective concentrations (MECs) were defined as the minimum concentration that led 100% sperm immobility within 20 seconds without awakening the next motility in Baker's buffer after 1 h of incubation at 37 °C. Trisindoline 16 showed the best inhibition activity with MEC of 0.34 ± 0.018 mg mL⁻¹. In comparison, nonoxynol-9 (N-9) as standard showed lower MEC of ∼0.5.¹³

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4.8 Miscellaneous activities

Compound 3 displayed moderate inhibition activity against xanthine oxidase with IC₅₀ of 179.6 ± 0.04 μg mL⁻¹ while standard inhibitor allopurinol showed IC₅₀ value of 7.4 ± 0.07 μg mL⁻¹.²⁵ Xanthine oxidase is an enzyme responsible for catalyzing the transformation of xanthine to uric acid as well as reducing oxygen (O₂) into reactive oxygen species (ROS). The abundance of uric acid causes oxidized lipid membrane, leading to hyperuricemia and obesity.¹¹⁴

Trisindoline 3 showed promising bioactivity as tyrosinase inhibitor with IC₅₀ value of 17.34 ± 0.04 μg mL⁻¹ while reference L-mimosine showed IC₅₀ value of 37.0 ± 0.03 μg mL⁻¹.²⁵ Tyrosinase enzyme is critical to melanogenesis as it catalyzes the production of melanin in skin, hair, and eye pigmentation.¹¹⁵

Trisindoline 3 was less potent as antioxidant since it showed IC₅₀ value of 431 ± 0.09 μg mL⁻¹ compared with the positive control of 3-tert-butyl-4-hydroxyanisole (BHA) with IC₅₀ value of 46 ± 0.22 μg mL⁻¹.²⁵

5. Future directions

Various routes and catalysts have been explored for trisindoline synthesis. In majority of cases, acids have been used to catalyze the reaction successfully. Ionic liquid-catalyzed condensation reaction of isatins with indoles have attracted attention since it is considerably environmental benign and requires simple operation giving high yields within short reaction time. Besides, many ionic liquid catalysts could be utilized to synthesize both symmetrical and unsymmetrical trisindolines. On other hand, only a handful of trisindolines have been synthesized using ionic liquids which warrants further exploration. Trisindolines emerge as a new class of bioactive compounds as it displays several promising bioactivities that need developing. However, limited analogues of trisindoline have been well-investigated and the structure activity relationship is reported on limited varieties of compounds especially in when trisindolines were explored as antitubercular and α-glucosidase inhibitors. Interestingly, there is also very limited studies on the biological activity of unsymmetrical trisindolines which should be explored.

6. Conclusions

Trisindolines are nitrogen heterocyclic structures with promising biological activities. This review provides comprehensive account of trisindolines including their natural occurrence, synthesis, and biological activities. Various routes of synthesis and catalysts used have been discussed in detail. The biological activities of trisindolines have also been discussed with a special focus on the structure activity relationship. This review aims to inspire further development of trisindolines as lead drug candidates.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the Nanyang Technological University, Singapore (CoE Start-up Grant), Ministry of Research, Technology and Higher Education, Republic of Indonesia (WCP, PMDSU, PDUPT Research Grant) and the United Arab Emirates University (grant code. G00003291/Project #852) for financial support.

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