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Review -Based : A Comprehensive Overview from a Pharmacological Perspective

Faisal Omar 1, Abu Montakim Tareq 1 , Ali M. Alqahtani 2 , Kuldeep Dhama 3 , Mohammed Abu Sayeed 1,*, Talha Bin Emran 4,* and Jesus Simal-Gandara 5,*

1 Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh; [email protected] (F.O.); [email protected] (A.M.T.) 2 Department of , College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia; [email protected] 3 Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, ; [email protected] 4 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh 5 Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo—Ourense Campus, E32004 Ourense, Spain * Correspondence: [email protected] (M.A.S.); [email protected] (T.B.E.); [email protected] (J.S.-G.); Tel.: +88-0-167-041-9435 (M.A.S.); +88-0-181-994-2214 (T.B.E.); +34-988-387000 (J.S.-G.)

Abstract: Plant-based indole alkaloids are very rich in pharmacological activities, and the indole nu- cleus is considered to contribute greatly to these activities. This review’s fundamental objective is to   summarize the pharmacological potential of indole alkaloids that have been derived from and provide a detailed evaluation of their established pharmacological activities, which may contribute to Citation: Omar, F.; Tareq, A.M.; identifying new lead compounds. The study was performed by searching various scientific databases, Alqahtani, A.M.; Dhama, K.; Sayeed, including Springer, , ACS Publications, Taylor and Francis, Thieme, Wiley Online Library, M.A.; Emran, T.B.; Simal-Gandara, J. ProQuest, MDPI, and online scientific books. A total of 100 indole compounds were identified and Plant-Based Indole Alkaloids: A reviewed. The most active compounds possessed a variety of pharmacological activities, includ- Comprehensive Overview from a Pharmacological Perspective. ing anticancer, antibacterial, antiviral, antimalarial, antifungal, anti-inflammatory, antidepressant, Molecules 2021, 26, 2297. https:// , hypotensive, anticholinesterase, antiplatelet, antidiarrheal, spasmolytic, antileishmanial, doi.org/10.3390/molecules26082297 lipid-lowering, antimycobacterial, and antidiabetic activities. Although some compounds have potent activity, some only have mild-to-moderate activity. The pharmacokinetic profiles of some Academic Editors: Enrique Barrajon, of the identified compounds, such as , , 7-hydroxymitragynine, vindoline, and Vicente Micol and , were also reviewed. Most of these compounds showed promising pharmacological activity. María Herranz-López An in-depth pharmacological evaluation of these compounds should be performed to determine whether any of these may serve as new leads. Received: 14 March 2021 Accepted: 12 April 2021 Keywords: indole; alkaloids; pharmacological activity; pharmacokinetic profile; scientific databases Published: 15 April 2021

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Nature has always been a blessing for the field of medicine, and peoples throughout history have used natural substances for the treatment of various diseases. The sources of natural substances can be both plants and , and an enormous number of pharmaco- logically active compounds have been derived from natural sources. Many compounds isolated from natural sources have been used as drugs for treatment purposes, either with Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. or without modifications. Through the work of ongoing research, thousands of active This article is an open access article compounds have been isolated from natural sources, which can be classified into multi- distributed under the terms and ple compound classes. Alkaloids refer to a broad class of compounds, and many of the conditions of the Creative Commons isolated bioactive compounds have been further classified as indole alkaloids. Many of Attribution (CC BY) license (https:// the therapeutically active indole alkaloids (Figure1) are isolated from plants, and these creativecommons.org/licenses/by/ compounds have had a noticeable impact on the practice of medicine. Adolf von Baeyer 4.0/). was the first to synthesize indole from oxindole using zinc dust in 1866 [1]. Due to the

Molecules 2021, 26, 2297. https://doi.org/10.3390/molecules26082297 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 28

Molecules 2021, 26, 2297 compounds have had a noticeable impact on the practice of medicine. Adolf von Baeyer2 of 26 was the first to synthesize indole from oxindole using zinc dust in 1866 [1]. Due to the occurrence of adverse effects following treatment with existing drug molecules, the search foroccurrence new compounds of adverse associated effects following with fewer treatment adverse with effects existing has gained drug molecules,immense attention the search fromfor newmedicinal compounds chemists associated and other with scientists fewer adverseworldwide. effects Some has of gained the indole immense compounds attention from medicinal chemists and other scientists worldwide. Some of the indole compounds that have since been developed, including and (anticancer agents), that have since been developed, including vincristine and vinblastine (anticancer agents), (an antihypertensive agent), (a cholinesterase inhibitor), and reserpine (an antihypertensive agent), physostigmine (a cholinesterase inhibitor), and (an anti-arrhythmic agent), are now used as therapeutic drugs. ajmaline (an anti-arrhythmic agent), are now used as therapeutic drugs.

Figure 1. Chemical structure of indole. Figure 1. Chemical structure of indole. This review summarizes current insights regarding the development of plant-based indoleThis alkaloids review summarizes with biological current activities. insights In this regarding review, the 100 development indole alkaloids of areplant-based discussed, indoleincluding alkaloids an overview with biological of their pharmacological activities. In this activities review, and 100 pharmacokinetic indole alkaloids profiles. are dis- All cussed,information including on the an compoundsoverview of was their retrieved pharmacological from scientific activities databases, and pharmacokinetic such as Springer, profiles.Elsevier, All ACS information Publications, on the Taylor compounds and Francis, was retrieved Thieme, Wileyfrom scientific Online Library, databases, ProQuest, such asMDPI, Springer, and Elsevier, online scientific ACS Publications, books. Taylor and Francis, Thieme, Wiley Online Li- brary, ProQuest, MDPI, and online scientific books. 2. Indole Alkaloids: An Overview 2. Indole Alkaloids: An Overview Indole (C8H7N) is a weakly basic molecule consisting of a pyrrole ring fused to a benzeneIndole nucleus, (C8H7N) and is a ten weaklyπ electrons basic movemolecule throughout consisting the of structure. a pyrrole The ring basic fused environment to a ben- zeneof indole nucleus, alkaloids and ten is π thought electrons tobe move caused throughout by the delocalization the structure. of The the lonebasic pair environment of ofelectrons indole alkaloids into the is free thought circulation to be ofcaused the π byelectronic the delocalization system. This of resultsthe lone in pair indole of nitrogen becoming electronsprotonated into at the the free C-3 circulation position, which of the isπ thermodynamicallyelectronic system. This more results stable in [ 2indole–4]. becom- ing protonatedIndole alkaloids at the C-3 have position, gained which popularity is thermodynamically due to their diverse more pharmacological stable [2–4]. activi- ties.Indole Although alkaloids both planthave andgained marine popularity sources due of indole to their alkaloids diverse arepharmacological now being extensively activi- ties.studied Although worldwide, both plant the presentand marine review sources emphasizes of indole only alkaloids those indole are now alkaloids being that exten- have sivelybeen studied derived worldwide, from plant sources. the present Indole review alkaloids emphasizes have been only identified those indole in several alkaloids prominent that haveplant been families, derived including from plant , sources. Indole , alkaloids Nyssaceae, have been and identified Loganiaceae, in several among prominentothers. Some plant of families, the identified including indole Apocyn alkaloidaceae, compounds Rubiaceae, have Nyssaceae, been highly and effectiveLogania- in ceae,pre-clinical among others. and clinical Some studies. of the identified Thousands indole of compounds compounds containing have the indole been highly nucleus effectivehave been in pre-clinical isolated from and plant clinical sources. studies. Their Thousands pharmacological of compounds activities containing were assessed, the within- dolesome nucleus now being have examinedbeen isolated in clinical from plant trials so andurces. some Their already pharmacological approved for activities therapeutic were use assessed,in humans. with Indole some now alkaloids being areexamined often characterized in clinical trials by and their some potent already biological approved activities, for therapeuticwhich are use relevant in humans. to thefield Indole of medicine,alkaloids are including often characterized anticancer, antibacterial, by their potent antiviral, bio- logicalantimalarial, activities, antifungal, which are anti-inflammatory, relevant to the field antidepressant, of medicine, including analgesic, anticancer, hypotensive, anti- an- bacterial,ticholinesterase, antiviral, antiplatelet,antimalarial, antidiarrheal, antifungal, anti-inflammatory, spasmolytic, antileishmanial, antidepressant, lipid-lowering, analgesic, hypotensive,antimycobacterial, anticholinesterase, and antidiabetic antiplatelet, activities antidiarrheal, [2–4]. spasmolytic, antileishmanial, lipid-lowering,3. Pharmacological antimycobacterial, Activities and antidiabetic activities [2–4]. 3.1. Antimicrobial Activity Scholarisins I, II, III, and scholarisine F were isolated from the leaves of rupestris, and the antifungal activities of these compounds were tested by the disk diffusion method. The zones of inhibition and the minimum inhibitory concentrations (MICs) were deter- mined against five species of fungi, and these compounds displayed inhibitory activities against two species of fungi (Gibberella pulicaris and Cercospora nicotianae), with MIC values of 0.64–0.69 mM, 1.37–1.44 µM, 1.80–1.91 µM, and 1.55–1.71 µM, respectively [5].

Molecules 2021, 26, x FOR PEER REVIEW 3 of 28

3. Pharmacological Activities 3.1. Antimicrobial Activity Scholarisins I, II, III, and scholarisine F were isolated from the leaves of Alstonia rupestris, and the antifungal activities of these compounds were tested by the disk diffu- sion method. The zones of inhibition and the minimum inhibitory concentrations (MICs) were determined against five species of fungi, and these compounds displayed inhibitory activities against two species of fungi (Gibberella pulicaris and Cercospora nicotianae), with Molecules 2021, 26, 2297 MIC values of 0.64–0.69 mM, 1.37–1.44 µM, 1.80–1.91 µM, and 1.55–1.71 µM, respectively3 of 26 [5]. Kopsihainins D, E, F, and kopsiflorine were isolated from the twigs of Kopsia hai- nanensis.Kopsihainins The antibacterial D, E, F, and activities kopsiflorine of these were isolatedfour compounds from the twigs were of examinedKopsia hainanensis. against StaphylococcusThe antibacterial aureus activities using of thesethe disk four diffusion compounds method. were examined These compounds against Staphylococcus exhibited inhib- aureus itoryusing activity, the disk forming diffusion antibacterial method. These regions compounds with diameters exhibited of inhibitory11.2, 9.1, 10.3, activity, and forming9.7 mm, respectivelyantibacterial [6]. regions with diameters of 11.2, 9.1, 10.3, and 9.7 mm, respectively [6]. Erchinines A and B have shown significantsignificant antibacterialantibacterial and antifungalantifungal activities against TrichophytonTrichophyton rubrum rubrum andand BacillusBacillus subtilis. subtilis. BothBoth compounds compounds were were isolated isolated from from the rootsthe roots of Ervatamia of Ervatamia chinensis, chinensis and they, and exhibited they exhibited potent activity potent, activity,with the withMIC values the MIC of 0.78 val- andues of0.78 0.78 µg/mL and 0.78againstµg/mL Bacillus against subtilisBacillus and 12.5 subtilis andand 6.25 12.5 µg/mL and 6.25againstµg/mL Trichophyton against rubrumTrichophyton, respectively rubrum, respectively[7]. [7]. Melokhanines B, B, D, D, E, E,and and F exhibited F exhibited excellent excellent antibacterial antibacterial activities activities against against Pseu- domonasPseudomonas aeruginosa aeruginosa. The. MIC The values MIC values for these for compounds these compounds were 5, were 4, 2, 5,and 4, 2 2, µM, and respec- 2 µM, tively.respectively. Moreover, Moreover, melokhanine melokhanine B and E B also and showed E also showed antibacterial antibacterial activity activity against againstEntero- coccusEnterococcus faecalis, faecalis with ,a with MIC a value MIC valueof 5 µM of for 5 µ Mboth for compounds both compounds (Figure (Figure 2) [8].2 )[8].

Figure 2. AntimicrobialAntimicrobial activity of indole alkaloids. 3.2. Antiviral Activity The compounds 17-nor-excelsinidine and strictamine were extracted from the twigs and leaves of Alstonia scholaris. These compounds were shown to significantly inhibit herpes simplex virus (HSV) and adenovirus (ADV), with half-maximal effective concentrations (EC50) of 1.09 and 0.36 µg/mL against HSV and 0.94 and 0.28 against ADV, respectively [9]. Trigonoliimine A was extracted from the leaves of Trigonostemon lii. This compound was evaluated for anti-HIV-1 activity using a microtiter syncytium formation infectivity assay and was found to exhibit a moderate level of inhibitory activity, with an EC50 value of 0.95 µg/mL [10]. Molecules 2021, 26, x FOR PEER REVIEW 4 of 28

3.2. Antiviral Activity The compounds 17-nor-excelsinidine and strictamine were extracted from the twigs and leaves of Alstonia scholaris. These compounds were shown to significantly inhibit her- pes simplex virus (HSV) and adenovirus (ADV), with half-maximal effective concentra- tions (EC50) of 1.09 and 0.36 µg/mL against HSV and 0.94 and 0.28 against ADV, respec- tively [9]. Trigonoliimine A was extracted from the leaves of Trigonostemon lii. This compound Molecules 2021, 26, 2297 was evaluated for anti-HIV-1 activity using a microtiter syncytium formation infectivity4 of 26 assay and was found to exhibit a moderate level of inhibitory activity, with an EC50 value of 0.95 µg/mL [10]. NaucleaoffinesNaucleaoffines A and B were were isolated isolated from from the the leaves leaves and and stems stems of of NaucleaNauclea officinalis officinalis.. Both of these compoundscompounds havehave shown shown significant significant effects effects against against HIV-1, HIV-1, with with EC EC50 values50 values of of0.06 0.06 and and 0.23 0.23µM, µM, whereas whereas the the positive positive control control demonstrated demonstrated an an EC EC5050 valuevalue of 0.018 µMµM (Figure 33))[ [11].11].

Figure 3. Antiviral activity of indole alkaloids. Figure 3. Antiviral activity of indole alkaloids. 3.3. Antidepressant Activity 3.3. Antidepressant Activity Mitragynine is an isolated from Korth. The antide- pressantMitragynine activity ofis mitragyninean indole alkaloid was examined isolated from using Mitragyna the forced speciosa swim Korth test (FST). The andantide- tail pressantsuspension activity test (TST) of mitragynine in a mouse modelwas examined of depression. using Mitragyninethe forced swim significantly test (FST) decreased and tail suspensionthe immobility test periods(TST) in of a micemouse in bothmodel the of FST depression. and TST Mitragynine without noticeable significantly effects de- on creasedlocomotor the activityimmobility in the periods open-field of mice test in when both administeredthe FST and TST at doseswithout of 10noticeable and 30 mg/kg. effects onThe locomotor release of corticosteroneactivity in the inopen-field mice exposed test when to the FSTadministered and TST wasat doses found of to 10 be and consid- 30 mg/kg.erably diminishedThe release followingof corticosterone treatment in mice with exposed mitragynine to the at FST doses and that TST provided was found effective to be considerablyantidepressant diminished effects [12 following]. treatment with mitragynine at doses that provided ef- fectiveLyaloside antidepressant and strictosamide effects [12]. exhibited an inhibitory effect against monoamine oxidase (MAO),Lyaloside although and this strictosamide effect was not exhibited significant. an However,inhibitory theseeffect compounds against monoamine may represent oxi- dasenew leads(MAO), for although the development this effect of analogswas not with significant. potential However, antidepressant these effects.compounds Lyaloside may representand stratosamide new leads inhibited for the development MAO-A with of half-maximal analogs with inhibitorypotential antidepressant concentrations effects. (IC50) Lyalosidevalues of 50.04and stratosamide± 1.09 and inhibited 132.5 ± 1.33 MAO-Aµg/mL, with respectively, half-maximal and inhibitory MAO-B concentra- inhibition tionsoccurred (IC50 at) values IC50 values of 50.04 of 306.6 ± 1.09± 1.40and and132.5 162.8 ± 1.33± 1.26 µg/mL,µg/mL. respectively, Lyaloside and and MAO-B strictosamide inhi- bitionwere isolated occurred from at ICPsychotria50 values suterellaof 306.6 and± 1.40Psychotria and 162.8 laciniata ± 1.26, µg/mL. respectively Lyaloside [13]. and stric- tosamideHarmane, were isolated norharmane, from Psychotria and suterella exhibited and Psychotria antidepressant-like laciniata, respectively activity when [13]. administered to mice subjected to the FST. In a dose-dependent manner, these compounds decreased the immobility duration with a 50% effective dose (ED50) of 11.5 mg/kg by intraperitoneal (i.p.) administration for harmane, 8.5 mg/kg i.p. for norharmane, and 8 mg/kg i.p. for harmine. These effects do not appear to be mediated by presynaptic monoaminergic mechanisms but are likely caused by an inverse-agonistic mechanism that involves the benzodiazepine receptors [14]. Psychollatine was isolated from the plant Psychotria umbellate. Psychollatine increased the number of crossings, rearings, and head-dips of treated mice during the hole-board test at the doses of 7.5 and 15 mg/kg. In the light/dark test, psychollatine increased the time spent in the light area and the latency to the first entry into the dark compartment when Molecules 2021, 26, x FOR PEER REVIEW 5 of 28

Harmane, norharmane, and harmine exhibited antidepressant-like activity when ad- ministered to mice subjected to the FST. In a dose-dependent manner, these compounds decreased the immobility duration with a 50% effective dose (ED50) of 11.5 mg/kg by in- traperitoneal (i.p.) administration for harmane, 8.5 mg/kg i.p. for norharmane, and 8 mg/kg i.p. for harmine. These effects do not appear to be mediated by presynaptic mono- aminergic mechanisms but are likely caused by an inverse-agonistic mechanism that in- volves the benzodiazepine receptors [14]. Psychollatine was isolated from the plant Psychotria umbellate. Psychollatine in-

Molecules 2021, 26, 2297 creased the number of crossings, rearings, and head-dips of treated mice during the hole-5 of 26 board test at the doses of 7.5 and 15 mg/kg. In the light/dark test, psychollatine increased the time spent in the light area and the latency to the first entry into the dark compartment whenadministered administered at a dose at a of dose 7.5 mg/kg.of 7.5 mg/kg. In the FST,In the psychollatine FST, psychollatine significantly significantly diminished dimin- the ishedduration the duration of immobility of immobility in mice at in doses miceof at 3doses and7.5 of 3 mg/kg and 7.5 (Figure mg/kg4 )[(Figure15]. 4) [15].

FigureFigure 4. 4. AntidepressantAntidepressant activity activity of of indole indole alkaloids. alkaloids. 3.4. Anticancer Activity 3.4. Anticancer Activity Tabersonine was isolated from the leaves and twigs of Melodinus fusiformis. This compoundTabersonine exhibited was isolated significant from anticancer the leaves activity and twigs against of Melodinus five human fusiformis tumor. This cell com- lines, pound exhibited significant anticancer activity against five human tumor cell lines, with with IC50 values of 4.6, 5.6, 14.8, 9.9, and 12.1 against SW480, SMMC-7721, HL-60, MCF-7, ICand50 values A-549 cells,of 4.6, respectively 5.6, 14.8, 9.9, [16 and]. 12.1 against SW480, SMMC-7721, HL-60, MCF-7, and A-549Brucine cells, respectively displayed significant[16]. cytotoxic activity against the human hepatoma cell line HepG2,Brucine with displayed IC50 values significant of 0.65, 0.32, cytotoxic and 0.10 activi mMty at against a different the time human interval hepatoma after treatment. cell line HepG2,Brucine waswith isolated IC50 values from theof 0.65, 0.32, of Strychnos and 0.10 nux-vomica mM at aL. different time and interval isostrychnine, after which were extracted from the same plant, also showed cytotoxic activity [17]. Naucleaorals A and B were isolated from the roots of Nauclea orientalis. Both com- pounds showed cytotoxic activity against the KB (human epidermoid carcinoma) and HeLa (human cervical carcinoma) cell lines. However, Naucleaoral A showed substantial cytotoxicity, with an IC50 value of 4.0 µg/mL against HeLa cells, whereas Naucleaoral B showed only very moderate cytotoxicity, with IC50 values of 7.8 and 9.5 µg/mL against the two cell lines [18]. Vallesiachotamine and iso-vallesiachotamine were isolated from the of Anthocephalus cadamba (Roxb) Miq. Both compounds showed potent anticancer activity, with IC50 values of 4.24 and 3.79 µM, respectively, against the human lung cancer cell line H1299 after 72 h of incubation [19]. Molecules 2021, 26, x FOR PEER REVIEW 6 of 28

treatment. Brucine was isolated from the seeds of Strychnos nux-vomica L. Strychnine and isostrychnine, which were extracted from the same plant, also showed cytotoxic activity [17]. Naucleaorals A and B were isolated from the roots of Nauclea orientalis. Both com- pounds showed cytotoxic activity against the KB (human epidermoid carcinoma) and HeLa (human cervical carcinoma) cell lines. However, Naucleaoral A showed substantial cytotoxicity, with an IC50 value of 4.0 µg/mL against HeLa cells, whereas Naucleaoral B showed only very moderate cytotoxicity, with IC50 values of 7.8 and 9.5 µg/mL against the two cell lines [18]. Vallesiachotamine and iso-vallesiachotamine were isolated from the fruits of Antho- cephalus cadamba (Roxb) Miq. Both compounds showed potent anticancer activity, with IC50 Molecules 2021, 26, 2297 6 of 26 values of 4.24 and 3.79 µM, respectively, against the human lung cancer cell line H1299 after 72 h of incubation [19]. ErvachininesErvachinines A, A, C, C, and D exhibited significant significant inhibitory effects against five five cancer cellcell lines, lines, including including HL-60 HL-60 human human myeloid myeloid leukemia leukemia cells, cells, SMMC-7721 SMMC-7721 hepatocellular hepatocellular car- cinomacarcinoma cells, cells, A-549 A-549 lung lung cancer cancer cells, cells, MCF-7 MCF-7 breast breast cancer cancer cells, cells, and and SW480 SW480 colon colon cancer cancer cells.cells. Except Except for for ervachinine D against MCF-7MCF-7 cells, all threethree compoundscompounds displayeddisplayed ICIC5050 values in the range of 0.84–4.63 µµMM against all fivefive cancercancer cellcell lines.lines. These compounds were extracted from the Ervatamia chinensis whole plant [[20].20]. JerantininesJerantinines A A and and B B were were extracted extracted from from the the plant plant TabernaemontanaTabernaemontana corymbosa. These These compoundscompounds exhibited exhibited inhibitory inhibitory effects effects against against three three cancer cancer cell cell lines, lines, as determined as determined by theby the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide bromide (MTT) (MTT) assay. assay. The half- The maximalhalf-maximal growth growth inhibitory inhibitory concentration concentration (GI5 (GI50)0) was wascalculated, calculated, which which showed showed that that je- rantininejerantinine A Adisplayed displayed an an inhibitory inhibitory effect effect against against breast, breast, colon, colon, and and lung lung carcinoma carcinoma cell lines,lines, with with the the GI50 GI50 values values less less than than 4.00 4.00 µM.µM. Jerantinine B showed significantsignificant activity againstagainst all all cell cell lines lines except except MCF-7 MCF-7 cells, cells, with with GI50 GI50 values values less less than than 1.00 1.00 µM.µM. Jerantinine A alsoalso blocked blocked the ability of cancer cell cellss to form colonies (Figure 5 5))[ [21].21].

FigureFigure 5. 5. AnticancerAnticancer activity activity of of indole indole alkaloids. 3.5. Anti-Inflammatory Activity

Melaxillines A and B, two alkaloids containing an indole nucleus, were isolated from the roots of Melodinus axillaris. Both compounds showed potent anti-inflammatory activity, as assessed using an in vitro assay to measure the inhibition of β-glucuronidase secretion induced by platelet-activating factor (PAF) in rat polymorphonuclear leukocytes (PMNs). The IC values of these two compounds were 1.51 and 2.62 µM, respectively [22]. 50 Perakine N4-oxide, raucaffrinoline N4-oxide, and vinorine N4-oxide were isolated from Alstonia yunnanensis. An in vitro anti-inflammatory activity assay revealed selective cyclooxidase 2 (COX-2) inhibition by these three compounds, with inhibitory values of 94.77%, 88.09%, and 94.05%, respectively; however, none of these compounds displayed any significant COX-1 inhibition (<45%) [23]. Scholarisins I and VI, two monoterpenoid indole alkaloids, were isolated from Alstonia rupestris. Both compounds displayed the selective inhibition of COX-2, with inhibitory values of 96.4% and 95.5%, respectively, with no significant inhibitory effects against COX-1 [5]. Molecules 2021, 26, x FOR PEER REVIEW 7 of 28

3.5. Anti-Inflammatory Activity Melaxillines A and B, two alkaloids containing an indole nucleus, were isolated from the roots of Melodinus axillaris. Both compounds showed potent anti-inflammatory activ- ity, as assessed using an in vitro assay to measure the inhibition of β-glucuronidase secre- tion induced by platelet-activating factor (PAF) in rat polymorphonuclear leukocytes (PMNs). The IC50 values of these two compounds were 1.51 and 2.62 µM, respectively [22]. Perakine N4-oxide, raucaffrinoline N4-oxide, and vinorine N4-oxide were isolated from Alstonia yunnanensis. An in vitro anti-inflammatory activity assay revealed selective cyclooxidase 2 (COX-2) inhibition by these three compounds, with inhibitory values of 94.77%, 88.09%, and 94.05%, respectively; however, none of these compounds displayed any significant COX-1 inhibition (<45%) [23]. Scholarisins I and VI, two monoterpenoid indole alkaloids, were isolated from Al- stonia rupestris. Both compounds displayed the selective inhibition of COX-2, with inhibi- tory values of 96.4% and 95.5%, respectively, with no significant inhibitory effects against Molecules 2021, 26, 2297 7 of 26 COX-1 [5]. Strictosamide showed anti-inflammatory activity against a mouse model of ear edemaStrictosamide induced by showed12-O-tetradecanoylphorbol-13-acetate anti-inflammatory activity against (TPA) a mouse at doses model of of 20 ear and edema 40 mg/kg.induced Strictosamide by 12-O-tetradecanoylphorbol-13-acetate administration significantly (TPA)diminished at doses the of ear 20 andswelling 40 mg/kg. rates from Stric- 143.9tosamide ± 8.8 to administration 108.4 ± 11.7 and significantly103.5 ± 16.0, representing diminished 24.7% the and ear 28.1% swelling inhibition rates against from inflammation,143.9 ± 8.8 to respectively. 108.4 ± 11.7 Strictosamide and 103.5 ± 16.0,substantially representing blocked 24.7% peritoneal and 28.1% capillary inhibition per- meabilityagainst inflammation, induced by acetic respectively. in mice, Strictosamide with inhibitory substantially rates of blocked 23.3% and peritoneal 33.4% capillaryat doses ofpermeability 20 and 40 mg/kg, induced respectively. by In another in mice, test, with strictosamide inhibitory rates significantly of 23.3% reduced and 33.4% leu- at kocytedoses ofcounts 20 and induced 40 mg/kg, by carb respectively.oxymethylcellulose In another test,sodium strictosamide (CMC–Na) significantly at doses of reduced 10, 20, andleukocyte 40 mg/kg, counts resulting induced in byreductions carboxymethylcellulose of 46.0%, 49.1%, sodium and 58.7%, (CMC–Na) respectively at doses (Figure of 10, 20,6) [24].and 40 mg/kg, resulting in reductions of 46.0%, 49.1%, and 58.7%, respectively (Figure6) [ 24].

FigureFigure 6. 6. Anti-inflammatoryAnti-inflammatory activity activity of of indole indole alkaloids. alkaloids. 3.6. Analgesic Activity Brucine and brucine N-oxide were extracted from the seeds of Strychnos nux-vomica. Three different tests, including the hot plate test, writhing test, and formalin test, were

conducted to determine whether these compounds exerted analgesic effects. In the forma- lin test, brucine showed potent inhibitory effects against both the early- and late-phase pain stimuli at doses ranging from 7.5 to 30 mg/kg. However, brucine N-oxide exhibited a significant inhibitory effect only against the late phase. In the writhing test, brucine (15 and 30 mg/kg) and brucine N-oxide (50 and 200 mg/kg) showed significant inhibition of the writhing response to the i.p. administration of acetic acid in mice. In the hot plate test, the ED50 value of brucine N-oxide was five and six times greater than that of brucine 30 and 60 min after drug administration, respectively, which indicated that brucine pro- longed the pain threshold of mice in a dose-dependent manner [25]. Mitragynine and 7-hydroxymitragynine were isolated from the plant Mitragyna speciosa [26,27]. The antinociceptive effects of mitragynine were examined using the hot plate test, which revealed a dose-dependent response at doses ranging from 3–35 mg/kg. The la- tency period increased after the administration of the 15 mg/kg dose. The most significant antinociceptive effect was observed at the 35 mg/kg mitragynine dose, which corresponded Molecules 2021, 26, 2297 8 of 26

with the longest latency time [26]. Similarly, 7-hydroxymitragynine demonstrated antinoci- ceptive activity in a dose-dependent manner (2.5–10 mg/kg) in the tail-flick and hotplate tests. The maximum possible effect (MPE) value of 7-hydroxymitragynine (5 mg/kg, sub- cutaneous (s.c.)) reached 100% between 15 and 30 min after administration in the tail-flick test. In the hotplate test, the MPE value of 7-hydroxymitragynine (10 mg/kg, s.c.) reached 94% at 15 min after administration [27]. Strictosamide exhibited analgesic activity in the writhing test, with no such effect observed in the hot plate test. The i.p. injection of strictosamide reduced acetic acid-induced writhing in mice in a dose-dependent manner. Strictosamide remarkably lengthened the pain latency of mice at doses of 20 and 40 mg/kg, resulting in latency periods 336.5 s and 345.8 s, respectively. When the writhing activity was counted, a significant reduction in writhing activity was observed for the 40 mg/kg dose of strictosamide, which reduced the count to 9.7 compared with the positive drug. The inhibition observed at doses of 20 and 40 mg/kg were 37.0% and 49.7%, respectively. This compound was isolated from the Nauclea officinalis [24]. Umbellatine was isolated from the leaves of Psychotria umbellate. Analgesic activity was investigated by conducting the tail-flick test, hot plate test, formalin test, and - Molecules 2021, 26, x FOR PEER REVIEWinduced pain test. In the four test models, umbellatine exhibited good activity against9 of 28 tail-flick test and hot plate test and significant activity against formalin test and capsaicin- induced pain test at the doses of 100–300 mg/kg (Figure7)[28].

FigureFigure 7. 7. AnalgesicAnalgesic activity activity of of indole indole alkaloids. alkaloids. 3.7. Antidiabetic Activity 3.7. Antidiabetic Activity Vindoline, vindolidine, vindolicine, and vindolinine represent four new indole-type alkaloidsVindoline, that were vindolidine, extracted vindolicine, from the leaves and vi ofndolinineCatharanthus represent roseus four(L.) new G. Don. indole-type All four alkaloidsalkaloids that induced were enhancedextracted glucosefrom the uptake leaves activityof in β-TC6 roseus and C(L.)2C1 G.2 cells Don. in All a dose-four alkaloidsdependent induced manner, enhanced and vindolicine glucose triggered uptake anactivity extreme in β increase-TC6 and in glucoseC2C12 cells uptake in a activity. dose- dependentIn another test,manner, all of and these vindolicine compounds triggered exhibited an extreme increase phosphatase in glucose 1Buptake (PTP-1B) ac- tivity. In another test, all of these compounds exhibited protein tyrosine phosphatase 1B (PTP-1B) inhibition activity, although only vindolicine showed significant inhibitory ac- tivity. The IC50 values of vindoline, vindolidine, vindolicine, and vindolinine against PTP- 1B were 36.5, 18.2, 11.6, and 14.1 µM, respectively [29]. Vindogentianine was isolated from leaf extracts and resulted in significant hypoglycemic activity in β-TC6 pancreatic and C2C12 muscle cells at treatment concentrations of 25.0, 50.0, and 100.0 µg/mL by inducing increased glucose uptake activ- ity. The compound also exhibited a significant antihyperglycemic effect in the PTP-1B in- hibition test, with an IC50 value of 15.28 ± 2.59 µg/mL [30]. was isolated from the plant Picralima nitida and significantly enhanced glucose uptake activity in fully differentiated 3T3-L1 adipocytes after 24 h incubation (Fig- ure 8) [31].

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inhibition activity, although only vindolicine showed significant inhibitory activity. The IC50 values of vindoline, vindolidine, vindolicine, and vindolinine against PTP-1B were 36.5, 18.2, 11.6, and 14.1 µM, respectively [29]. Vindogentianine was isolated from Catharanthus roseus leaf extracts and resulted in significant hypoglycemic activity in β-TC6 pancreatic and C2C12 muscle cells at treatment concentrations of 25.0, 50.0, and 100.0 µg/mL by inducing increased glucose uptake activity. The compound also exhibited a significant antihyperglycemic effect in the PTP-1B inhibition test, with an IC50 value of 15.28 ± 2.59 µg/mL [30]. Akuammicine was isolated from the plant Picralima nitida and significantly Molecules 2021, 26, x FOR PEER REVIEW 10 of 28 enhanced glucose uptake activity in fully differentiated 3T3-L1 adipocytes after 24 h incubation (Figure8)[31].

FigureFigure 8. 8. AntidiabeticAntidiabetic activity activity of of indole indole alkaloids. 3.8. Antimalarial Activity 3.8. Antimalarial Activity and olivacine, two indole alkaloids, exhibited potential in vitro antimalarial activityEllipticine against Plasmodiumand olivacine, falciparum two indoleand in alkaloids, vivo activity exhibited in Plasmodium potential berghei in vitro-infected antimalar- mice. ialThese activity two compoundsagainst Plasmodium were isolated falciparum from Aspidosperma and in vivo vargasiiactivityand in PlasmodiumAspidosperma berghei olivaceum.-in- fected mice. These two compounds were isolated from Aspidosperma vargasii and Aspido- Olivacine significantly inhibited P. falciparum growth, with an IC50 value of 1.2 µM against sperma olivaceum. Olivacine significantly inhibited P. falciparum growth, with an IC50 value the K1 P. falciparum strain. Ellipticine displayed significant antimalarial effects, with IC50 ofvalues 1.2 µM of 0.81against and the 0.35 K1µ MP. againstfalciparum the strainP. falciparum. Ellipticinestrains displayed K1 and significant 3D7, respectively. antimalarial Both effects,compounds with IC displayed50 values highof 0.81 selectivity and 0.35 indicesµM against against theP. P. falciparum falciparum3D7 strains (>1.2 K1× and103 3D7,and respectively.>3.4 × 102, respectively). Both compounds The indisplaye vivo antimalariald high selectivity activity indices of these against compounds P. falciparum was eval-3D7 (>1.2uated × in103P. and berghei- >3.4infected × 102, respectively). mice in a four-day The in vivo suppressive antimalarial test. activity Ellipticine of these showed com- a poundssignificant was effect evaluated at an oral in P. dose berghei- of 50infected mg/kg/day mice in (100% a four-day inhibition suppressive versus controls test. Ellipticine on days showedfive and a seven). significant The meaneffect survivalat an oral time dose (MST) of 50 of mg/kg/day the animals (100% was greaterinhibition than versus 40 days con- at trolsthe same on days oral five dose. and Olivacine seven). showedThe mean higher survival activity time at (MST) the dose of the equal animals to 50 mg/kg/daywas greater thanin this 40 test. days The at the range same of inhibitionoral dose. wasOlivacine 90%–97% showed at day higher five andactivity day at seven the dose after equal the oral to 50and mg/kg/day subcutaneous in this administration test. The range of of the inhibition drug, with was an 90%–97% MST of 23–27 at day days five [and32]. day seven after the oral and subcutaneous administration of the drug, with an MST of 23–27 days [32]. Flinderoles A, B, and C showed selective antimalarial activity against the Dd2 strain of P. falciparum. These compounds exhibited parasite growth inhibition with IC50 values of 1.42, 0.15, and 0.34 µM, respectively. These compounds were isolated from Flindersia acuminate and F. amboinensis [33]. Apisdospermine, aspidospermine, demethoxy-aspidospermine, vallesine, and palo- sine were tested for their antimalarial activities against a chloroquine-resistant strain of P. falciparum. These compounds displayed better activity after incubation for 72 h with IC50 values of 3.8, 4.1, 5.6, 6.2, and 12.7 µM, respectively (Figure 9) [34].

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Flinderoles A, B, and C showed selective antimalarial activity against the Dd2 strain of P. falciparum. These compounds exhibited parasite growth inhibition with IC50 values of 1.42, 0.15, and 0.34 µM, respectively. These compounds were isolated from Flindersia acuminate and F. amboinensis [33]. Apisdospermine, aspidospermine, demethoxy-aspidospermine, vallesine, and palo- Molecules 2021, 26, x FOR PEER REVIEW 11 of 28 sine were tested for their antimalarial activities against a chloroquine-resistant strain of P. falciparum. These compounds displayed better activity after incubation for 72 h with IC50 values of 3.8, 4.1, 5.6, 6.2, and 12.7 µM, respectively (Figure9)[34].

Figure 9. Antimalarial activityFigure 9. Antimalarialof indole alkaloids. activity of indole alkaloids. Geissolosimine, geissospermine, geissoschizoline, and geissoschizone were evaluated Geissolosimine,for in vitro geissospermine,antimalarial activity geissoschi against thezoline, chloroquine-sensitive and geissoschizone strain of P. falciparumwere evalu- ated for in vitro(D10), antimalarial revealing IC activity50 values ofagainst 0.55, 3.17, the 4.16, chloroquine-sensitive and 3.19 µg/mL, respectively. strain Among of P. these falcipa- compounds, geissolosimine exhibited the greatest antiplasmodial activity, suggesting that rum (D10), revealingit may representIC50 values a promising of 0.55, lead 3.17, for antimalarial 4.16, and drug 3.19 discovery. µg/mL, All respectively. of these compounds Among these compounds,were geissolosimine isolated from the stem exhibited bark of Geissospermum the greatest vellosii antiplasmodial(Figure 10)[35]. activity, suggest- ing that it may represent a promising lead for antimalarial . All of these compounds were isolated from the stem bark of Geissospermum vellosii (Figure 10) [35].

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FigureFigure 10. 10. AntimalarialAntimalarial activity activity of of indole indole alkaloids. alkaloids. 3.9. Hypotensive Activity 3.9. Hypotensive Activity Naucline, angustine, angustidine, nauclefine, and naucletine were isolated from the Naucline, angustine, angustidine, nauclefine, and naucletine were isolated from the bark of the Nauclea officinalis. These compounds displayed hypotensive effects against bark of the Nauclea officinalis. These compounds displayed hypotensive effects against phe- phenylephrine (PE)-induced contractions of rat aortic rings associated with intact endothe- nylephrine (PE)-induced contractions of rat aortic rings associated with intact endothe- lium. Naucline showed moderate vasorelaxant activity, resulting in 90% relaxation at lium.1 × 10 Naucline−5 M.The showed remaining moderate compounds vasorelaxant showed activity, significant resulting vasorelaxant in 90%activity, relaxation resulting at 1 × −5 10in greater M.The than remaining 90% relaxation compounds at 1 ×showed10−5 M significant in an isolated vasorelaxant rat aorta [activity,36]. resulting in −5 greaterAlstilobanines than 90% relaxation A, B, and at C 1 and× 10 undulifoline M in an isolated displayed rat aorta slow [36]. relaxation activity against PE-inducedAlstilobanines contractions A, B, inand thoracic C and rat undulifo aortic ringsline displayed with intact slow endothelium. relaxation Theactivity per- againstcentages PE-induced of relaxation contractions induced by in thesethoracic compounds rat aortic wererings 44.3%,with intact 21.2%, endothelium. 28%, and 33.3%, The percentagesrespectively, of with relaxation alstilobanine induced A showing by these more compounds potent relaxation were 44.3%, activity 21.2%, than 28%, the otherand 33.3%,compounds. respectively, The first with three alstilobanine compounds A showin were isolatedg more frompotentAlstonia relaxation angustiloba activity, than whereas the otherundulifoline compounds. was extracted The first from threeAlstonia compounds undulifolia were[37 isolated]. from Alstonia angustiloba, whereasTaberniacins undulifoline A was and extracted B, two from new Alstonia indole undulifolia alkaloids, [37]. were isolated from TabernaemontanaTaberniacins divaricata A and B, andtwo displayednew indole hypotensive alkaloids, were activity isolated by inducing from Tabernaemontana vasorelaxation divaricatato counteract and displayed the PE-induced hypotensive contraction activity in by an in isolatedducing vasorelaxation rat aorta. Both to alkaloids counteract exhib- the PE-inducedited moderate contraction levels of in vasorelaxant an isolated activityrat aorta. in Both an isolated alkaloids rat exhibited aorta. The moderate IC50 values levels of oftaberniacins vasorelaxant A andactivity B were in an 2.86 isolatedµM and rat 580 aorta. nM, The respectively, IC50 values and ofvasorelaxation taberniacins A activity and B wereincreased 2.86 µM in a and concentration-dependent 580 nM, respectively, and manner vasorelaxation [38]. activity increased in a concen- tration-dependentVillocarine A demonstratedmanner [38]. vasorelaxation activity in a rat aortic ring, with concentration- dependentVillocarine inhibitory A demonstrated effects against vasorelaxation vasocontraction activity in aorta in a rat depolarized aortic ring, by with a high concen- potas- tration-dependentsium concentration inhibitory and against effects PE-mediated against vasocontraction contraction in thein aorta presence depolarized of nicardipine. by a highVillocarine potassium A exhibited concentration excellent and activity against during PE-mediated the initial contraction stage, within in the 10–30 presence min after of nicardipine.injection, with Villocarine potent vasorelaxant A exhibited effects excellent observed activity at 30duringµM against the initial PE-mediated stage, within contrac- 10– 30tion min in after a rat injection, aorta. Villocarine with potent A exhibited vasorelaxa a moderatent effects levelobserved of inhibition at 30 µM at against 30 µM PE-me- against diatedPE and contraction 1 µM-induced in a contractionrat aorta. Villocarine of the aortic A exhibited rings in the a moderate presence oflevel nicardipine of inhibition (1 µ M)at 30in aµM Ca 2+against-free medium. PE and Villocarine1 µM-induced showed contraction slightly lessof the vascular aortic relaxationrings in the activity presence in aortic of nicardipinetissues with (1 no µM) endothelium. in a Ca2+-free Villocarine medium. A wasVillocarine isolated showed from Uncaria slightly villosa less(Figure vascular 11) relax- [39]. ation activity in aortic tissues with no endothelium. Villocarine A was isolated from Un- caria villosa (Figure 11) [39].

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FigureFigure 11. 11. HypotensiveHypotensive activity activity of of indole indole alkaloids. alkaloids. 3.10. Anticholinesterase Activity 3.10. Anticholinesterase Activity Macusine B, vinorine, isoreserpiline, and rescinnamine are four indole alkaloids Macusine B, vinorine, isoreserpiline, and rescinnamine are four indole alkaloids iso- isolated from the bark of Rauvolfia reflexa. These compounds showed inhibitory activities lated from the bark of reflexa. These compounds showed inhibitory activities against the cholinesterase enzyme, with the IC50 values of 48.39, 35.06, 24.89, and 11.01 µM, against the cholinesterase enzyme, with the IC50 values of 48.39, 35.06, 24.89, and 11.01 respectively. Rescinnamine displayed the most significant anticholinesterase activity among µM, respectively. Rescinnamine displayed the most significant anticholinesterase activity these four compounds [40]. among these four compounds [40]. hydroxyindolenine and rupicoline were identified in the Voacangine hydroxyindolenine and rupicoline were identified in the chloroform ex- extract of Tabernaemontana australis stalks. These compounds were investigated for their tractanticholinesterase of Tabernaemontana activity australis and displayed stalks. These activities compounds at concentrations were investigated similar to for those their of an- the ticholinesterasestandard compounds activity physostigmine and displayed and activiti galanthaminees at concentrations [41]. similar to those of the standardCoronaridine compounds and physostigm voacangineine were and isolatedgalanthamine from the[41]. stems of Ervatamia hainanensis. TheseCoronaridine compounds and displayed voacangine significant were isolated inhibitory from activities the stems against of Ervatamia the cholinesterase hainanensis. These compounds displayed significant inhibitory activities against the cholinesterase en- enzyme, with IC50 values of 8.6 and 4.4 µM, respectively, in in vitro experiments [42]. zyme,Angustidine, with IC50 values nauclefine, of 8.6 and and 4.4 angustine, µM, respectively, three indole in in alkaloids, vitro experiments were extracted [42]. from the plantAngustidine,Nauclea officinalisnauclefine,. Their and cholinesteraseangustine, three inhibitory indole alkaloids, activities were were extracted evaluated, from and the plant Nauclea officinalis. Their cholinesterase inhibitory activities were evaluated, and all three compounds demonstrated anticholinesterase activity, with IC50 values of 1.03, all7.70, three and compounds 4.98 µM, respectively, demonstrated against anticholinesterase the butyrylcholinesterase activity, with enzyme IC50 (Figurevalues of12 )[1.03,43]. 7.70, and 4.98 µM, respectively, against the butyrylcholinesterase enzyme (Figure 12) [43].

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Figure 12. Anticholinesterase activity of Indole alkaloids. FigureFigure 12. 12. AnticholinesteraseAnticholinesterase activity activity of of Indole alkaloids. 3.11. Antiplatelet Antiplatelet Activity Activity 3.11. Antiplatelet Activity Harmane, harmine, and harmol were isolated from the plant Perganum harmala L . The Harmane, harmine, and harmol were isolated from the plant Perganum harmala L. The antiplatelet activities activities of of th theseese three three compounds compounds were were examined examined using using the the selective selective inhibi- inhibi- antiplatelettion of collagen-mediated activities of these platelet three activation.compounds The were IC examined50 values of using these the three selective compounds inhibi- tion of collagen-mediated platelet activation. The IC50 values of these three compounds tion of collagen-mediated platelet activation. The IC50 values of these three compounds were 113.7 ±± 8.4,8.4, 132.9 132.9 ± ±16.6,16.6, and and 200 200 ± 4.6± µM,4.6 µ respectively.M, respectively. The Theunderlying underlying mechanism mecha- were 113.7 ± 8.4, 132.9 ± 16.6, and 200 ± 4.6 µM, respectively. The underlying mechanism ofnism this of effect this effectwas also was proposed also proposed in that instudy. that study.These compounds These compounds had no hadinhibitory no inhibitory effects of this effect was also proposed in that study. These compounds had no inhibitory effects oneffects arachidonic on arachidonic acid- or acid- thrombin-induced or thrombin-induced platelet platelet aggregation aggregation at concentrations at concentrations of 200 of on arachidonic acid- or thrombin-induced platelet aggregation at concentrations of 200 µM200 µ(FigureM (Figure 13) [44].13)[ 44]. µM (Figure 13) [44].

Figure 13. Antiplatelet activity of indole alkaloids. Figure 13. Antiplatelet activity of indole alkaloids. Figure 13. Antiplatelet activity of indole alkaloids. 3.12. Antidiarrheal Antidiarrheal Activity Activity 3.12. Antidiarrheal Activity Kurryam and and koenimbine koenimbine were were isolated isolated from from the the seeds seeds of of MurrayaMurraya koenigii koenigii Spreng Spreng.. TheseKurryam compounds and showedshowedkoenimbine significant significant were antidiarrhealisolated antidiarrheal from activity theactivity seeds in in a of castora Murrayacastor -induced oil-induced koenigii diarrhea Spreng diar-. Theserhearat model. rat compounds model. The results The showed showedresults significant thatshowed the meanantidiarrhealthat defecationthe mean activity ofdefecation rats in treated a castor of withrats oil-induced koenimbinetreated diar-with at rheakoenimbinedoses rat of 10,model. 30,at doses and The 50 of results mg/kg 10, 30, showedand were 50 2.51 mg/kg that± 0.58, thweree 1.94mean 2.51± 0.81,±defecation 0.58, and 1.94 1.29 ±of 0.81,± rats0.21, and treated respectively, 1.29 ± with0.21, koenimbinerespectively,whereas rats at whereas treated doses withof rats 10, treated the 30, sameand with 50 dose mg/kg the of sa kurryam mewere dose 2.51 hadof ± kurryam 0.58, mean 1.94 defecation had ± 0.81, mean and of defecation 2.351.29 ±± 0.21,0.35, of respectively,2.351.88 ± 0.35,0.28, 1.88 and whereas ± 1.21 0.28,± rats and0.25, treated 1.21 respectively ± 0.25, with respectively the [45 sa].me dose [45]. of kurryam had mean defecation of 2.35 ±Bisnordihydrotoxiferine 0.35, 1.88 ± 0.28, and 1.21 was was ± extracted 0.25, extracted respectively from from the the root [45]. root bark bark of Strychnos of Strychnos trinervis trinervis (Vell.) (Vell.) Mart. MartThe antidiarrhealBisnordihydrotoxiferine. The antidiarrheal effect waseffect evaluated was was extracted evaluated in castor from in oil-,castor the magnesiumroot oil-, bark magnesium of sulfate-,Strychnos sulfate-, and trinervis arachidonic and (Vell.) ara- Martchidonicacid-induced. The acid-induced antidiarrheal diarrhea diarrhea models, effect was andmodels, evaluated activity and was activity in castor calculated was oil-, calculated asmagnesium the percent as the sulfate-,inhibition. percent and inhibi- Thisara- chidoniction.compound This acid-induced compound inhibited inhibited castor diarrhea oil-induced castormodels, oil-indu and diarrhea activityced diarrhea with was an calculated inhibitionwith an inhibitionas percentage the percent percentage ranging inhibi- tion.from This 70.0% compound to 100.0% inhibited at various castor doses. oil-indu Bisnordihydrotoxiferineced diarrhea with exhibited an inhibition 92.5% percentage inhibition

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ranging from 70.0% to 100.0% at various doses. Bisnordihydrotoxiferine exhibited 92.5% inhibitionat a dose ofat 25a dose mg/kg of 25 against mg/kg magnesium-induced against magnesium-induced diarrhea anddiarrhea 94.6% and inhibition 94.6% inhibi- at the tion12.5 at mg/kg the 12.5 dose mg/kg against dose arachidonic against arachidonic acid-induced acid-induced diarrhea (Figure diarrhea 14 (Figure)[46]. 14) [46].

Figure 14. Antidiarrheal activity of indole alkaloids. Figure 14. Antidiarrheal activity of indole alkaloids. 3.13. Spasmolytic Activity 3.13. Spasmolytic Activity Trinervine is a tertiary indole alkaloid extracted from the root bark of Strychnos trinervis. TheTrinervine spasmolytic is activity a tertiary was indole evaluated alkaloid for extracted this compound from the using root four bark different of Strychnos methods, tri- nervisincluding. The arachidonic spasmolytic acid activity (AA)- was and evaluated 5-hydroxytryptamine for this compound (5-HT)-induced using four contractions different methods,of the rat including fundic strip arachidonic and the -acid (AA)- and and carbachol-mediated 5-hydroxytryptamine contractions (5-HT)-induced of the contractionsguinea-pig ileum.of the rat The fundic values strip (mean and± thestandard histamine- error) and of carbachol-mediated the antagonistic potency contrac- of tionstrinervine of the against guinea-pig these ileum. four models The values were (mea 3.96 ±n ±0.16 standard (AA), 3.54error)± 0.15of the (5-HT), antagonistic 4.25 ± 0.16po- tency(Histamine), of trinervine 4.04 ± against0.12 (Carbachol). these four models Trinervine were yielded 3.96 ± 0.16 a non-competitive, (AA), 3.54 ± 0.15 antagonistic,(5-HT), 4.25 ±spasmolytic 0.16 (Histamine), activity 4.04 on ± isolated 0.12 (Carbachol). gastrointestinal Trinervine smooth yielded muscles a non-competitive, [47]. antago- nistic,Bisnordihydrotoxiferine spasmolytic activity on was isolated extracted gastrointestinal from the root ofsmoothStrychnos muscles diuaricuns [47].. Acetylcholine- andBisnordihydrotoxiferine oxytocin-induced contractions was extracted of the ratfrom uterus the root and of acetylcholine- Strychnos diuaricuns and histamine-. Acetyl- -induced and contractions oxytocin-induced of the guinea-pigcontractions ileum of the were rat uterus used and to evaluateacetylcholine- the contraction and hista- mine-inducedinhibition mediated contractions by bisnordihydrotoxiferine. of the guinea-pig ileum Thewere percentages used to evaluate of inhibition the contraction against inhibitionacetylcholine- mediated and oxytocin-induced by bisnordihydrotoxiferine. contractions The in perc the ratentages uterus of rangedinhibition from against 21.1% ac- to etylcholine-77.4% and from and 36.6%oxytocin-induc to 85.0%,ed respectively, contractions at threein the different rat uterus doses. ranged The from percentages 21.1% to of 77.4%inhibition and from against 36.6% contractions to 85.0%, causedrespectively, by acetylcholine at three different and histamine doses. The in percentages the guinea-pig of inhibitionileum ranged against from contractions 25.0% to 57.2% caused and 51.5%by acetylcholine to 91.1%, respectively, and histamine at three in the different guinea-pig doses ileum(Figure ranged 15)[48 from]. 25.0% to 57.2% and 51.5% to 91.1%, respectively, at three different dosesNormacusine (Figure 15) [48]. B is a tertiary indole alkaloid that was isolated from the root bark of StrychnosNormacusine atlantica .B Normacusineis a tertiary indole B reduced alkaloid PE- that and was -induced isolated from the contractions root bark of in Strychnosrat aortic atlantica rings, with. Normacusine a molar antagonist B reducedpotency PE- and (serotonin-inducedpA2) value of 7.05 contractions± 0.11, and in non- rat aorticcompetitively rings, with inhibits a molar 5-HT-induced antagonist potency contractions (pA2) with value a p ofA2 7.05 value ± 0.11, of 7.02 and± non-compet-0.08 [49]. itivelyHarmine, inhibits 5-HT-induced harman, and contractions were with isolated a pA2 from value the of seeds7.02 ± of0.08Peganum [49]. harmala L. The relaxationHarmine, harman, potency ofand these harmaline compounds were againstisolated histamine, from the seeds carbachol, of Peganum and KCl-induced harmala L. Thecontractions relaxation revealed potency EC50 of these values compounds for harmane, against harmine, histamine, and harmaline carbachol, of and 28 ± KCl-in-3, 16 ± duced4, and contractions 20 ± 3 µM against revealed carbachol; EC50 values 21 ± for2, 10harmane,± 2, and harmine, 143 ± 20 andµM harmaline against histamine, of 28 ± 3,

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16 ± 4, and 20 ± 3 µM against carbachol; 21 ± 2, 10 ± 2, and 143 ± 20 µM against histamine, 51 51± 5,± 5, 37 37± ±3, 3, andand 131131 ± 3030 µMµM against against KCl, KCl, respectively. respectively. Harmine Harmine displayed displayed the most the most potencypotency among among the the three three indoleindole alkaloids alkaloids (Figure (Figure 15) 15 [50].)[50 ].

Figure 15. Figure 15.Spasmolytic Spasmolytic activity of of indole indole alkaloids. alkaloids. 3.14. Antileishmanial Activity 3.14. Antileishmanial Activity Ramiflorines A and B were isolated from Aspidosperma ramiflorum. These two indole Ramiflorines A and B were isolated from Aspidosperma ramiflorum. These two indole alkaloidsalkaloids exhibited exhibited significant significant effects effects against against LeishmaniaLeishmania amazonensis amazonensis, a parasite, a parasite that causes that causes a diseasea disease known knownas as leishmaniasis.leishmaniasis. Ramiflorines Ramiflorines A and A and B displayed B displayed inhibitory inhibitory activity activity againstagainst the the parasite, parasite, with with LDLD5050 valuesvalues of of 16.37 16.37 ± ±1.61.6 and and 4.97 4.97 ± 0.9± mg/mL,0.9 mg/mL, respectively, respectively, whichwhich was was 3–10-fold 3–10-fold higherhigher than the the impacts impacts of ofthe the whole-plant whole-plant alkaloidal alkaloidal extract. extract. Their Their Molecules 2021, 26, x FOR PEER REVIEW 17 of 28 modesmodes of of action action were were notnot determined but but migh mightt be besimilar similar to the to effects the effects exerted exerted by other by other corynanthecorynanthe dimeric dimeric indoleindole alkaloids (Figure (Figure 16) 16 [51].)[51 ].

Figure 16. AntileishmanialFigure 16. activityAntileishmanial of indole alkaloids. activity of indole alkaloids.

3.15. Lipid-Lowering Activity Ellipticine and 9-methoxyellipticine were isolated from borbonica. A triglyc- eride assay in the 3T3-L1 adipocyte model was used to evaluate the lipid-lowering activity of these two compounds. The results indicated that both compounds significantly reduced the formation of lipid droplet by 80% at 10 µmol × L−1 and exerted a dose-dependent re- duction in lipid formation at a concentration range of 0.01–10 µmol × L−1. The EC50 values of ellipticine and 9-methoxyellipticine were 0.41 and 0.92 µmol × L−1, respectively. This activity might be due to the retardation of adipogenesis and lipogenesis through interca- lation into supercoiled DNA [52]. was isolated from the plant minor [53]. At doses of 20 and 30 mg/kg, vincamine exhibited significant reductions in the levels of serum triglycerides (TG), total (TC), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipo- protein cholesterol (VLDL-C), and a comparative increase in high-density lipoprotein cho- lesterol (HDL-C), resulting in the overall improvement of the lipid profile of rats (Figure 17) [54].

Figure 17. Lipid-lowering activity of indole alkaloids.

3.16. Antimycobacterial Activity is an iboga-type indole alkaloid isolated from the root of Tabernaemon- tana ternifolia that displayed weak inhibitory activity against Mycobacterium tuberculosis. Coronaridine exhibited 90% inhibition against the bacterium, with a MIC of 82.64 µg/mL [55].

Molecules 2021, 26, x FOR PEER REVIEW 17 of 28

Figure 16. Antileishmanial activity of indole alkaloids. Molecules 2021, 26, 2297 16 of 26 3.15. Lipid-Lowering Activity

3.15.Ellipticine Lipid-Lowering and 9-methoxyellipticine Activity were isolated from Ochrosia borbonica. A triglyc- eride assay in the 3T3-L1 adipocyte model was used to evaluate the lipid-lowering activity Ellipticine and 9-methoxyellipticine were isolated from Ochrosia borbonica. A triglyc- of these two compounds. The results indicated that both compounds significantly reduced eride assay in the 3T3-L1 adipocyte model was used to evaluate the lipid-lowering activity the formation of lipid droplet by 80% at 10 µmol × L−1 and exerted a dose-dependent re- of these two compounds. The results indicated that both compounds significantly reduced duction in lipid formation at a concentration range of 0.01–10 µmol × L−1. The EC50 values the formation of lipid droplet by 80% at 10 µmol × L−1 and exerted a dose-dependent of ellipticine and 9-methoxyellipticine were 0.41 and 0.92 µmol × L−1, respectively. This reduction in lipid formation at a concentration range of 0.01–10 µmol × L−1. The EC activity might be due to the retardation of adipogenesis and lipogenesis through interca-50 values of ellipticine and 9-methoxyellipticine were 0.41 and 0.92 µmol × L−1, respectively. lation into supercoiled DNA [52]. This activity might be due to the retardation of adipogenesis and lipogenesis through Vincamine was isolated from the plant Vinca minor [53]. At doses of 20 and 30 mg/kg, intercalation into supercoiled DNA [52]. vincamine exhibited significant reductions in the levels of serum triglycerides (TG), total Vincamine was isolated from the plant Vinca minor [53]. At doses of 20 and 30 mg/kg, cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipo- vincamine exhibited significant reductions in the levels of serum triglycerides (TG), total proteincholesterol cholesterol (TC), low-density (VLDL-C), lipoprotein and a comparative cholesterol increase (LDL-C), in high-density and very-low-density lipoprotein lipopro- cho- lesteroltein cholesterol (HDL-C), (VLDL-C), resulting and in athe comparative overall improvement increase in high-density of the lipid lipoproteinprofile of rats cholesterol (Figure 17)(HDL-C), [54]. resulting in the overall improvement of the lipid profile of rats (Figure 17) [54].

Figure 17. Lipid-lowering activity of indole alkaloids. Figure 17. Lipid-lowering activity of indole alkaloids. 3.16. Antimycobacterial Activity 3.16. Antimycobacterial Activity Coronaridine is an iboga-type indole alkaloid isolated from the root of TabernaemontanaCoronaridine is ternifolia an iboga-typethat indole displayed alkaloid weak isolated inhibitory from the root activity of Tabernaemon- against tanaMycobacterium ternifolia that tuberculosis displayed. Coronaridine weak inhibitory exhibited activity 90% against inhibition Mycobacterium against the tuberculosis bacterium,. Coronaridinewith a MIC of exhibited 82.64 µg/mL 90% [inhibition55]. against the bacterium, with a MIC of 82.64 µg/mL [55]. Globospiramine, a new spirobisindole alkaloid that displayed significant antimy- cobacterial activity against Mycobacterium tuberculosis, was isolated from Voacanga globosa. This compound exhibited potent inhibitory activity against the bacterium, with a MIC of 4.00 µg/mL in a microplate Alamar blue assay and a MIC of 5.20 µg/mL in a low- recovery assay [56]. and voacangine were isolated from the plant Tabernaemontana citrifolia and were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis. Both of these compounds displayed inhibitory effects against the bacterium, with MICs of 50.00 µg/mL for each (Figure 18)[57]. Voacamine is a bis-indole-type alkaloid isolated from the root of Tabernaemontana arborea. The compound showed inhibitory activity against the causative agent of tuberculosis, Mycobacterium tuberculosis. The results showed that the MIC and the IC50 values were 15.60 and 16.30 µg/mL, respectively (Table1, Figure 19)[58]. Molecules 2021, 26, x FOR PEER REVIEW 18 of 28

Globospiramine, a new spirobisindole alkaloid that displayed significant antimyco- bacterial activity against Mycobacterium tuberculosis, was isolated from Voacanga globosa. This compound exhibited potent inhibitory activity against the bacterium, with a MIC of 4.00 µg/mL in a microplate Alamar blue assay and a MIC of 5.20 µg/mL in a low-oxygen recovery assay [56]. Ibogaine and voacangine were isolated from the plant Tabernaemontana citrifolia and were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis. Both of these compounds displayed inhibitory effects against the bacterium, with MICs of Molecules 2021, 26, 2297 17 of 26 50.00 µg/mL for each (Figure 18) [57].

Figure 18. AntimycobacterialFigure 18. Antimycobacterial activity of indole alkaloids. activity of indole alkaloids. Table 1. Plant source and pharmacological activity of indole compounds. Voacamine is a bis-indole-type alkaloid isolated from the root of Tabernaemontana ar- Posology Compoundsborea. The Plant compound Source showed(Route, inhibitory Dose) activitySubject against the Method causative agent Identified of tuberculo- Effect References sis, Mycobacterium tuberculosis. The results showed that Discthe MIC diffusion and the IC50 values were Scholarisine I, II, III, F Alstonia rupestris - Fungi Antifungal [5] 15.60 and 16.30 µg/mL, respectively (Table 1, Figure 19) [58].method Alstonia rupestris - Enzyme Enzyme inhibition Scholarisine I, VI assay Anti-inflammatory [5] Disc agar diffusion Kopsihainin D, E, F Kopsia hainanensis - Antibacterial [6] method Disc agar diffusion Kopsiflorine Kopsia hainanensis - Bacteria Antibacterial [6] method Ervatamia Bacteria Erchinine A, B - Broth microdilution Antibacterial, [7] chinensis method Antifungal Melodinus - Bacteria Broth microdilution Melokhanine B, D, E, F khasianus method Antibacterial [8] Melodinus - Bacteria Broth microdilution Melokhanine B, D, E, F khasianus method Antibacterial [8] Strictamine Alstonia scholaris - Virus - Antiviral [9] 17-nor-excelsinidine Alstonia scholaris - Virus - Antiviral [9] Microtiter syncytium Trigonoliimine Trigonostemon lii - Virus Antiviral [10] formation infectivity assay Naucleaoffine A, B Nauclea officinalis Virus Antiviral [11] Intraperitoneal, Mitragynine Mitragyna speciosa Mice Forced swim test, 10 and Tail suspension test Antidepressant [12] 30 mg/kg Psychotria suterella - Rat brain Enzymatic assay Lyaloside mitochondria Antidepressant [13] Molecules 2021, 26, 2297 18 of 26

Table 1. Cont.

Posology Compounds Plant Source (Route, Dose) Subject Method Identified Effect References

Psychotria laciniata - Rat brain Enzymatic assay Strictosamide mitochondria Antidepressant [13] Intraperitoneal, Harmane Mice Forced swim test Antidepressant [14] 5–15 mg/kg Intraperitoneal, Norharmane Peganum harmala Mice Forced swim test Antidepressant [14] 2.5–10 mg/kg Intraperitoneal, Harmine Peganum harmala Mice Forced swim test Antidepressant [14] 5–15 mg/kg Psychotria 3, 7.5, and Mice Hole-board test, Psychollatine umbellate 15 mg/kg Forced swim test Antidepressant [15] Melodinus Human Tabersonine fusiformis - tumor cell MTT assay Anticancer [16] line Human Strychnos Brucine - hepatoma cell MTT-colorimetric Anticancer nux-vomica assay [17] line Human Naucleaoral A, B Nauclea orientalis - cancer cell MTT-colorimetric Anticancer [18] line assay Human lung Anthocephalus Vallesiachotamine cadamba - cancer cell MTT assay Anticancer [19] line Human lung Anthocephalus Iso-vallesiachotamine cadamba - cancer cell MTT assay Anticancer [19] line Ervatamia Human Ervachinine A, C, D chinensis - cancer cell MTT assay Anticancer [20] line Tabernaemontana Human Jerantinine A, B corymbosa cancer cell MTT assay Anticancer [21] line Platelet-activating Melodinus Melaxilline A, B axillaris. - Rat factor induced Anti-inflammatory [22] inhibition assay Alstonia - Enzyme Enzyme inhibition Perakine N4-oxide yunnanensis. assay Anti-inflammatory [23] Alstonia - Enzyme Enzyme inhibition Raucaffrinoline N4-oxide yunnanensis. assay Anti-inflammatory [23] Alstonia - Enzyme Enzyme inhibition Vinorine N4-oxide yunnanensis. assay Anti-inflammatory [23] Intraperitoneal, Hot plate test, Strictosamide Nauclea officinalis 20 and Mice Analgesic [24] 40 mg/kg Writhing test Intravenous, Strictosamide Psychotria laciniata 20 and Mice Acetic acid and Anti-inflammatory [24] 40 mg/kg TPA-induced assay Intraperitoneal, Strychnos Brucine nux-vomica 30, 15, and Mice Formalin test Analgesic [25] 7.5 mg/kg Intraperitoneal, Strychnos Brucine nux-vomica 30, 20, 14.7, and Mice Hot plate test Analgesic [25] 10.3 mg/kg Intraperitoneal, Strychnos Brucine nux-vomica 30, 15, 7.5, and Mice Writhing test Analgesic [25] 3.75 mg/kg Intraperitoneal, Strychnos Brucine N-oxide nux-vomica 200, 100 and Mice Formalin test Analgesic [25] 50 mg/kg Strychnos Intraperitoneal, Brucine N-oxide nux-vomica 200, 140, 98, Mice Hot plate test Analgesic [25] and 68 mg/kg Strychnos Intraperitoneal, Brucine N-oxide nux-vomica 200, 100, 50, Mice Writhing test Analgesic [25] and 25 mg/kg Intraperitoneal, Mitragynine Mitragyna speciosa Mice Hot plate test Analgesic [26] 3–35 mg/kg Hot plate test, Tail 7-hydroxymitragynine Mitragyna speciosa Subcutaneous, Mice Analgesic [27] 2.5–10 mg/kg flick test Tail-flick test, Hot-plate test, Psychotria Umbellatine umbellate 100–300 mg/kg Mice Formalin test and Analgesic [28] Capsaicin-induced pain test Enzyme, Enzyme inhibition Catharanthus assay, Glucose Vindoline roseus - Myoblast Antidiabetic [29] cell uptake activity assay Molecules 2021, 26, 2297 19 of 26

Table 1. Cont.

Posology Compounds Plant Source (Route, Dose) Subject Method Identified Effect References

Enzyme, Enzyme inhibition Catharanthus assay, Glucose Vindolidine roseus - Myoblast Antidiabetic [29] cell uptake activity assay Enzyme, Enzyme inhibition Catharanthus assay, Glucose Vindolicine roseus - Myoblast Antidiabetic [29] cell uptake activity assay Enzyme, Enzyme inhibition Catharanthus assay, Glucose Vindolinine roseus - Myoblast Antidiabetic [29] cell uptake activity assay Enzyme, Enzyme inhibition Catharanthus assay, Glucose Vindogentianine roseus - Myoblast Antidiabetic [30] cell uptake activity assay Myoblast Akuammicine Picralima nitida - Glucose uptake Antidiabetic [31] cell activity assay Oral, Aspidosperma Subcutaneous, Mice Suppressive test Ellipticine vargasii 50, 10 and Antimalarial [32] 1 mg/kg/day Oral, Aspidosperma Subcutaneous, Mice Suppressive test Olivacine olivaceum. 100, 50, 10, and Antimalarial [32] 1 mg/kg/day Flindersia Flinderole A, B, C acuminate - Malarial Micrdilution Antimalarial [33] F. amboinensis Parasite method - Malarial Micrdilution Apisdospermin Parasite method Antimalarial [34] Aspidosperma - Malarial Micrdilution Aspidospermine pyrifolium Parasite method Antimalarial [34] Demethoxy- Aspidosperma - Malarial Micrdilution Antimalarial [34] aspidospermine pyrifolium Parasite method Aspidosperma - Malarial Micrdilution Vallesine pyrifolium Parasite method Antimalarial [34] Aspidosperma - Malarial Micrdilution Palosine pyrifolium Parasite method Antimalarial [34] Geissospermum Malarial Parasite lactate Geissolosimine vellosii - dehydrogenase Antimalarial [35] Parasite assay Geissospermum Malarial Parasite lactate Geissospermine vellosii - dehydrogenase Antimalarial [35] Parasite assay Geissospermum Malarial Parasite lactate Geissoschizoline vellosii - dehydrogenase Antimalarial [35] Parasite assay Geissospermum Malarial Parasite lactate Geissoschizone vellosii - dehydrogenase Antimalarial [35] Parasite assay Phenylephrine- Nauclea Injection, Naucline Rat Hypotensive [36] officinalis × −5 induced 1 10 M assay Phenylephrine- Nauclea Injection, Angustine Rat Hypotensive [36] officinalis × −5 induced 1 10 M vasodilation assay Phenylephrine- Nauclea Injection, Angustidine Rat Hypotensive [36] officinalis × −5 induced 1 10 M vasodilation assay Phenylephrine- Nauclea Injection, Nauclefine Rat Hypotensive [36] officinalis × −5 induced 1 10 M vasodilation assay Phenylephrine- Nauclea Injection, Naucletine Rat Hypotensive [36] officinalis × −5 induced 1 10 M vasodilation assay Phenylephrine- Alstonia Alstilobanine A, B, C angustiloba - Rat induced Hypotensive [37] vasodilation assay Phenylephrine- Alstonia Undulifoline undulifolia - Rat induced Hypotensive [37] vasodilation assay Phenylephrine- Tabernaemontana Taberniacin A, B divaricata - Rat induced Hypotensive [38] vasodilation assay Phenylephrine- Uncaria villosa Injection, Villocarine A 30 µM Rat induced Hypotensive [39] vasodilation assay Macusine B Rauvolfia reflexa - Cholinesterase Cholinesterase Enzyme Inhibition assay Anticholinesterase [40] Vinorine Rauvolfia reflexa - Cholinesterase Cholinesterase Enzyme Inhibition assay Anticholinesterase [40] Molecules 2021, 26, 2297 20 of 26

Table 1. Cont.

Posology Compounds Plant Source (Route, Dose) Subject Method Identified Effect References

Rauvolfia reflexa - Cholinesterase Cholinesterase Isoreserpiline Enzyme Inhibition assay Anticholinesterase [40] Rescinnamine Rauvolfia reflexa - Cholinesterase Cholinesterase Enzyme Inhibition assay Anticholinesterase [40] Voacangine Tabernaemontana - Cholinesterase Cholinesterase Anticholinesterase [41] hydroxyindolenine australis Enzyme Inhibition assay Tabernaemontana - Cholinesterase Cholinesterase Rupicoline australis Enzyme Inhibition assay Anticholinesterase [41] Ervatamia - Cholinesterase Cholinesterase Coronaridine hainanensis Enzyme Inhibition assay Anticholinesterase [42] Ervatamia Voacangine - Cholinesterase Cholinesterase hainanensis Enzyme Inhibition assay Anticholinesterase [42] Nauclea officinalis - Cholinesterase Cholinesterase Angustidine Enzyme Inhibition assay Anticholinesterase [43] Nauclea officinalis - Cholinesterase Cholinesterase Nauclefine Enzyme Inhibition assay Anticholinesterase [43] Angustine Nauclea officinalis - Cholinesterase Cholinesterase Enzyme Inhibition assay Anticholinesterase [43] Harmane Perganum harmala 100–200 µM Rabbit - Platelet Antiplatelet [44] Harmine Perganum harmala 100–200 µM Rabbit - Platelet Antiplatelet [44] Perganum harmala 100–200 µM Rabbit - Harmol Platelet Antiplatelet [44] Kurryam Murraya koenigii 10, 30, and Rat Castor oil-induced Antidiarrheal [45] 50 mg/kg test Murraya koenigii 10, 30, and Rat Castor oil-induced Koenimbine 50 mg/kg test Antidiarrheal [45] Castor oil, Intraperitoneal, Magnesium sulfate, Bisnordihydrotoxiferine Strychnos trinervis Rat, Mice and Arachidonic Antidiarrheal [46] 3.12–25.00 mg/kg acid-induced diarrhea test Rat fundic Arachidonic acid, 5- strip, hydroxytryptamine, Trinervine Strychnos trinervis - Guinea-pig Histamine, and Spasmolytic [47] Carbachol mediated ileum contractions Acetylcholine, Rat uterus Oxytocin-induced Strychnos Guinea-pig Bisnordihydrotoxiferine diuaricuns - contraction, and Spasmolytic [48] ileum Histamine-induced contractions Phenylephrine and Normacusine B Strychnos atlantica 0.1, 0.3, 1.0, and Rat aorta 3.0 µM Serotonin-induced Spasmolytic [49] contractions. Histamine, Guinea-Pig Carbachol, and Harmine Perganum harmala 1–100 µM Spasmolytic [50] Trachea KCl-induced contractions Histamine, Guinea-Pig Carbachol, and Harmane Perganum harmala 1–100 µM Spasmolytic [50] Trachea KCl-induced contractions Histamine, Guinea-Pig Carbachol, and Harmaline Perganum harmala 1–100 Mm Spasmolytic [50] Trachea KCl-induced contractions Aspidosperma Ramiflorine A, B ramiflorum - Parasite Antileishmanial [51] Mouse Ellipticine Ochrosia borbonica 0.01–10 µmol·L−1 fibroblast Triglyceride assay Lipid-lowering [52] cells Mouse 9-methoxyellipticine Ochrosia borbonica 0.01–10 µmol·L−1 fibroblast Triglyceride assay Lipid-lowering [52] cells Oral, Vincamine Vinca minor 20 and Rat Lipid-lowering [53,54] 30 mg/kg Tabernaemontana Microplate Alamar Coronaridine - Bacteria Antimycobacterial [55] ternifolia blue assay Microplate Alamar Globospiramine Voacanga globosa - Bacteria blue assay and Antimycobacterial [56] Low-oxygen recovery assay Tabernaemontana - Bacteria Bactec radiometric Ibogaine citrifolia methodology Antimycobacterial [57] Tabernaemontana Voacangine - Bacteria Bactec radiometric citrifolia methodology Antimycobacterial [57] Tabernaemontana Voacamine - Bacteria Resazurin arborea. microtiter assay Antimycobacterial [58] Molecules 2021, 26, x FOR PEER REVIEW 22 of 28

Guinea-Pig Histamine, Carbachol, and KCl- Harmaline Perganum harmala 1–100 Μm Spasmolytic [50] Trachea induced contractions Ramiflorine A, B Aspidosperma ramiflorum - Parasite Antileishmanial [51] Mouse Ellipticine Ochrosia borbonica 0.01–10 µmol·L–1 Triglyceride assay Lipid-lowering [52] fibroblast cells Mouse 9-methoxyellipticine Ochrosia borbonica 0.01–10 µmol·L–1 Triglyceride assay Lipid-lowering [52] fibroblast cells Oral, Vincamine Vinca minor Rat Lipid-lowering [53,54] 20 and 30 mg/kg Tabernaemontana Coronaridine - Bacteria Microplate Alamar blue assay Antimycobacterial [55] ternifolia Microplate Alamar blue assay and Globospiramine Voacanga globosa - Bacteria Antimycobacterial [56] Low-oxygen recovery assay Tabernaemontana Ibogaine - Bacteria Bactec radiometric methodology Antimycobacterial [57] Molecules 2021, 26, 2297 citrifolia 21 of 26 Tabernaemontana Voacangine - Bacteria Bactec radiometric methodology Antimycobacterial [57] citrifolia Voacamine Tabernaemontana arborea. - Bacteria Resazurin microtiter assay Antimycobacterial [58]

Figure 19. An overview of the pharmacological activities of major indole alkaloids.

4. Pharmacokinetic Profile

A pharmacokinetics (pk) study of a compound describes four basic phenomena that occur when a foreign substance (xenobiotic) enters the body: absorption, distribution, or biotransformation, and excretion. The kinetics of these four phenomena help researchers understand, analyze, and predict the biological activities of xenobiotics [59]. Absorption describes the process through which a drug enters the body’s circulation at the site of administration across biological membranes. The rate and extent of absorption depend on the route and the site of administration, and the chemical properties of the drug. Absorption directly affects the bioavailability of substances in the blood and can occur through various mechanisms, including passive and facilitated diffusion, active transport, endocytosis, and exocytosis. Distribution is the next step, during which substances from the bloodstream enter into tissues. Distribution is affected by cardiac output, local blood flow, capillary permeability, tissue volume, regional pH, the degree of plasma binding, and the substances’ relative lipophilicity. Metabolism is a fundamental process through which a substance is chemically altered within the body to facilitate excretion, which typically occurs in the . Metabolism involves Phase I and Phase II reactions. Although the Molecules 2021, 26, 2297 22 of 26

primary goal of this process is to facilitate excretion, metabolism can convert the active form of a substance into an inactive form or activate a previously inactive form, as in the case of prodrugs. After metabolism, substances leave the body through a process known as excretion, which can occur through many methods, including in urine, feces, sweat, milk, and expired air. Some of the compounds reviewed in this article were subjected to pk studies (Table2).

Table 2. Pharmacokinetic profiles of indole alkaloids.

Compound Name Parameters Brucine Harmane Vindoline Mitragynine 7-OH-mitragynine Administration Route Oral, IV Oral, IV Oral, IV Oral Oral Oral Bioavailability 40.31%–47.15% 19.41% 5.4% - - Oral: 606.3 ng/mL h, AUC Ratio: 1:1.9:5.3 (at different doses) - IV: 2245.7 (first dose), -- 2258.0 (second dose) ng/mL h Oral: 606.6 ng/mL, Oral: 1059.56 ± 91.06 ng/mL, Cmax 929.22–1451.58 µg/L IV: 1595.9 (first dose), 0.63 ± 0.18 µg/mL - IV: 583.19 ng/mL 2913.9 ng/mL (second dose) ± T Oral: 0.23 0.06 h, ± - max 0.3–0.5 h IV: 0.03 h Oral: 0.3 h 1.83 1.25 h Oral: 0.5 h t1/2 -- IV: 1.0 h (first dose), - 24 min 1.4 h (second dose) Oral; 21.6 L/kg Vd -- IV: 2.0 L/kg (first dose), 89.50 ± 30.30 L/kg - 3.3 L/kg (second dose) Oral: 26.6 L/h/kg CL - - IV: 1.4 L/h/kg (first dose), - 43.2 ± 3.5 mL/min/kg 1.4 L/h/kg (second dose) References [60][64][63][61][62]

Brucine is among the major indole alkaloids with various potent pharmacological activities. The pk properties of brucine were investigated after intravenous and oral ad- ministration to rats, which resulted in some significant outcomes. The determination of the apparent partition coefficient, plasma protein binding, and other pk properties were evaluated. Brucine showed no sign of degradation in gastrointestinal pH conditions, and the total concentration of the drug in both the water and oil phase did not change after 2 h of incubation at pH 1–7.8, indicating relative stability under acidic conditions. The pH has a substantial effect on the apparent partition coefficient, particularly in the range of pH 6–7.8. Brucine showed a partition coefficient below 0.1 due to complete protonation at pH 1–5. The apparent partition coefficient of brucine under different pH conditions in- dicated that the most likely absorption site was the intestine because brucine became ionized under stomach-like pH conditions. The protein binding assay revealed that the majority of brucine was primarily bound to the rat plasma protein, with the unbound fraction representing 34.4% ± 3.0%, 35.1% ± 2.9%, and 40.4% ± 2.7% of the total at treat- ment concentrations of 500, 1250, and 2500 µg/L, respectively. After administering single intravenous doses of 2.5, 5, and 10 mg/kg, the ratio of the mean area under the curve (AUC) values was 1:1.9:5.3 when the dose increased at a ratio of 1:2:4. The total body clearance drastically decreased at the 10 mg/kg dose, whereas the terminal elimination half-life (T1/2) increased in a dose-dependent fashion. Brucine was rapidly absorbed (Tmax = 0.3–0.5 h) and achieved a mean maximum serum concentration (Cmax) between 929.22 and 1451.58 µg/L after oral administration. The absolute oral bioavailability was 40.31%–47.15%. The increase in AUC was proportional to the increase in dose. Both the oral and intravenous administration routes for brucine showed non-linear pk properties overall [60]. A single dose of 40 mg mitragynine (kg/body wt.) was given to six rats, and a non-compartmental pk analysis was performed. Mitragynine was rapidly absorbed af- ter oral administration, reaching a Cmax of 0.63 ± 0.18 µg/mL at 1.83 ± 1.25 h (Tmax), with an absorption rate constant (ka) of 1.43 ± 0.90 h−1. Mitragynine showed a high volume of distribution (Vd/F, 89.50 ± 30.30 L/kg) due to distribution into highly perfused and lipid-containing tissues, specifically the brain, which is the site of action for mitragy- nine. Mitragynine displayed a slow elimination, with an elimination rate constant (λz) of Molecules 2021, 26, 2297 23 of 26

0.07 ± 0.01 h−1 and a clearance rate (Cl/F) of 1.60 ± 0.58 L/h. The half-lives of absorp- tion (t1/2 ab) and elimination (t1/2 λz) were 0.48 ± 0.36 and 9.43 ± 1.74 h, respectively. The mean residence time (MRT0→∞) was 14.00 ± 2.84 h [61]. Another study showed that mitragynine experienced 26% degradation in simulated gastric fluid, indicating that mitragynine was unstable in gastric fluid, whereas stability was demonstrated in simu- lated intestinal fluid. Another mitragynine-like compound, 7-hydroxymitragynine, was degraded by up to 27% in simulated gastric juice, which might be due to conversion to mitragynine (23%), whereas only 6% degradation was observed in simulated intestinal fluid. Both of these compounds exhibited greater than 90% protein binding, as deter- mined by the equilibrium analysis. In addition, 7-hydroxymitragynine was shown to have moderate intestinal and blood–brain barrier (BBB) permeability with a significant conversion to mitragynine. It showed an intermediate level of intestinal absorption. It was rapidly metabolized by Phase I metabolic enzymes, with a short T1/2 of 24 min. The high clearance of 43.2 ± 3.5 mL/min/kg in the presence of human liver micro- somes results in low bioavailability and limited distribution to tissues. Mitragynine and 7-hydroxymitragynine exhibited significant P-gp (P-glycoprotein) inhibition, similar to verapamil, indicating the possibility of drug-drug interactions when coadministered with drugs that are P-gp substrates [62]. The pk study of vindoline was characterized by the use of a non-compartmental method. Doses of 15 mg/kg (oral), 3 mg/kg (IV), and 6 mg/kg (IV) of vindoline were administered to rats. The area under the plasma concentration-time curves, AUC (0-t) and AUC (0-∞,) were 606.3 and 609.1 ng/mL h, respectively for the oral dose, 2245.7 and 3776.2 ng/mL h for the low-dose IV administration, and 2258.0 and 3788.4 ng/mL h for the high-dose IV administration. For the oral dose, the T1/2, the plasma clearance (CL), and the apparent volume of distribution (V) were 0.5 h, 26.6 L/h/kg, and 21.6 L/kg, respectively. For the IV doses, the T1/2, CL, and V values were 1.0 h, 1.4 L/h/kg, and 2.0 L/kg, respectively, for the 3 mg/kg concentration and 1.4 h, 1.6 L/h/kg, and 3.3 L/kg for the 6 mg/kg concentration, indicating a dose-dependent increase in these parameters. The Cmax and Tmax were calculated, resulting in values of 606.6 ng/mL and 0.3 h, respectively, for the oral dose. For the IV vindoline administration, a dose-dependent increase in Cmax was observed, with values of 1595.9 and 2913.9 ng/mL, respectively, observed for the 3 and 6 mg/kg concentrations. The bioavailability of vindoline after oral administration was 5.4% [63]. Harmane was immediately absorbed into the blood circulation, with a high Cmax of 1059.56 ± 91.06 ng/mL and a short Tmax of 0.23 ± 0.06 h after the administration of a single oral dose at 30.0 mg/kg body weight in rats. The plasma concentration-time curve for harmane displayed a rapid decrease, with an elimination half-life (T1/2e) of 2.26 ± 0.53 h, and the levels fell below the detection limits within 8 h after administration. The oral bioavailability of harmane was 19.41%. The absorption rate constant (Ka), distribution rate constant (Kd), and elimination rate constant (Ke) were 3.64, 1.51, and 0.32 per hour. Other parameters were also evaluated in that study. After an intravenous bolus administration of harmane at a dose of 1.0 mg/kg, the harmane plasma concentration versus time curve yielded a sharp decline in the concentration, followed by a fast phase of decrease, with a T1/2e of 4.71 ± 1.46 h, until the levels fell below the detection limits. The volume of distri- bution (Vd) value for harmane was relatively high. The Cmax value was 583.19 ng/mL at a Tmax of 0.03 h. The Ka, Kd, and Ke values were 4.18, 1.54, and 0.16 per hour. The metabolic process for harmane was also determined, and sulfate conjugation appeared to be the most prominent process [64].

5. Conclusions and Future Perspectives Indole alkaloids of plant origin have demonstrated diverse potential pharmacological activities; therefore, we reviewed various indole compounds and discussed their respective pharmacological importance. Although the therapeutic importance of these compounds has been evaluated, in many cases, an insufficient number of studies have examined their efficacy and safety. The effects demonstrated by various compounds, including Molecules 2021, 26, 2297 24 of 26

strictosamide (antidepressant, analgesic, and anti-inflammatory), mitragynine (analgesic and antidepressant), harmane (antidepressant, spasmolytic, and antiplatelet), brucine (analgesic and anticancer), ellipticine (antimalarial and lipid-lowering), globospiramine (antimycobacterial), vindogentianine (antidiabetic), tabersonine (anticancer), scholarisine I (antifungal and anti-inflammatory), angustine (anticholinesterase and hypotensive), sug- gest that further in-depth studies should be performed to endorse the clinical effectiveness of these compounds. In addition, the mechanistic activities at the sites of action and studies should be thoroughly investigated to identify suitable lead compounds for further development. Due to the lack of extensive pharmacological information regarding these compounds obtained from previous studies, new clinical studies that are performed using well-developed methodologies remain necessary to identify new therapeutic agents with increased efficacy and reduced side effects. The pk properties of some compounds have also shown promising results that should be explored further. This review can be useful for researchers who plan to extensively study indole alkaloids in the future.

Author Contributions: Conceptualization, methodology, and writing—original draft preparation, F.O.; investigation and writing—review and editing, A.M.T., A.M.A., K.D., T.B.E., and J.S.-G.; visual- ization, supervision, and project administration, M.A.S. and J.S.-G.; funding acquisition, J.S.-G. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Available data are presented in the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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