Exploiting the Indole Scaffold to Design Compounds Binding
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molecules Review Exploiting the Indole Scaffold to Design Compounds y Binding to Different Pharmacological Targets Sabrina Taliani 1,* , Federico Da Settimo 1, Claudia Martini 1 , Sonia Laneri 2, Ettore Novellino 2 and Giovanni Greco 2,* 1 Department of Pharmacy, University of Pisa, Via Bonanno Pisano, 6, 56126 Pisa, Italy; [email protected] (F.D.S.); [email protected] (C.M.) 2 Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano, 49, 80131 Naples, Italy; [email protected] (S.L.); [email protected] (E.N.) * Correspondence: [email protected] (S.T.); [email protected] (G.G.); Tel.: +39-050-2219547 (S.T.); +39-081-678645 (G.G.) The authors wish to dedicate this review to the memory of Professor Barbara Cosimelli, our dear friend and y colleague, who was a key participant in the research discussed herein. Academic Editors: Marco Catto and Cosimo Damiano Altomare Received: 20 April 2020; Accepted: 15 May 2020; Published: 16 May 2020 Abstract: Several indole derivatives have been disclosed by our research groups that have been collaborating for nearly 25 years. The results of our investigations led to a variety of molecules binding selectively to different pharmacological targets, specifically the type A γ-aminobutyric acid (GABAA) chloride channel, the translocator protein (TSPO), the murine double minute 2 (MDM2) protein, the A2B adenosine receptor (A2B AR) and the Kelch-like ECH-associated protein 1 (Keap1). Herein, we describe how these works were conceived and carried out thanks to the versatility of indole nucleus to be exploited in the design and synthesis of drug-like molecules. Keywords: type A γ-aminobutyric acid (GABAA) chloride channel; translocator protein (TSPO); murine double Minute 2 (MDM2) protein; A2B adenosine receptor (A2B AR); Kelch-like ECH-associated protein 1 (Keap1) 1. Introduction During the last 25 years our research groups have been engaged in preparing and testing several indole derivatives as ligands for some pharmacologically relevant targets: namely, the type A γ-aminobutyric acid chloride channel, the translocator protein, the murine double minute 2 protein, the A2B adenosine receptor and the Kelch-like ECH-associated protein 1. We chose indole as a privileged scaffold owing to its recognized ability of being exploited to obtain drug-like molecules [1]. In virtue of its chemical reactivity, this heterocycle is amenable to be readily modified in order to introduce multiple decorations, so to obtain a multitude of indole-based compounds. Indole is widely distributed among biologically active molecules, either natural (many alkaloids, tryptophan, plant hormones) and synthetic, acting on a huge number of therapeutic targets [1]. The present review summarizes our studies taking indole as the polar star of our medicinal chemistry strategies. 2. Indole Derivatives as Ligands of the Benzodiazepine Receptor Many drugs structurally related to diazepam bind to a site known for a long time as the benzodiazepine receptor (BzR). Although this term was changed in 1998 to “benzodiazepine binding site” [2] the acronym BzR has been widely used for decades and it is still usually employed by the scientific community. This binding site is located within the transmembrane type A γ-aminobutyric acid (GABAA) chloride channel, one of the most important members of the family of pentameric Molecules 2020, 25, 2331; doi:10.3390/molecules25102331 www.mdpi.com/journal/molecules Molecules 2020,, 2525,, 2331x FOR PEER REVIEW 22 of of 2726 acid (GABAA) chloride channel, one of the most important members of the family of pentameric ligand-gatedligand-gated ionion channels channels [2]. When[2]. When this channel this ischannel activated is byactivated interaction by with interaction the neurotransmitter with the GABA,neurotransmitter the flow of GABA, chloride the into flow the of cell chloride increases into and the produces cell increases hyperpolarisation. and produces Mammals hyperpolarisation. express a numberMammals of GABAexpressA aisoforms number localized of GABA inAthe isoforms CNS which localized are composed in the CNS by which five subunits: are composed two β3 ,by one fiveγ2 andsubunits: two α twoamong β3,six one types γ2 and (α1, αtwo2, α 3α, αamong4, α5, α 6six). Such types a pentameric(α1, α2, α3, organization α4, α5, α6). (FigureSuch a1 )pentameric originates theorganization following (Figure six GABA 1) Aorigsubtypes:inates theα1 followingβ3γ2, α2β 3sixγ2 ,GABAα3β3γA2, subtypes:α4β3γ2, α 5αβ1β3γ3γ22,and α2β3αγ62β, α3γ3β23[γ32–, 5α].4β The3γ2, aboveα5β3γ2 subtypesand α6β3γ can2 [3–5]. be also The named above bysubtypes specifying can thebe alsoα subunit named which by specifying imparts specific the α subunit physiological which andimparts pharmacological specific physiological properties and to thepharmacological GABAA complex properties [6–10]. to The theα 1GABAsubtype,A complex the dominant [6–10]. one,The isα1 presentsubtype, in the both dominant the cortex one, and is present cerebellum in both and the mediates cortex and sedation; cerebellum the α and2 and mediatesα3 subtypes sedation; are foundthe α2 mainlyand α3 subtypes in the cortex are andfound the mainly hippocampus in the cortex andare and involved the hippocampus in anxiolytic and and are myorelaxant involved in eanxiolyticffects; the andα5 subtypemyorelaxant is largely effects; expressed the α5 subtype in the hippocampusis largely expressed and is in associated the hippocampus with cognition and is processesassociated likewith learning cognition and processes memorising; like thelearningα4 and andα6 memorising;subtypes, less the investigated, α4 and α6 subtypes, are known less as benzodiazepine-insensitiveinvestigated, are known as binding benzodiazepine-insensi sites because theytive do binding not bind sites diazepam because but they recognize do not several bind non-benzodiazepinediazepam but recognize ligands. several non-benzodiazepine ligands. β 3 γ α 2 GABA site n Cl- BzR β 3 αn Figure 1.1. SchematicSchematic representation representation of of the the organization organization of theof fivethe five protein protein subunits subunits composing composing the major the GABAmajor AGABAcomplexA complex isoforms. isoforms. There areThere two areβ3 subunits,two β3 subunits, one γ2 subunitsone γ2 subunits and two and among two six amongα subunits six α (wheresubunits n varies(where from n varies 1 to 6).from The 1 circleto 6). in The bold circle corresponds in bold corresponds to the chloride to channel.the chloride The channel. binding sitesThe ofbinding the neurotransmitter sites of the neurotransmitter GABA and of theGABA BzR and ligands of the are BzR evidenced ligands by are filled evidenced circles and, by filled respectively, circles aand, square. respectively, a square. Following the introduction in the clinical usage of chlordiazepoxide in 1960, a huge number of chemically heterogeneous classes of compounds have been reported in literature as BzR ligands [11]. [11]. This bindingbinding site site is is located located at theat theα/γ αsubunits’/γ subunits’ interface, interface, distinct distinct from thefrom GABA the bindingGABA binding sites situated sites atsituatedα/β interfaces at α/β interfaces (Figure1 ).(Figure 1). The pharmacologicalpharmacological actions actions of BzRof BzR ligands ligands range range from fullfrom agonism full agonism (associated (associated with anxiolytic, with anticonvulsant,anxiolytic, anticonvulsant, sedative-hypnotic, sedative-hypnotic, and myorelaxant and myorelaxant effects) to effects) antagonism to antagonism (implying (implying the ability the to reverseability to sedation reverse caused sedation by caused agonists) by and agonists) to inverse and agonismto inverse (characterized agonism (characterized by anxiogenic, by anxiogenic, somnolytic andsomnolytic proconvulsant and proconvulsant effects) [12,13 effects)]. [12,13]. In 19871987 SchofieldSchofield andand coworkerscoworkers reportedreported thethe sequencesequence and the functionalfunctional expression of the GABAA channel [14]. [14]. Subsequently Subsequently to to this pioneeri pioneeringng work, further knowledge about the subunitssubunits composing the GABAGABAAA isoformsisoforms was was achieved [15–17]. [15–17]. Since 2000, molecular geneticsgenetics experimentsexperiments and measurements of binding and eefficacyfficacy ofof BzRBzR ligandsligands atat eacheach ofof thethe GABAGABAAA isoformsisoforms [[18–21]18–21] paved thethe wayway forfor the the search search of of compounds compounds provided provided by by affi affinity-nity- and and/or/or effi efficacy-basedcacy-based selectivity selectivity for αfor1, α12,/ α32/,αα35, αBzR5 BzR subtypes subtypes [22 [22].]. Currently, thethe manymany BzR ligands available as drugs are agonists endowed with the above- mentioned depressantdepressant e ffeffectsects (ascribed (ascribed to their to their action action on the αon1 subtype)the α1 subtype) and the antagonist and the flumazenil,antagonist employedflumazenil, as employed antidote as to antidote treat benzodiazepine to treat benzod overdose.iazepine overdose. Given the Given therapeutic the therapeutic potential potential of BzR ligands,of BzR ligands, this class this of compoundsclass of compounds has been has one been of the one most of intriguingthe most intriguing and challenging and challenging field of medicinal field of chemistrymedicinal research.chemistry research. Our studies of indole derivatives as BzR ligands began in 1985 with the synthesissynthesis and the evaluation of the binding