molecules Review Plant-Based Indole Alkaloids: 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 Pharmacology, 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, India; [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 plants 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, Elsevier, 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:// analgesic, 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 brucine, mitragynine, 7-hydroxymitragynine, vindoline, and Vicente Micol and harmane, 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 indoles 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 animals, 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 vincristine and vinblastine (anticancer agents), that have since been developed, including vincristine and vinblastine (anticancer agents), reserpine (an antihypertensive agent), physostigmine (a cholinesterase inhibitor), and reserpine (an antihypertensive agent), physostigmine (a cholinesterase inhibitor), and ajmaline (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 nitrogen 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 Apocynaceae, sources. Indole Rubiaceae, 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 alkaloid 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,