pharmaceuticals Review An Overview of the Biological ActivityActivity ofof Pyrrolo[3,4Pyrrolo[3,4-‐c]pyridine Derivatives 1 2, Anna WWójcickaójcicka 1 and Aleksandra Redzicka 2,** 1 1 DepartmentDepartment of of Pharmaceutical Pharmaceutical Technology Technology,, Faculty Faculty of of Pharmacy, Pharmacy, Wroclaw Wroclaw Medical University, BorowskaBorowska 211A, 211A, 50 50-556‐556 Wroc Wrocław,ław, Poland; Poland; [email protected] [email protected] 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 5050-556‐556 Wroc Wrocław,ław, Poland Poland * Correspondence: [email protected] * Correspondence: [email protected] Abstract: Pyrrolo[3,4Pyrrolo[3,4-‐cc]pyridine]pyridine is is one one of of the the six six structural structural isomers isomers of the bicyclic ring system containingcontaining a a pyrrole moiety fused to a pyridine nucleus. The broad spectrum of pharmacological propertiesproperties of pyrrolo[3,4 pyrrolo[3,4-‐c]pyridine]pyridine derivatives is is the the main reason for developing new compounds containingcontaining this this scaffold. scaffold. This This review review presents presents studies studies on on the the biological biological activity activity of of pyrrolo[3,4 pyrrolo[3,4-‐ cc]pyridines]pyridines that that have have been been reported reported in in the scientific scientific literature. Most of these derivatives have been studiedstudied as as analgesic and sedative agents. Biological Biological investigations investigations have have shown shown that that pyrrolo[3,4 pyrrolo[3,4-‐ cc]pyridines]pyridines can can be be used to to treat diseases of the nervous and immune systems. Their antidiabetic, antimycobacterial,antimycobacterial, antiviral, antiviral, and antitumor activities also have been found. Keywords:Keywords: pyrrolo[3,4-pyrrolo[3,4‐cc]pyridine;]pyridine; pyrrolepyrrole heterocycles; heterocycles; biological biological activity; activity; structure-activity structure‐activity rela- relationships;tionships; analgesic analgesic activity; activity; azaizoindoles; azaizoindoles; anticancer anticancer activity activity Citation: Wójcicka, A.; Redzicka, A. AnCitation: OverviewWójcicka, of the Biological A.; Redzicka, A. ActivityAn Overview of Pyrrolo[3,4 of the Biological‐c]pyridine 1. Introduction Introduction Derivatives.Activity of Pyrrolo[3,4- Pharmaceuticalsc]pyridine 2021, 14, Pyrrolopyridines areare heterocyclic heterocyclic compounds compounds containing containing a five-membered a five‐membered pyrrole pyrrole ring 354.Derivatives. https://doi.org/10.3390/Pharmaceuticals 2021, 14, ringfused fused to a six-membered to a six‐membered pyridine pyridine ring. They ring. are alsoThey called are azaindolesalso called or azaindoles azaizoindoles, or ph14040354354. https://doi.org/10.3390/ azaizoindoles,depending on the depending arrangement on the of arrangement nitrogen atoms of in nitrogen the bicyclic atoms structure. in the bicyclic Pyrrolopyridines structure. ph14040354 occur in six isomeric forms (Figure1). Academic Editor: Antonella Messore Pyrrolopyridines occur in six isomeric forms (Figure 1). Academic Editor: Antonella Messore Received: 28 February 2021 H N Accepted:Received: 289 April February 2021 2021 Published:Accepted: 911 April April 2021 2021 NH Published: 11 April 2021 N Publisher’s Note: MDPI stays N N N H neutralPublisher’s with Note: regardMDPI to jurisdictional stays neutral claims in published maps and with regard to jurisdictional claims in 1H‐pyrrolo[2,3‐b]pyridine 6H‐pyrrolo[3,4‐b]pyridine 1H‐pyrrolo[3,2‐b]pyridine institutionalpublished maps affiliations. and institutional affil- iations. H N Copyright: © 2021 by the authors. NH Licensee MDPI, Basel, Switzerland. Copyright: © 2021 by the authors. N N This article is an open access article N Licensee MDPI, Basel, Switzerland. N distributed under the terms and This article is an open access article H conditions of the Creative Commons distributed under the terms and Attribution (CC BY) license conditions of the Creative Commons 1H‐pyrrolo[2,3‐c]pyridine 2H‐pyrrolo[3,4‐c]pyridine 1H‐pyrrolo[3,2‐c]pyridine (http://creativecommons.org/licenses Attribution (CC BY) license (https:// /by/4.0/). creativecommons.org/licenses/by/ Figure 1. IsomericIsomeric forms forms of pyrrolopyridines. 4.0/). Pharmaceuticals 2021, 14, 354. https://doi.org/10.3390/ph14040354 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 354. https://doi.org/10.3390/ph14040354 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 354 2 of 26 25 TheThe pyrrolopyridinepyrrolopyridine scaffold scaffold occurs occurs in polyheterocyclicin polyheterocyclic compounds compounds of natural of natural origin. origin.The best The known best is known the alkaloid is the camptotheca alkaloid camptotheca1, isolated from 1, isolated the Camptotheca from the acuminata Camptothecatree. acuminataAs a topoisomerase tree. As a topoisomerase I inhibitor, it has I inhibitor, found application it has found in application cancer treatment in cancer and treatment is active andagainst is active HIV-1 against [1]. Other HIV alkaloids‐1 [1]. Other containing alkaloids the containing pyrrolopyridine the pyrrolopyridine system in their system structure in theirinclude structure pumiloside include2a ,pumiloside deoxypumiloside 2a, deoxypumiloside2b isolated from 2bOphiorrhiza isolated from pumila Ophiorrhiza[2], and pumilavariolin [2], B 3a and, deoxyvariolin variolin B B3a3b, deoxyvariolinisolated from an B antarctic3b isolated sponge fromKirkpatrickia an antarctic variolosa sponge[3], Kirkpatrickiaand the antiviral variolosa alkaloid [3], and mappicin the antiviral4, which alkaloid was mappicin isolated from 4, whichMappia was foetida isolated[4], from and Mappiaanticancer foetida meriolin [4], and derivatives anticancer5a–b meriolin[3] (Figure derivatives2). 5a‐b [3] (Figure 2). O O N O N N 1 O N H H H O HO O 2a OH N H NH2 O OH R N 3a) R= OH HO OH 3b) R= H N N O N H2N N H H O O 2b N OH H N N NH2 O OH 4 R N HO HO OH 5a) R= H 5b) R= OCH3 N N H FigureFigure 2. 2. AlkaloidsAlkaloids 1–51–5 containingcontaining pyrrolopyridine pyrrolopyridine scaffold. scaffold. DueDue to their structure containing two important pharmacophores, i.e., pyrrole and pyridine, pyrrolopyridines have have been been the subject of many pharmacological studies over thethe last last hundred hundred years. years. Pyrrole Pyrrole derivatives derivatives show show a a wide wide range range of of pharmacological pharmacological activity. activity. PyrrolesPyrroles could build the structure of porphyrin rings. Many of the drugs drugs contain a pyrrole pyrrole ring,ring, forfor example,example, nootropic nootropic (Piracetam), (Piracetam), anti-inflammatory anti‐inflammatory (Indometacin), (Indometacin), statins statins (Flu- (Fluvastatin),vastatin), neuroleptics neuroleptics (Molindone), (Molindone), drugs drugs used toused treat to insomnia treat insomnia (Zopiclone), (Zopiclone), migraine migraine(Sumatriptan), (Sumatriptan), Parkinson diseaseParkinson (Procyclidine), disease (Procyclidine), and erection disorders and erection (Tadalafil). disorders Com- (Tadalafil).pounds containing Compounds a pyrrole containing ring found a pyrrole in essential ring found oils arein usedessential as anticancer oils are used agents as anticancer(5-iodotubercidin) agents (5 [5‐iodotubercidin)] and antibacterial [5] agentsand antibacterial (Cefepim, agents Doripenem, (Cefepim, Meropenem) Doripenem, [6]. Meropenem)Fostemsavir has [6]. recently Fostemsavir been approved has recently for HIV been treatment. approved Drugs for HIV containing treatment. a pyrrolopy- Drugs containingridine scaffold a pyrrolopyridine such as Vemurafenib scaffold or such Pexidartinib as Vemurafenib are used or inPexidartinib anticancer are therapy used [3in]. anticancerPyrrolo[3,2- therapyc]pyridine [3]. Pyrrolo[3,2 derivatives‐c show]pyridine inhibitory derivatives effect show against inhibitory FMS kinase effect andagainst are FMSpromising kinase candidates and are for promising anticancer candidates and antiarthritic for anticancer drug development and antiarthritic [7]. drug developmentThis review [7]. presents biologically active derivatives of the pyrrolo[3,4-c]pyridine iso- c mer.This Pyrrolo[3,4- review ]pyridinepresents biologically derivatives haveactive not derivatives been introduced of the into pyrrolo[3,4 medicine‐c so]pyridine far, but as it results from studies presented in the literature, many of them show biological activity. isomer. Pyrrolo[3,4‐c]pyridine derivatives have not been introduced into medicine so far, Pharmaceuticals 2021, 14, 354 3 of 26 but as it results from studies presented in the literature, many of them show biological activity. 2. Biological Activity of Pyrrolo[3,4‐c]pyridine Derivatives 2.1. Antidiabetic Activity of Pyrrolo[3,4‐c]pyridine Derivatives Knutsen et al. [8] described 4‐substituted 6‐methyl‐pyrrolo[3,4‐c]pyridine‐1,3(2H)‐ dione derivatives 6 (Figure 3) that effectively reduce blood glucose levels without affecting the concentration of circulating insulin. The present compounds reduce blood glucose levels by stimulating glucose uptake into muscle and fat cells. Pharmaceuticals 2021, 14, 354 The ability of pyrrolo[3,4‐c]pyridine‐1,3(2H)‐dione derivatives 6 to stimulate the3 of 25 incorporation of glucose into lipids was tested. The maximum increase in insulin sensitivity achieved